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{{short description|Human protein}}
{{short description|Human protein}}
{{Infobox_gene}}
{{Infobox_gene}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
'''Cyclin-dependent kinase 4''' also known as '''cell division protein kinase 4''' is an [[enzyme]] that in humans is encoded by the ''CDK4'' [[gene]]. CDK4 is a member of the [[cyclin-dependent kinase]] family.
'''Cyclin-dependent kinase 4 (CDK4),''' also known as '''cell division protein kinase 4,''' is an [[enzyme]] that is encoded by the ''CDK4'' [[gene]] in humans. CDK4 is a member of the [[cyclin-dependent kinase]] family, a group of serine/threonine kinases which regulate the cell cycle.<ref name="Hives_2023">{{cite journal | vauthors = Hives M, Jurecekova J, Holeckova KH, Kliment J, Sivonova MK | title = The driving power of the cell cycle: cyclin-dependent kinases, cyclins and their inhibitors | journal = Bratislavske Lekarske Listy | volume = 124 | issue = 4 | pages = 261–266 | date = 2023 | pmid = 36598318 | doi = 10.4149/BLL_2023_039 | doi-access = free }}</ref> CDK4 regulates the G1/S transition by contributing to the phosphorylation of retinoblastoma (RB) protein, which leads to the release of protein factors like E2F1 that promote S-phase progression.<ref name="Baker_2012">{{cite journal | vauthors = Baker SJ, Reddy EP | title = CDK4: A Key Player in the Cell Cycle, Development, and Cancer | journal = Genes & Cancer | volume = 3 | issue = 11–12 | pages = 658–669 | date = November 2012 | pmid = 23634254 | pmc = 3636745 | doi = 10.1177/1947601913478972 }}</ref> It is regulated by cyclins like cyclin D proteins, regulatory kinases, and cyclin kinase inhibitors (CKIs).<ref name="Baker_2012" /> Dysregulation of the CDK4 pathway is common in many cancers, and CDK4 is a new therapeutic target in cancer treatment.<ref>{{cite journal | vauthors = Sobhani N, D'Angelo A, Pittacolo M, Roviello G, Miccoli A, Corona SP, Bernocchi O, Generali D, Otto T | title = Updates on the CDK4/6 Inhibitory Strategy and Combinations in Breast Cancer | journal = Cells | volume = 8 | issue = 4 | pages = 321 | date = April 2019 | pmid = 30959874 | pmc = 6523967 | doi = 10.3390/cells8040321 | doi-access = free }}</ref>

== Structure ==
The CDK4 gene is located on chromosome 12 in humans.<ref name="entrez">{{cite web |title=Entrez Gene: CDK4 cyclin-dependent kinase 4 |url=https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1019}}</ref> The gene is composed of 4,583 base pairs which together code for the 303 amino acid protein with a molecular mass of 33,730 Da.<ref name="entrez" /><ref>{{Cite web |title=CDK4 - Cyclin-dependent kinase 4 - Homo sapiens (Human) - CDK4 gene & protein |url=https://www.uniprot.org/uniprot/P11802}}</ref> All CDK proteins, including CDK4, have two lobes: the smaller N-terminal lobe (which contains an inhibitory G-loop), and the C terminal lobe (which contains an activation domain and a T-loop). Between these two lobes is the serine/threonine kinase domain where ATP binds. In its completely inactive form, CDK4's T-loop blocks the ATP binding site, and the surrounding amino acid side chains prevent ATP binding.<ref name="Hives_2023" /> The kinase's activity increases when it dimerizes with the corresponding cyclin, cyclin D, which causes a conformational change at the ATP binding site. CDK activating kinase (CAK) then phosphorylates the T172 site (located on the T-loop).<ref name="Baker_2012" /><ref>{{cite journal | vauthors = Gharbi SI, Pelletier LA, Espada A, Gutiérrez J, Sanfeliciano SM, Rauch CT, Ganado MP, Baquero C, Zapatero E, Zhang A, Benach J, Russell AM, Cano L, Gomez S, Broughton H, Pulliam N, Perez CM, Torres R, Debets MF, de Dios A, Puig O, Hilgers MT, Lallena MJ | title = Crystal structure of active CDK4-cyclin D and mechanistic basis for abemaciclib efficacy | journal = npj Breast Cancer | volume = 8 | issue = 1 | pages = 126 | date = November 2022 | pmid = 36446794 | pmc = 9709041 | doi = 10.1038/s41523-022-00494-y }}</ref><ref>{{cite journal | vauthors = Łukasik P, Załuski M, Gutowska I | title = Cyclin-Dependent Kinases (CDK) and Their Role in Diseases Development-Review | journal = International Journal of Molecular Sciences | volume = 22 | issue = 6 | pages = 2935 | date = March 2021 | pmid = 33805800 | pmc = 7998717 | doi = 10.3390/ijms22062935 | doi-access = free }}</ref> These two actions move the T-loop out of the active ATP-binding site and make ATP binding more favorable.

Notably, CDK6 is very related to CDK4 in both structure and function. They share 71% of their amino acids and both regulate the G1/S transition by phosphorylating Rb. CDK4 and 6 differ in their cellular localization and other off-pathway roles, however are commonly referred together as CDK4/6.<ref name="Hives_2023" />

The CDK4 protein is similar to the fungi gene products of S. cerevisiae cdc28 and S. pombe cdc2.<ref name="entrez" />


== Function ==
== Function ==
⚫
[[File:Role of CDK4, cyklin D, Rb and E2F in cell cycle regulation.jpg|thumb|Role of CDK4, cyklin D, Rb and E2F in cell cycle regulation.]]
CDK4 is the catalytic subunit of the protein-kinase complex CDK4-cyclin D, which plays a role in G1/S cell cycle progression.<ref name="Baker_2012" /> During G1 phase, the cell grows and prepares for the DNA replication that occurs in the S phase. There is a G1/S checkpoint which acts as a committed step to enter S-phase. This checkpoint ensures that cells moving toward mitosis are large enough and do not have DNA damage that could be passed on to daughter cells.<ref>{{Citation |last1=Weitzman |first1=M. D. |title=Cell Cycle: DNA Damage Checkpoints |date=2013-01-01 |encyclopedia=Encyclopedia of Biological Chemistry (Second Edition) |pages=410–416 |editor-last=Lennarz |editor-first=William J. |url=https://www.sciencedirect.com/science/article/abs/pii/B9780123786302004199 |access-date=2024-12-16 |place=Waltham |publisher=Academic Press |isbn=978-0-12-378631-9 |last2=Wang |first2=J. Y. J. |editor2-last=Lane |editor2-first=M. Daniel}}</ref>


The protein encoded by this gene is a member of the [[Serine/threonine-specific protein kinase|Ser/Thr protein kinase family]]. This protein is highly similar to the gene products of ''[[S. cerevisiae]]'' cdc28 and ''[[S. pombe]]'' cdc2. It is a catalytic subunit of the protein kinase complex that is important for [[cell cycle]] G1 phase progression. The activity of this kinase is restricted to the G1-S phase, which is controlled by the regulatory subunits D-type cyclins and CDK inhibitor [[p16 (gene)|p16<sup>INK4a</sup>]]. This kinase was shown to be responsible for the phosphorylation of [[retinoblastoma gene]] product ([[Retinoblastoma protein|Rb]]).<ref name = "entrez"/> Ser/Thr-kinase component of cyclin D-CDK4 (DC) complexes that phosphorylate and inhibit members of the [[Retinoblastoma protein|retinoblastoma (RB) protein family including RB1]] and regulate the cell-cycle during G1/S transition. Phosphorylation of RB1 allows dissociation of the transcription factor [[E2F]] from the RB/E2F complexes and the subsequent transcription of E2F target genes which are responsible for the progression through the G1 phase. Hypophosphorylates RB1 in early G1 phase. Cyclin D-CDK4 complexes are major integrators of various mitogenic and antimitogenic signals. Also phosphorylates [[SMAD3]] in a cell-cycle-dependent manner and represses its transcriptional activity. Component of the ternary complex, cyclin D/CDK4/CDKN1B, required for nuclear translocation and activity of the cyclin D-CDK4 complex.<ref>{{Cite web|title=CDK4 - Cyclin-dependent kinase 4 - Homo sapiens (Human) - CDK4 gene & protein|url=https://www.uniprot.org/uniprot/P11802}}</ref>
There are two models of CDK4 cell cycle regulation. The older model proposes that the kinase is responsible for the phosphorylation of [[retinoblastoma gene]] product ([[Retinoblastoma protein|Rb]]). The Ser/Thr-kinase component of cyclin D-CDK4 (DC) forms complexes that phosphorylate and inhibit members of the [[Retinoblastoma protein|retinoblastoma (RB) protein family including RB1]] and regulate the cell-cycle during G1/S transition. Phosphorylation of RB1 allows dissociation of the transcription factor [[E2F]] from the RB/E2F complexes and the subsequent transcription of E2F target genes which are responsible for the progression through the G1 phase. In this model, CDK4 inhibits Rb, which inhibits E2F, which promotes progression into S phase.

The newer model, as proposed in a 2014 paper by Narasimha et al., The CDK4-cyclin D complex phosphorylates the retinoblastoma tumor suppressor protein (Rb) and its related proteins p107 and p130, which go on to inhibit cell cycle progression.<ref name="Baker_2012" /> As a kinase, the CDK4 serine/threonine active site converts ATP to ADP and transfers the removed phosphate group to Rb. Rb is mono-phosphorylated in early G1 by the CDK4-cyclin D complex. When mono-phosphorylated, Rb exists as one of the 14 isoforms, which bind to protein factors like E1a, and proteins in the E2F family.<ref name="Narasimha_2014">{{cite journal | vauthors = Narasimha AM, Kaulich M, Shapiro GS, Choi YJ, Sicinski P, Dowdy SF | title = Cyclin D activates the Rb tumor suppressor by mono-phosphorylation | journal = eLife | volume = 3 | pages = e02872 | date = June 2014 | pmid = 24876129 | pmc = 4076869 | doi = 10.7554/eLife.02872 | editor-first = Roger | doi-access = free | editor-last = Davis }}</ref>

The new model of CDK4 regulation posits that at the G1/S checkpoint, if a cell seems healthy, CDK2 (a different cyclin dependent kinase) inactivates Rb, and these protein factors are released back into the cell. E2F proteins then activate the transcription of genes that cause S-phase progression.<ref name="Baker_2012" /> However, if at the G1/S checkpoint a cell detects DNA damage, it will response by activating the CDK4-cyclin D complex to mono-phosphorylate, and activate Rb. This prevents Rb from dissociating from E2F protins, which prevents them from activating the transcription of the S-phase progression genes.<ref name="Narasimha_2014" />

While CDK4 primarily regulates the cell cycle through phosphorylation of Rb, there is evidence of a secondary, more direct role independent of Rb. CDK4 may be able to directly phosphorylate transcription factors and co-regulators like Smad3, MYC, FOXM1, and MEP50 to regulate the cell cycle, survival and senescence.

Interestingly, CDK4-null mutant mice are viable, and in-vitro experiments show that cell proliferation is not significantly affected, likely due to compensatory roles played by other CDKs. However, CDK plays a significant role in cancer development.<ref name="Baker_2022">{{cite journal | vauthors = Baker SJ, Poulikakos PI, Irie HY, Parekh S, Reddy EP | title = CDK4: a master regulator of the cell cycle and its role in cancer | journal = Genes & Cancer | volume = 13 | pages = 21–45 | date = 2022 | pmid = 36051751 | pmc = 9426627 | doi = 10.18632/genesandcancer.221 }}</ref>

== Mechanisms of regulation ==
CDK4 is only active during the G1-S phase, which controlled by cyclin D and CDK inhibitors. CDK activity is negatively regulated by cyclin kinase inhibitors (CKIs), which belong to one of two families. The INK4 family of CKIs are inhibitors which bind and inhibit CDK4/6, also preventing subsequent binding to cyclin D. The Cip/Kip family inhibitors are not specific to CDK4/6, and instead bind and inhibit the cyclin-CDK complex.<ref name="Hives_2023" />

CDK4 activity is positively regulated by cyclin D, which creates a conformational change in CDK4 that opens the active site for kinase activity. Cyclins are proteins that change concentration periodically during the cell cycle. They are extremely specific and diverse, which serves to regulate the cell cycle with precision. Cyclin D levels oscillate during the G1 phase, first increasing and accumulating, then rapidly decreasing during the transition to the S phase.<ref name="Hives_2023" /> Cyclin D levels are stimulated by growth factors, without which cyclin D levels would stay low regardless of cell cycle stage.<ref name="Baker_2022" /> After its role in G1 is complete, cyclin D is translocated from the nucleus to the cytoplasm in S phase, modulating the nuclear cyclin D levels, and therefore modulating the activity of CDK4 to promote the S phase transition.<ref name="Hives_2023" />


== Clinical significance ==
== Clinical significance ==
⚫
[[File:Role of CDK4, cyklin D, Rb and E2F in cell cycle regulation.jpg|thumb|Role of CDK4, cyklin D, Rb and E2F in cell cycle regulation.]]
⚫
Mutations in this gene as well as in its related proteins including D-type cyclins, p16(INK4a), CDKN2A and Rb were all found to be associated with tumorigenesis of a variety of cancers. One specific point mutation of CDK4 (R24C) was first identified in melanoma patients. This mutation was introduced also in animal models and its role as a cancer driver oncogene was studied thoroughly. Nowadays, deregulated CDK4 is considered to be a potential therapeutic target in some cancer types and various CDK4 inhibitors are being tested for cancer treatment in clinical trials.<ref>{{Cite journal|last1=Sheppard|first1=K. E.|last2=McArthur|first2=G. A.|date=2013-10-01|title=The Cell-Cycle Regulator CDK4: An Emerging Therapeutic Target in Melanoma|journal=Clinical Cancer Research|language=en|volume=19|issue=19|pages=5320–5328|doi=10.1158/1078-0432.CCR-13-0259|pmid=24089445|issn=1078-0432|doi-access=free}}</ref><ref>{{Cite journal|last1=Sobhani|last2=D’Angelo|last3=Pittacolo|last4=Roviello|last5=Miccoli|last6=Corona|last7=Bernocchi|last8=Generali|last9=Otto|date=2019-04-06|title=Updates on the CDK4/6 Inhibitory Strategy and Combinations in Breast Cancer|journal=Cells|language=en|volume=8|issue=4|pages=321|doi=10.3390/cells8040321|pmid=30959874|pmc=6523967|issn=2073-4409|doi-access=free}}</ref>


=== Cancer ===
Multiple polyadenylation sites of this gene have been reported.<ref name="entrez">{{cite web | title = Entrez Gene: CDK4 cyclin-dependent kinase 4| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1019}}</ref>
Cancer, or uncontrolled cell proliferation, is believed to result from disturbances to mechanisms that usually control cell proliferation (tumor suppressors) and mechanisms that normally encourage cell proliferation (proto-oncogenes). Cell cycle regulation mechanisms called checkpoints, like G1/S, are in place to prevent this uncontrolled division.<ref name="Baker_2012" />

⚫
Mutations in the CDK4 gene as well as in its related proteins including D-type cyclins, p16(INK4a), CDKN2A and Rb were all found to be associated with tumorigenesis of a variety of cancers, including sarcomas, gliomas, lymphomas and tumors of the mammary gland.<ref name="Baker_2022" /> One specific point mutation of CDK4 (R24C) was first identified in melanoma patients. This mutation was introduced also in animal models and its role as a cancer driver oncogene was studied thoroughly.<ref name="Baker_2022" /> Nowadays, deregulated CDK4 is considered to be a potential therapeutic target in some cancer types and various CDK4 inhibitors are being tested for cancer treatment in clinical trials. Multiple polyadenylation sites of this gene have been reported.


⚫
Cyclin D and CDK4/6 activities are observed to be up-regulated in certain cancers, sparking interest in the development of small-molecule inhibitors of CDK4/6. [[Ribociclib]] are [[US FDA]] approved CDK4 and CDK6 inhibitors for the treatment of [[estrogen receptor]] positive/ [[HER2]] negative advanced breast cancer.<ref>{{cite web |title=Approved Drugs > Ribociclib (Kisqali) |url=https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm546438.htm |access-date=12 September 2017 |website=[[Food and Drug Administration]]}}</ref>
It is regulated by [[Cyclin D]].


===Inhibitors===
=== HIV ===
There is some evidence that CDK4 plays a role in the HIV-1 restriction pathway in primary microphages. Cell cycle control plays a major role in determining susceptibility to HIV-1 infection. Active CDKs phosphorylate SAMHD1, deactivating the enzyme which usually can restrict HIV-1 replication. A complex formed by cyclin D2-CDK4-p21 lowers the amount of active CDK in the cell, allowing SAMHD1 to exist in its active, dephosphorylated form that restricts HIV-1 replication.<ref>{{cite journal | vauthors = Badia R, Pujantell M, Riveira-Muñoz E, Puig T, Torres-Torronteras J, Martí R, Clotet B, Ampudia RM, Vives-Pi M, Esté JA, Ballana E | title = The G1/S Specific Cyclin D2 Is a Regulator of HIV-1 Restriction in Non-proliferating Cells | journal = PLOS Pathogens | volume = 12 | issue = 8 | pages = e1005829 | date = August 2016 | pmid = 27541004 | pmc = 4991798 | doi = 10.1371/journal.ppat.1005829 | doi-access = free }}</ref>
⚫
[[Ribociclib]] are [[US FDA]] approved CDK4 and CDK6 inhibitors for the treatment of [[estrogen receptor]] positive/ [[HER2]] negative advanced breast cancer.<ref>{{cite web|title=Approved Drugs > Ribociclib (Kisqali)|website=[[Food and Drug Administration]] |url=https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm546438.htm|access-date=12 September 2017}}</ref>


⚫
== Interactions ==
See also [[CDK inhibitor]] for inhibitors of various CDKs.


⚫
==Interactions==
Cyclin-dependent kinase 4 has been shown to [[Protein-protein interaction|interact]] with:
Cyclin-dependent kinase 4 has been shown to [[Protein-protein interaction|interact]] with:
{{div col|colwidth=20em}}
{{div col|colwidth=20em}}
* [[CDC37]],<ref name = pmid17353931>{{cite journal |vauthors=Ewing RM, Chu P, Elisma F, Li H, Taylor P, Climie S, McBroom-Cerajewski L, Robinson MD, O'Connor L, Li M, Taylor R, Dharsee M, Ho Y, Heilbut A, Moore L, Zhang S, Ornatsky O, Bukhman YV, Ethier M, Sheng Y, Vasilescu J, Abu-Farha M, Lambert JP, Duewel HS, Stewart II, Kuehl B, Hogue K, Colwill K, Gladwish K, Muskat B, Kinach R, Adams SL, Moran MF, Morin GB, Topaloglou T, Figeys D | title = Large-scale mapping of human protein-protein interactions by mass spectrometry | journal = Mol. Syst. Biol. | volume = 3 | issue = 1| pages = 89 | year = 2007 | pmid = 17353931 | pmc = 1847948 | doi = 10.1038/msb4100134}}</ref><ref name = pmid8703009>{{cite journal |vauthors=Dai K, Kobayashi R, Beach D | title = Physical interaction of mammalian CDC37 with CDK4 | journal = J. Biol. Chem. | volume = 271 | issue = 36 | pages = 22030–4 | year = 1996 | pmid = 8703009 | doi = 10.1074/jbc.271.36.22030| doi-access = free }}</ref><ref name = pmid9150368>{{cite journal |vauthors=Lamphere L, Fiore F, Xu X, Brizuela L, Keezer S, Sardet C, Draetta GF, Gyuris J | title = Interaction between Cdc37 and Cdk4 in human cells | journal = Oncogene | volume = 14 | issue = 16 | pages = 1999–2004 | year = 1997 | pmid = 9150368 | doi = 10.1038/sj.onc.1201036| doi-access = free }}</ref><ref name = pmid8666233>{{cite journal |vauthors=Stepanova L, Leng X, Parker SB, Harper JW | title = Mammalian p50Cdc37 is a protein kinase-targeting subunit of Hsp90 that binds and stabilizes Cdk4 | journal = Genes Dev. | volume = 10 | issue = 12 | pages = 1491–502 | year = 1996 | pmid = 8666233 | doi = 10.1101/gad.10.12.1491| doi-access = free }}</ref>
* [[CDC37]],<ref name = pmid17353931>{{cite journal | vauthors = Ewing RM, Chu P, Elisma F, Li H, Taylor P, Climie S, McBroom-Cerajewski L, Robinson MD, O'Connor L, Li M, Taylor R, Dharsee M, Ho Y, Heilbut A, Moore L, Zhang S, Ornatsky O, Bukhman YV, Ethier M, Sheng Y, Vasilescu J, Abu-Farha M, Lambert JP, Duewel HS, Stewart II, Kuehl B, Hogue K, Colwill K, Gladwish K, Muskat B, Kinach R, Adams SL, Moran MF, Morin GB, Topaloglou T, Figeys D | title = Large-scale mapping of human protein-protein interactions by mass spectrometry | journal = Molecular Systems Biology | volume = 3 | issue = 1 | pages = 89 | year = 2007 | pmid = 17353931 | pmc = 1847948 | doi = 10.1038/msb4100134 }}</ref><ref name = pmid8703009>{{cite journal | vauthors = Dai K, Kobayashi R, Beach D | title = Physical interaction of mammalian CDC37 with CDK4 | journal = The Journal of Biological Chemistry | volume = 271 | issue = 36 | pages = 22030–22034 | date = September 1996 | pmid = 8703009 | doi = 10.1074/jbc.271.36.22030 | doi-access = free }}</ref><ref name = pmid9150368>{{cite journal | vauthors = Lamphere L, Fiore F, Xu X, Brizuela L, Keezer S, Sardet C, Draetta GF, Gyuris J | title = Interaction between Cdc37 and Cdk4 in human cells | journal = Oncogene | volume = 14 | issue = 16 | pages = 1999–2004 | date = April 1997 | pmid = 9150368 | doi = 10.1038/sj.onc.1201036 | s2cid = 25236893 | doi-access = }}</ref><ref name = pmid8666233>{{cite journal | vauthors = Stepanova L, Leng X, Parker SB, Harper JW | title = Mammalian p50Cdc37 is a protein kinase-targeting subunit of Hsp90 that binds and stabilizes Cdk4 | journal = Genes & Development | volume = 10 | issue = 12 | pages = 1491–1502 | date = June 1996 | pmid = 8666233 | doi = 10.1101/gad.10.12.1491 | doi-access = free }}</ref>
* [[CDKN1B]],<ref name = pmid11360184/><ref name = pmid10908655/>
* [[CDKN1B]],<ref name = pmid11360184/><ref name = pmid10908655/>
* [[CDKN2B]],<ref name = pmid16189514/><ref name = pmid16169070>{{cite journal | pmid = 16179252|vauthors=Ghavidel A, Cagney G, Emili A | title = A skeleton of the human protein interactome | journal = Cell | volume = 122 | issue = 6 | pages = 830–2 | year = 2005 | doi = 10.1016/j.cell.2005.09.006|s2cid=7410135 | doi-access = free }}</ref>
* [[CDKN2B]],<ref name = pmid16189514/><ref name = pmid16169070>{{cite journal | vauthors = Ghavidel A, Cagney G, Emili A | title = A skeleton of the human protein interactome | journal = Cell | volume = 122 | issue = 6 | pages = 830–832 | date = September 2005 | pmid = 16179252 | doi = 10.1016/j.cell.2005.09.006 | s2cid = 7410135 | doi-access = free }}</ref>
* [[CDKN2C]],<ref name = pmid17353931/><ref name = pmid8001816>{{cite journal |vauthors=Guan KL, Jenkins CW, Li Y, Nichols MA, Wu X, O'Keefe CL, Matera AG, Xiong Y | title = Growth suppression by p18, a p16INK4/MTS1- and p14INK4B/MTS2-related CDK6 inhibitor, correlates with wild-type pRb function | journal = Genes Dev. | volume = 8 | issue = 24 | pages = 2939–52 | year = 1994 | pmid = 8001816 | doi = 10.1101/gad.8.24.2939| doi-access = free }}</ref>
* [[CDKN2C]],<ref name = pmid17353931/><ref name = pmid8001816>{{cite journal | vauthors = Guan KL, Jenkins CW, Li Y, Nichols MA, Wu X, O'Keefe CL, Matera AG, Xiong Y | title = Growth suppression by p18, a p16INK4/MTS1- and p14INK4B/MTS2-related CDK6 inhibitor, correlates with wild-type pRb function | journal = Genes & Development | volume = 8 | issue = 24 | pages = 2939–2952 | date = December 1994 | pmid = 8001816 | doi = 10.1101/gad.8.24.2939 | doi-access = free }}</ref>
* [[CEBPA]],<ref name = pmid11684017>{{cite journal |vauthors=Wang H, Iakova P, Wilde M, Welm A, Goode T, Roesler WJ, Timchenko NA | title = C/EBPalpha arrests cell proliferation through direct inhibition of Cdk2 and Cdk4 | journal = Mol. Cell | volume = 8 | issue = 4 | pages = 817–28 | year = 2001 | pmid = 11684017 | doi = 10.1016/S1097-2765(01)00366-5| doi-access = free }}</ref>
* [[CEBPA]],<ref name = pmid11684017>{{cite journal | vauthors = Wang H, Iakova P, Wilde M, Welm A, Goode T, Roesler WJ, Timchenko NA | title = C/EBPalpha arrests cell proliferation through direct inhibition of Cdk2 and Cdk4 | journal = Molecular Cell | volume = 8 | issue = 4 | pages = 817–828 | date = October 2001 | pmid = 11684017 | doi = 10.1016/S1097-2765(01)00366-5 | doi-access = free }}</ref>
* [[Cyclin D1|CCND1]],<ref name = pmid11360184/><ref name = pmid10908655>{{cite journal |vauthors=Cariou S, Donovan JC, Flanagan WM, Milic A, Bhattacharya N, Slingerland JM | title = Down-regulation of p21WAF1/CIP1 or p27Kip1 abrogates antiestrogen-mediated cell cycle arrest in human breast cancer cells | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 97 | issue = 16 | pages = 9042–6 | year = 2000 | pmid = 10908655 | pmc = 16818 | doi = 10.1073/pnas.160016897 | bibcode = 2000PNAS...97.9042C| doi-access = free }}</ref><ref name = pmid10580009/><ref name = pmid8259215/><ref name = pmid9837900>{{cite journal |vauthors=Taulés M, Rius E, Talaya D, López-Girona A, Bachs O, Agell N | title = Calmodulin is essential for cyclin-dependent kinase 4 (Cdk4) activity and nuclear accumulation of cyclin D1-Cdk4 during G1 | journal = J. Biol. Chem. | volume = 273 | issue = 50 | pages = 33279–86 | year = 1998 | pmid = 9837900 | doi = 10.1074/jbc.273.50.33279| doi-access = free }}</ref><ref name = pmid9228064>{{cite journal |vauthors=Coleman KG, Wautlet BS, Morrissey D, Mulheron J, Sedman SA, Brinkley P, Price S, Webster KR | title = Identification of CDK4 sequences involved in cyclin D1 and p16 binding | journal = J. Biol. Chem. | volume = 272 | issue = 30 | pages = 18869–74 | year = 1997 | pmid = 9228064 | doi = 10.1074/jbc.272.30.18869| doi-access = free }}</ref>
* [[Cyclin D1|CCND1]],<ref name = pmid11360184/><ref name = pmid10908655>{{cite journal | vauthors = Cariou S, Donovan JC, Flanagan WM, Milic A, Bhattacharya N, Slingerland JM | title = Down-regulation of p21WAF1/CIP1 or p27Kip1 abrogates antiestrogen-mediated cell cycle arrest in human breast cancer cells | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 97 | issue = 16 | pages = 9042–9046 | date = August 2000 | pmid = 10908655 | pmc = 16818 | doi = 10.1073/pnas.160016897 | doi-access = free | bibcode = 2000PNAS...97.9042C }}</ref><ref name = pmid10580009/><ref name = pmid8259215/><ref name = pmid9837900>{{cite journal | vauthors = Taulés M, Rius E, Talaya D, López-Girona A, Bachs O, Agell N | title = Calmodulin is essential for cyclin-dependent kinase 4 (Cdk4) activity and nuclear accumulation of cyclin D1-Cdk4 during G1 | journal = The Journal of Biological Chemistry | volume = 273 | issue = 50 | pages = 33279–33286 | date = December 1998 | pmid = 9837900 | doi = 10.1074/jbc.273.50.33279 | doi-access = free }}</ref><ref name = pmid9228064>{{cite journal | vauthors = Coleman KG, Wautlet BS, Morrissey D, Mulheron J, Sedman SA, Brinkley P, Price S, Webster KR | title = Identification of CDK4 sequences involved in cyclin D1 and p16 binding | journal = The Journal of Biological Chemistry | volume = 272 | issue = 30 | pages = 18869–18874 | date = July 1997 | pmid = 9228064 | doi = 10.1074/jbc.272.30.18869 | doi-access = free }}</ref>
* [[Cyclin D3|CCND3]],<ref name = pmid11360184>{{cite journal |vauthors=Lin J, Jinno S, Okayama H | title = Cdk6-cyclin D3 complex evades inhibition by inhibitor proteins and uniquely controls cell's proliferation competence | journal = Oncogene | volume = 20 | issue = 16 | pages = 2000–9 | year = 2001 | pmid = 11360184 | doi = 10.1038/sj.onc.1204375| doi-access = free }}</ref><ref name = pmid16189514>{{cite journal |vauthors=Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M | title = Towards a proteome-scale map of the human protein-protein interaction network | journal = Nature | volume = 437 | issue = 7062 | pages = 1173–8 | year = 2005 | pmid = 16189514 | doi = 10.1038/nature04209| bibcode = 2005Natur.437.1173R | s2cid = 4427026 }}</ref><ref name = pmid14641107>{{cite journal |vauthors=Arsenijevic T, Degraef C, Dumont JE, Roger PP, Pirson I | title = A novel partner for D-type cyclins: protein kinase A-anchoring protein AKAP95 | journal = Biochem. J. | volume = 378 | issue = Pt 2 | pages = 673–9 | year = 2004 | pmid = 14641107 | pmc = 1223988 | doi = 10.1042/BJ20031765}}</ref><ref name = pmid10342870>{{cite journal |vauthors=Zhang Q, Wang X, Wolgemuth DJ | title = Developmentally regulated expression of cyclin D3 and its potential in vivo interacting proteins during murine gametogenesis | journal = Endocrinology | volume = 140 | issue = 6 | pages = 2790–800 | year = 1999 | pmid = 10342870 | doi = 10.1210/endo.140.6.6756| doi-access = free }}</ref>
* [[Cyclin D3|CCND3]],<ref name = pmid11360184>{{cite journal | vauthors = Lin J, Jinno S, Okayama H | title = Cdk6-cyclin D3 complex evades inhibition by inhibitor proteins and uniquely controls cell's proliferation competence | journal = Oncogene | volume = 20 | issue = 16 | pages = 2000–2009 | date = April 2001 | pmid = 11360184 | doi = 10.1038/sj.onc.1204375 | s2cid = 25204152 | doi-access = }}</ref><ref name = pmid16189514>{{cite journal | vauthors = Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M | title = Towards a proteome-scale map of the human protein-protein interaction network | journal = Nature | volume = 437 | issue = 7062 | pages = 1173–1178 | date = October 2005 | pmid = 16189514 | doi = 10.1038/nature04209 | s2cid = 4427026 | bibcode = 2005Natur.437.1173R }}</ref><ref name = pmid14641107>{{cite journal | vauthors = Arsenijevic T, Degraef C, Dumont JE, Roger PP, Pirson I | title = A novel partner for D-type cyclins: protein kinase A-anchoring protein AKAP95 | journal = The Biochemical Journal | volume = 378 | issue = Pt 2 | pages = 673–679 | date = March 2004 | pmid = 14641107 | pmc = 1223988 | doi = 10.1042/BJ20031765 }}</ref><ref name = pmid10342870>{{cite journal | vauthors = Zhang Q, Wang X, Wolgemuth DJ | title = Developmentally regulated expression of cyclin D3 and its potential in vivo interacting proteins during murine gametogenesis | journal = Endocrinology | volume = 140 | issue = 6 | pages = 2790–2800 | date = June 1999 | pmid = 10342870 | doi = 10.1210/endo.140.6.6756 | s2cid = 45094232 | doi-access = }}</ref>
* [[Drebrin-like|DBNL]],<ref name = pmid17353931/>
* [[Drebrin-like|DBNL]],<ref name = pmid17353931/>
* [[MyoD]],<ref name = pmid10601020>{{cite journal |vauthors=Zhang JM, Zhao X, Wei Q, Paterson BM | title = Direct inhibition of G(1) cdk kinase activity by MyoD promotes myoblast cell cycle withdrawal and terminal differentiation | journal = EMBO J. | volume = 18 | issue = 24 | pages = 6983–93 | year = 1999 | pmid = 10601020 | pmc = 1171761 | doi = 10.1093/emboj/18.24.6983}}</ref><ref name = pmid10022835>{{cite journal |vauthors=Zhang JM, Wei Q, Zhao X, Paterson BM | title = Coupling of the cell cycle and myogenesis through the cyclin D1-dependent interaction of MyoD with cdk4 | journal = EMBO J. | volume = 18 | issue = 4 | pages = 926–33 | year = 1999 | pmid = 10022835 | pmc = 1171185 | doi = 10.1093/emboj/18.4.926}}</ref>
* [[MyoD]],<ref name = pmid10601020>{{cite journal | vauthors = Zhang JM, Zhao X, Wei Q, Paterson BM | title = Direct inhibition of G(1) cdk kinase activity by MyoD promotes myoblast cell cycle withdrawal and terminal differentiation | journal = The EMBO Journal | volume = 18 | issue = 24 | pages = 6983–6993 | date = December 1999 | pmid = 10601020 | pmc = 1171761 | doi = 10.1093/emboj/18.24.6983 }}</ref><ref name = pmid10022835>{{cite journal | vauthors = Zhang JM, Wei Q, Zhao X, Paterson BM | title = Coupling of the cell cycle and myogenesis through the cyclin D1-dependent interaction of MyoD with cdk4 | journal = The EMBO Journal | volume = 18 | issue = 4 | pages = 926–933 | date = February 1999 | pmid = 10022835 | pmc = 1171185 | doi = 10.1093/emboj/18.4.926 }}</ref>
* [[P16 (gene)|P16]],<ref name = pmid17353931/><ref name = pmid10580009/><ref name = pmid8259215/><ref name = pmid9228064/><ref name = pmid8805225>{{cite journal |vauthors=Fåhraeus R, Paramio JM, Ball KL, Laín S, Lane DP | title = Inhibition of pRb phosphorylation and cell-cycle progression by a 20-residue peptide derived from p16CDKN2/INK4A | journal = Curr. Biol. | volume = 6 | issue = 1 | pages = 84–91 | year = 1996 | pmid = 8805225 | doi = 10.1016/S0960-9822(02)00425-6| s2cid = 23024663 | url = https://www.pure.ed.ac.uk/ws/files/12111645/Inhibition_of_pRb_phosphorylation_and_cell_cycle_progression.pdf }}</ref><ref name = pmid15065884/>
* [[P16 (gene)|P16]],<ref name = pmid17353931/><ref name = pmid10580009/><ref name = pmid8259215/><ref name = pmid9228064/><ref name = pmid8805225>{{cite journal | vauthors = Fåhraeus R, Paramio JM, Ball KL, Laín S, Lane DP | title = Inhibition of pRb phosphorylation and cell-cycle progression by a 20-residue peptide derived from p16CDKN2/INK4A | journal = Current Biology | volume = 6 | issue = 1 | pages = 84–91 | date = January 1996 | pmid = 8805225 | doi = 10.1016/S0960-9822(02)00425-6 | hdl-access = free | s2cid = 23024663 | hdl = 20.500.11820/9e95b5cc-be55-4c50-bfd9-04eb51b3e3f9 }}</ref><ref name = pmid15065884/>
* [[PCNA]],<ref name = pmid8259215>{{cite journal | pmid = 8259207|vauthors=Nasmyth K, Hunt T | title = Cell cycle. Dams and sluices | journal = Nature | volume = 366 | issue = 6456 | pages = 634–5 | year = 1993 | doi = 10.1038/366634a0|s2cid=4270052 | doi-access = free }}</ref><ref name = pmid8101826>{{cite journal |vauthors=Xiong Y, Zhang H, Beach D | title = Subunit rearrangement of the cyclin-dependent kinases is associated with cellular transformation | journal = Genes Dev. | volume = 7 | issue = 8 | pages = 1572–83 | year = 1993 | pmid = 8101826 | doi = 10.1101/gad.7.8.1572| doi-access = free }}</ref> and
* [[PCNA]],<ref name = pmid8259215>{{cite journal | vauthors = Nasmyth K, Hunt T | title = Cell cycle. Dams and sluices | journal = Nature | volume = 366 | issue = 6456 | pages = 634–635 | date = December 1993 | pmid = 8259207 | doi = 10.1038/366634a0 | s2cid = 4270052 | doi-access = free }}</ref><ref name = pmid8101826>{{cite journal | vauthors = Xiong Y, Zhang H, Beach D | title = Subunit rearrangement of the cyclin-dependent kinases is associated with cellular transformation | journal = Genes & Development | volume = 7 | issue = 8 | pages = 1572–1583 | date = August 1993 | pmid = 8101826 | doi = 10.1101/gad.7.8.1572 | doi-access = free }}</ref> and
* [[SERTAD1]].<ref name = pmid10580009>{{cite journal |vauthors=Sugimoto M, Nakamura T, Ohtani N, Hampson L, Hampson IN, Shimamoto A, Furuichi Y, Okumura K, Niwa S, Taya Y, Hara E | title = Regulation of CDK4 activity by a novel CDK4-binding protein, p34(SEI-1) | journal = Genes Dev. | volume = 13 | issue = 22 | pages = 3027–33 | year = 1999 | pmid = 10580009 | pmc = 317153 | doi = 10.1101/gad.13.22.3027}}</ref><ref name = pmid15065884>{{cite journal |vauthors=Li J, Melvin WS, Tsai MD, Muscarella P | title = The nuclear protein p34SEI-1 regulates the kinase activity of cyclin-dependent kinase 4 in a concentration-dependent manner | journal = Biochemistry | volume = 43 | issue = 14 | pages = 4394–9 | year = 2004 | pmid = 15065884 | doi = 10.1021/bi035601s| citeseerx = 10.1.1.386.140 }}</ref>
* [[SERTAD1]].<ref name = pmid10580009>{{cite journal | vauthors = Sugimoto M, Nakamura T, Ohtani N, Hampson L, Hampson IN, Shimamoto A, Furuichi Y, Okumura K, Niwa S, Taya Y, Hara E | title = Regulation of CDK4 activity by a novel CDK4-binding protein, p34(SEI-1) | journal = Genes & Development | volume = 13 | issue = 22 | pages = 3027–3033 | date = November 1999 | pmid = 10580009 | pmc = 317153 | doi = 10.1101/gad.13.22.3027 }}</ref><ref name = pmid15065884>{{cite journal | vauthors = Li J, Melvin WS, Tsai MD, Muscarella P | title = The nuclear protein p34SEI-1 regulates the kinase activity of cyclin-dependent kinase 4 in a concentration-dependent manner | journal = Biochemistry | volume = 43 | issue = 14 | pages = 4394–4399 | date = April 2004 | pmid = 15065884 | doi = 10.1021/bi035601s | citeseerx = 10.1.1.386.140 }}</ref>
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==References==
== References ==
{{reflist|colwidth=35em}}
{{reflist|colwidth=35em}}


==Further reading==
== Further reading ==
{{refbegin|colwidth=35em}}
{{refbegin|colwidth=35em}}
*{{cite journal | author=Hanks SK |title=Homology probing: identification of cDNA clones encoding members of the protein-serine kinase family |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=84 |issue= 2 |pages= 388–92 |year= 1987 |pmid= 2948189 |doi=10.1073/pnas.84.2.388 | pmc=304212 |bibcode=1987PNAS...84..388H |doi-access=free }}
* {{cite journal | vauthors = Hanks SK | title = Homology probing: identification of cDNA clones encoding members of the protein-serine kinase family | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 84 | issue = 2 | pages = 388–392 | date = January 1987 | pmid = 2948189 | pmc = 304212 | doi = 10.1073/pnas.84.2.388 | doi-access = free | bibcode = 1987PNAS...84..388H }}
*{{cite journal |title=Evidence for different modes of action of cyclin-dependent kinase inhibitors: p15 and p16 bind to kinases, p21 and p27 bind to cyclins |journal=Oncogene |volume=11 |issue= 8 |pages= 1581–8 |year= 1995 |pmid= 7478582 |author1=Hall M |author2=Bates S |author3=Peters G }}
* {{cite journal | vauthors = Hall M, Bates S, Peters G | title = Evidence for different modes of action of cyclin-dependent kinase inhibitors: p15 and p16 bind to kinases, p21 and p27 bind to cyclins | journal = Oncogene | volume = 11 | issue = 8 | pages = 1581–1588 | date = October 1995 | pmid = 7478582 }}
*{{cite journal |title=Identification of human cyclin-dependent kinase 8, a putative protein kinase partner for cyclin C |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=92 |issue= 19 |pages= 8871–5 |year= 1995 |pmid= 7568034 |doi=10.1073/pnas.92.19.8871 |display-authors=3 |author1=Tassan JP |author2=Jaquenoud M |author3=Léopold P |name-list-style=vanc |last4=Schultz |first4=SJ |last5=Nigg |first5=EA |pmc=41069 |bibcode=1995PNAS...92.8871T |doi-access=free }}
* {{cite journal | vauthors = Tassan JP, Jaquenoud M, Léopold P, Schultz SJ, Nigg EA | title = Identification of human cyclin-dependent kinase 8, a putative protein kinase partner for cyclin C | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 92 | issue = 19 | pages = 8871–8875 | date = September 1995 | pmid = 7568034 | pmc = 41069 | doi = 10.1073/pnas.92.19.8871 | doi-access = free | bibcode = 1995PNAS...92.8871T }}
*{{cite journal |title=Mapping of gene loci in the Q13-Q15 region of chromosome 12 |journal=Chromosome Res. |volume=3 |issue= 4 |pages= 261–2 |year= 1995 |pmid= 7606365 |doi=10.1007/BF00713052 |display-authors=3 |author1=Mitchell EL |author2=White GR |author3=Santibanez-Koref MF |name-list-style=vanc |last4=Varley |first4=JM |last5=Heighway |first5=J |s2cid=6029915 }}
* {{cite journal | vauthors = Mitchell EL, White GR, Santibanez-Koref MF, Varley JM, Heighway J | title = Mapping of gene loci in the Q13-Q15 region of chromosome 12 | journal = Chromosome Research | volume = 3 | issue = 4 | pages = 261–262 | date = June 1995 | pmid = 7606365 | doi = 10.1007/BF00713052 | s2cid = 6029915 }}
*{{cite journal |title=A p16INK4a-insensitive CDK4 mutant targeted by cytolytic T lymphocytes in a human melanoma |journal=Science |volume=269 |issue= 5228 |pages= 1281–4 |year= 1995 |pmid= 7652577 |doi=10.1126/science.7652577 |display-authors=3 |author1=Wölfel T |author2=Hauer M |author3=Schneider J |name-list-style=vanc |last4=Serrano |first4=M |last5=Wölfel |first5=C |last6=Klehmann-hieb |first6=E |last7=De Plaen |first7=E |last8=Hankeln |first8=T |last9=Meyer Zum Büschenfelde |first9=KH |bibcode=1995Sci...269.1281W |s2cid=37848897 }}
* {{cite journal | vauthors = Wölfel T, Hauer M, Schneider J, Serrano M, Wölfel C, Klehmann-Hieb E, De Plaen E, Hankeln T, Meyer zum Büschenfelde KH, Beach D | title = A p16INK4a-insensitive CDK4 mutant targeted by cytolytic T lymphocytes in a human melanoma | journal = Science | volume = 269 | issue = 5228 | pages = 1281–1284 | date = September 1995 | pmid = 7652577 | doi = 10.1126/science.7652577 | s2cid = 37848897 | bibcode = 1995Sci...269.1281W }}
*{{cite journal |title=Novel INK4 proteins, p19 and p18, are specific inhibitors of the cyclin D-dependent kinases CDK4 and CDK6 |journal=Mol. Cell. Biol. |volume=15 |issue= 5 |pages= 2672–81 |year= 1995 |pmid= 7739547 |doi= 10.1128/MCB.15.5.2672|display-authors=3 |author1=Hirai H |author2=Roussel MF |author3=Kato JY |name-list-style=vanc |last4=Ashmun |first4=RA |last5=Sherr |first5=CJ |pmc=230497 }}
* {{cite journal | vauthors = Hirai H, Roussel MF, Kato JY, Ashmun RA, Sherr CJ | title = Novel INK4 proteins, p19 and p18, are specific inhibitors of the cyclin D-dependent kinases CDK4 and CDK6 | journal = Molecular and Cellular Biology | volume = 15 | issue = 5 | pages = 2672–2681 | date = May 1995 | pmid = 7739547 | pmc = 230497 | doi = 10.1128/MCB.15.5.2672 }}
*{{cite journal |title=Identification of human and mouse p19, a novel CDK4 and CDK6 inhibitor with homology to p16ink4 |journal=Mol. Cell. Biol. |volume=15 |issue= 5 |pages= 2682–8 |year= 1995 |pmid= 7739548 |doi= 10.1128/MCB.15.5.2682|display-authors=3 |author1=Chan FK |author2=Zhang J |author3=Cheng L |name-list-style=vanc |last4=Shapiro |first4=DN |last5=Winoto |first5=A |pmc=230498 }}
* {{cite journal | vauthors = Chan FK, Zhang J, Cheng L, Shapiro DN, Winoto A | title = Identification of human and mouse p19, a novel CDK4 and CDK6 inhibitor with homology to p16ink4 | journal = Molecular and Cellular Biology | volume = 15 | issue = 5 | pages = 2682–2688 | date = May 1995 | pmid = 7739548 | pmc = 230498 | doi = 10.1128/MCB.15.5.2682 }}
*{{cite journal |title=Growth suppression by p18, a p16INK4/MTS1- and p14INK4B/MTS2-related CDK6 inhibitor, correlates with wild-type pRb function |journal=Genes Dev. |volume=8 |issue= 24 |pages= 2939–52 |year= 1995 |pmid= 8001816 |doi=10.1101/gad.8.24.2939 |display-authors=3 |author1=Guan KL |author2=Jenkins CW |author3=Li Y |name-list-style=vanc |last4=Nichols |first4=MA |last5=Wu |first5=X |last6=O'Keefe |first6=CL |last7=Matera |first7=AG |last8=Xiong |first8=Y |doi-access=free }}
* {{cite journal | vauthors = Guan KL, Jenkins CW, Li Y, Nichols MA, Wu X, O'Keefe CL, Matera AG, Xiong Y | title = Growth suppression by p18, a p16INK4/MTS1- and p14INK4B/MTS2-related CDK6 inhibitor, correlates with wild-type pRb function | journal = Genes & Development | volume = 8 | issue = 24 | pages = 2939–2952 | date = December 1994 | pmid = 8001816 | doi = 10.1101/gad.8.24.2939 | doi-access = free }}
*{{cite journal |title=Regulation of cyclin D-dependent kinase 4 (cdk4) by cdk4-activating kinase |journal=Mol. Cell. Biol. |volume=14 |issue= 4 |pages= 2713–21 |year= 1994 |pmid= 8139570 |doi= 10.1128/MCB.14.4.2713|author1=Kato JY |author2=Matsuoka M |author3=Strom DK |author4=Sherr CJ |pmc=358637}}
* {{cite journal | vauthors = Kato JY, Matsuoka M, Strom DK, Sherr CJ | title = Regulation of cyclin D-dependent kinase 4 (cdk4) by cdk4-activating kinase | journal = Molecular and Cellular Biology | volume = 14 | issue = 4 | pages = 2713–2721 | date = April 1994 | pmid = 8139570 | pmc = 358637 | doi = 10.1128/MCB.14.4.2713 }}
*{{cite journal |title=Coamplification of the CDK4 gene with MDM2 and GLI in human sarcomas |journal=Cancer Res. |volume=53 |issue= 22 |pages= 5535–41 |year= 1993 |pmid= 8221695 |display-authors=3 |author1=Khatib ZA |author2=Matsushime H |author3=Valentine M |name-list-style=vanc |last4=Shapiro |first4=DN |last5=Sherr |first5=CJ |last6=Look |first6=AT }}
* {{cite journal | vauthors = Khatib ZA, Matsushime H, Valentine M, Shapiro DN, Sherr CJ, Look AT | title = Coamplification of the CDK4 gene with MDM2 and GLI in human sarcomas | journal = Cancer Research | volume = 53 | issue = 22 | pages = 5535–5541 | date = November 1993 | pmid = 8221695 }}
*{{cite journal |title=A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4 |journal=Nature |volume=366 |issue= 6456 |pages= 704–7 |year= 1994 |pmid= 8259215 |doi= 10.1038/366704a0 |author1=Serrano M |author2=Hannon GJ |author3=Beach D |bibcode=1993Natur.366..704S |s2cid=4368128 }}
* {{cite journal | vauthors = Serrano M, Hannon GJ, Beach D | title = A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4 | journal = Nature | volume = 366 | issue = 6456 | pages = 704–707 | date = December 1993 | pmid = 8259215 | doi = 10.1038/366704a0 | s2cid = 4368128 | bibcode = 1993Natur.366..704S }}
*{{cite journal |title=Chromosomal mapping of human CDK2, CDK4, and CDK5 cell cycle kinase genes |journal=Cytogenet. Cell Genet. |volume=66 |issue= 1 |pages= 72–4 |year= 1994 |pmid= 8275715 |doi=10.1159/000133669 |author1=Demetrick DJ |author2=Zhang H |author3=Beach DH }}
* {{cite journal | vauthors = Demetrick DJ, Zhang H, Beach DH | title = Chromosomal mapping of human CDK2, CDK4, and CDK5 cell cycle kinase genes | journal = Cytogenetics and Cell Genetics | volume = 66 | issue = 1 | pages = 72–74 | year = 1994 | pmid = 8275715 | doi = 10.1159/000133669 }}
*{{cite journal |title=Direct binding of cyclin D to the retinoblastoma gene product (pRb) and pRb phosphorylation by the cyclin D-dependent kinase CDK4 |journal=Genes Dev. |volume=7 |issue= 3 |pages= 331–42 |year= 1993 |pmid= 8449399 |doi=10.1101/gad.7.3.331 |display-authors=3 |author1=Kato J |author2=Matsushime H |author3=Hiebert SW |name-list-style=vanc |last4=Ewen |first4=ME |last5=Sherr |first5=CJ |doi-access=free }}
* {{cite journal | vauthors = Kato J, Matsushime H, Hiebert SW, Ewen ME, Sherr CJ | title = Direct binding of cyclin D to the retinoblastoma gene product (pRb) and pRb phosphorylation by the cyclin D-dependent kinase CDK4 | journal = Genes & Development | volume = 7 | issue = 3 | pages = 331–342 | date = March 1993 | pmid = 8449399 | doi = 10.1101/gad.7.3.331 | doi-access = free }}
*{{cite journal |title=Germline mutations in the p16INK4a binding domain of CDK4 in familial melanoma |journal=Nat. Genet. |volume=12 |issue= 1 |pages= 97–9 |year= 1996 |pmid= 8528263 |doi= 10.1038/ng0196-97 |display-authors=3 |author1=Zuo L |author2=Weger J |author3=Yang Q |name-list-style=vanc |last4=Goldstein |first4=AM |last5=Tucker |first5=MA |last6=Walker |first6=GJ |last7=Hayward |first7=N |last8=Dracopoli |first8=NC |s2cid=29727436 }}
* {{cite journal | vauthors = Zuo L, Weger J, Yang Q, Goldstein AM, Tucker MA, Walker GJ, Hayward N, Dracopoli NC | title = Germline mutations in the p16INK4a binding domain of CDK4 in familial melanoma | journal = Nature Genetics | volume = 12 | issue = 1 | pages = 97–99 | date = January 1996 | pmid = 8528263 | doi = 10.1038/ng0196-97 | s2cid = 29727436 }}
*{{cite journal |title=A "double adaptor" method for improved shotgun library construction |journal=Anal. Biochem. |volume=236 |issue= 1 |pages= 107–13 |year= 1996 |pmid= 8619474 |doi= 10.1006/abio.1996.0138 |display-authors=3 |author1=Andersson B |author2=Wentland MA |author3=Ricafrente JY |name-list-style=vanc |last4=Liu |first4=W |last5=Gibbs |first5=RA }}
* {{cite journal | vauthors = Andersson B, Wentland MA, Ricafrente JY, Liu W, Gibbs RA | title = A "double adaptor" method for improved shotgun library construction | journal = Analytical Biochemistry | volume = 236 | issue = 1 | pages = 107–113 | date = April 1996 | pmid = 8619474 | doi = 10.1006/abio.1996.0138 }}
*{{cite journal |title=Differential regulation of retinoblastoma protein function by specific Cdk phosphorylation sites |journal=J. Biol. Chem. |volume=271 |issue= 14 |pages= 8313–20 |year= 1996 |pmid= 8626527 |doi=10.1074/jbc.271.14.8313 |author1=Knudsen ES |author2=Wang JY |doi-access=free }}
* {{cite journal | vauthors = Knudsen ES, Wang JY | title = Differential regulation of retinoblastoma protein function by specific Cdk phosphorylation sites | journal = The Journal of Biological Chemistry | volume = 271 | issue = 14 | pages = 8313–8320 | date = April 1996 | pmid = 8626527 | doi = 10.1074/jbc.271.14.8313 | doi-access = free }}
*{{cite journal |title=Cyclin-dependent kinases are inactivated by a combination of p21 and Thr-14/Tyr-15 phosphorylation after UV-induced DNA damage |journal=J. Biol. Chem. |volume=271 |issue= 22 |pages= 13283–91 |year= 1996 |pmid= 8662825 |doi=10.1074/jbc.271.22.13283 |author1=Poon RY |author2=Jiang W |author3=Toyoshima H |author4=Hunter T |doi-access=free }}
* {{cite journal | vauthors = Poon RY, Jiang W, Toyoshima H, Hunter T | title = Cyclin-dependent kinases are inactivated by a combination of p21 and Thr-14/Tyr-15 phosphorylation after UV-induced DNA damage | journal = The Journal of Biological Chemistry | volume = 271 | issue = 22 | pages = 13283–13291 | date = May 1996 | pmid = 8662825 | doi = 10.1074/jbc.271.22.13283 | doi-access = free }}
*{{cite journal |title=Mammalian p50Cdc37 is a protein kinase-targeting subunit of Hsp90 that binds and stabilizes Cdk4 |journal=Genes Dev. |volume=10 |issue= 12 |pages= 1491–502 |year= 1996 |pmid= 8666233 |doi=10.1101/gad.10.12.1491 |author1=Stepanova L |author2=Leng X |author3=Parker SB |author4=Harper JW |doi-access=free }}
* {{cite journal | vauthors = Stepanova L, Leng X, Parker SB, Harper JW | title = Mammalian p50Cdc37 is a protein kinase-targeting subunit of Hsp90 that binds and stabilizes Cdk4 | journal = Genes & Development | volume = 10 | issue = 12 | pages = 1491–1502 | date = June 1996 | pmid = 8666233 | doi = 10.1101/gad.10.12.1491 | doi-access = free }}
*{{cite journal |title=Physical interaction of mammalian CDC37 with CDK4 |journal=J. Biol. Chem. |volume=271 |issue= 36 |pages= 22030–4 |year= 1996 |pmid= 8703009 |doi=10.1074/jbc.271.36.22030 |author1=Dai K |author2=Kobayashi R |author3=Beach D |doi-access=free }}
* {{cite journal | vauthors = Dai K, Kobayashi R, Beach D | title = Physical interaction of mammalian CDC37 with CDK4 | journal = The Journal of Biological Chemistry | volume = 271 | issue = 36 | pages = 22030–22034 | date = September 1996 | pmid = 8703009 | doi = 10.1074/jbc.271.36.22030 | doi-access = free }}
*{{cite journal |title=Inhibition of pRb phosphorylation and cell-cycle progression by a 20-residue peptide derived from p16CDKN2/INK4A |journal=Curr. Biol. |volume=6 |issue= 1 |pages= 84–91 |year= 1996 |pmid= 8805225 |doi=10.1016/S0960-9822(02)00425-6 |display-authors=3 |author1=Fåhraeus R |author2=Paramio JM |author3=Ball KL |name-list-style=vanc |last4=Laín |first4=S |last5=Lane |first5=DP |s2cid=23024663 |url=https://www.pure.ed.ac.uk/ws/files/12111645/Inhibition_of_pRb_phosphorylation_and_cell_cycle_progression.pdf }}
* {{cite journal | vauthors = Fåhraeus R, Paramio JM, Ball KL, Laín S, Lane DP | title = Inhibition of pRb phosphorylation and cell-cycle progression by a 20-residue peptide derived from p16CDKN2/INK4A | journal = Current Biology | volume = 6 | issue = 1 | pages = 84–91 | date = January 1996 | pmid = 8805225 | doi = 10.1016/S0960-9822(02)00425-6 | hdl-access = free | s2cid = 23024663 | hdl = 20.500.11820/9e95b5cc-be55-4c50-bfd9-04eb51b3e3f9 }}
{{refend}}
{{refend}}


==External links==
== External links ==
* {{MeshName|Cyclin-Dependent+Kinase+4}}
* {{MeshName|Cyclin-Dependent+Kinase+4}}
* {{UCSC genome browser|CDK4}}
* {{UCSC genome browser|CDK4}}

Latest revision as of 06:57, 30 December 2024

CDK4
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesCDK4, CMM3, PSK-J3, cyclin-dependent kinase 4, cyclin dependent kinase 4
External IDsOMIM: 123829; MGI: 88357; HomoloGene: 55429; GeneCards: CDK4; OMA:CDK4 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

1019

12567

Ensembl

ENSG00000135446

n/a

UniProt

P11802

P30285

RefSeq (mRNA)

NM_052984
NM_000075

NM_009870
NM_001355005

RefSeq (protein)

NP_000066

NP_034000
NP_001341934

Location (UCSC)Chr 12: 57.75 – 57.76 Mbn/a
PubMed search[2][3]
Wikidata
View/Edit HumanView/Edit Mouse

Cyclin-dependent kinase 4 (CDK4), also known as cell division protein kinase 4, is an enzyme that is encoded by the CDK4 gene in humans. CDK4 is a member of the cyclin-dependent kinase family, a group of serine/threonine kinases which regulate the cell cycle.[4] CDK4 regulates the G1/S transition by contributing to the phosphorylation of retinoblastoma (RB) protein, which leads to the release of protein factors like E2F1 that promote S-phase progression.[5] It is regulated by cyclins like cyclin D proteins, regulatory kinases, and cyclin kinase inhibitors (CKIs).[5] Dysregulation of the CDK4 pathway is common in many cancers, and CDK4 is a new therapeutic target in cancer treatment.[6]

Structure

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The CDK4 gene is located on chromosome 12 in humans.[7] The gene is composed of 4,583 base pairs which together code for the 303 amino acid protein with a molecular mass of 33,730 Da.[7][8] All CDK proteins, including CDK4, have two lobes: the smaller N-terminal lobe (which contains an inhibitory G-loop), and the C terminal lobe (which contains an activation domain and a T-loop). Between these two lobes is the serine/threonine kinase domain where ATP binds. In its completely inactive form, CDK4's T-loop blocks the ATP binding site, and the surrounding amino acid side chains prevent ATP binding.[4] The kinase's activity increases when it dimerizes with the corresponding cyclin, cyclin D, which causes a conformational change at the ATP binding site. CDK activating kinase (CAK) then phosphorylates the T172 site (located on the T-loop).[5][9][10] These two actions move the T-loop out of the active ATP-binding site and make ATP binding more favorable.

Notably, CDK6 is very related to CDK4 in both structure and function. They share 71% of their amino acids and both regulate the G1/S transition by phosphorylating Rb. CDK4 and 6 differ in their cellular localization and other off-pathway roles, however are commonly referred together as CDK4/6.[4]

The CDK4 protein is similar to the fungi gene products of S. cerevisiae cdc28 and S. pombe cdc2.[7]

Function

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Role of CDK4, cyklin D, Rb and E2F in cell cycle regulation.

CDK4 is the catalytic subunit of the protein-kinase complex CDK4-cyclin D, which plays a role in G1/S cell cycle progression.[5] During G1 phase, the cell grows and prepares for the DNA replication that occurs in the S phase. There is a G1/S checkpoint which acts as a committed step to enter S-phase. This checkpoint ensures that cells moving toward mitosis are large enough and do not have DNA damage that could be passed on to daughter cells.[11]

There are two models of CDK4 cell cycle regulation. The older model proposes that the kinase is responsible for the phosphorylation of retinoblastoma gene product (Rb). The Ser/Thr-kinase component of cyclin D-CDK4 (DC) forms complexes that phosphorylate and inhibit members of the retinoblastoma (RB) protein family including RB1 and regulate the cell-cycle during G1/S transition. Phosphorylation of RB1 allows dissociation of the transcription factor E2F from the RB/E2F complexes and the subsequent transcription of E2F target genes which are responsible for the progression through the G1 phase. In this model, CDK4 inhibits Rb, which inhibits E2F, which promotes progression into S phase.

The newer model, as proposed in a 2014 paper by Narasimha et al., The CDK4-cyclin D complex phosphorylates the retinoblastoma tumor suppressor protein (Rb) and its related proteins p107 and p130, which go on to inhibit cell cycle progression.[5] As a kinase, the CDK4 serine/threonine active site converts ATP to ADP and transfers the removed phosphate group to Rb. Rb is mono-phosphorylated in early G1 by the CDK4-cyclin D complex. When mono-phosphorylated, Rb exists as one of the 14 isoforms, which bind to protein factors like E1a, and proteins in the E2F family.[12]

The new model of CDK4 regulation posits that at the G1/S checkpoint, if a cell seems healthy, CDK2 (a different cyclin dependent kinase) inactivates Rb, and these protein factors are released back into the cell. E2F proteins then activate the transcription of genes that cause S-phase progression.[5] However, if at the G1/S checkpoint a cell detects DNA damage, it will response by activating the CDK4-cyclin D complex to mono-phosphorylate, and activate Rb. This prevents Rb from dissociating from E2F protins, which prevents them from activating the transcription of the S-phase progression genes.[12]

While CDK4 primarily regulates the cell cycle through phosphorylation of Rb, there is evidence of a secondary, more direct role independent of Rb. CDK4 may be able to directly phosphorylate transcription factors and co-regulators like Smad3, MYC, FOXM1, and MEP50 to regulate the cell cycle, survival and senescence.

Interestingly, CDK4-null mutant mice are viable, and in-vitro experiments show that cell proliferation is not significantly affected, likely due to compensatory roles played by other CDKs. However, CDK plays a significant role in cancer development.[13]

Mechanisms of regulation

[edit]

CDK4 is only active during the G1-S phase, which controlled by cyclin D and CDK inhibitors. CDK activity is negatively regulated by cyclin kinase inhibitors (CKIs), which belong to one of two families. The INK4 family of CKIs are inhibitors which bind and inhibit CDK4/6, also preventing subsequent binding to cyclin D. The Cip/Kip family inhibitors are not specific to CDK4/6, and instead bind and inhibit the cyclin-CDK complex.[4]

CDK4 activity is positively regulated by cyclin D, which creates a conformational change in CDK4 that opens the active site for kinase activity. Cyclins are proteins that change concentration periodically during the cell cycle. They are extremely specific and diverse, which serves to regulate the cell cycle with precision. Cyclin D levels oscillate during the G1 phase, first increasing and accumulating, then rapidly decreasing during the transition to the S phase.[4] Cyclin D levels are stimulated by growth factors, without which cyclin D levels would stay low regardless of cell cycle stage.[13] After its role in G1 is complete, cyclin D is translocated from the nucleus to the cytoplasm in S phase, modulating the nuclear cyclin D levels, and therefore modulating the activity of CDK4 to promote the S phase transition.[4]

Clinical significance

[edit]

Cancer

[edit]

Cancer, or uncontrolled cell proliferation, is believed to result from disturbances to mechanisms that usually control cell proliferation (tumor suppressors) and mechanisms that normally encourage cell proliferation (proto-oncogenes). Cell cycle regulation mechanisms called checkpoints, like G1/S, are in place to prevent this uncontrolled division.[5]

Mutations in the CDK4 gene as well as in its related proteins including D-type cyclins, p16(INK4a), CDKN2A and Rb were all found to be associated with tumorigenesis of a variety of cancers, including sarcomas, gliomas, lymphomas and tumors of the mammary gland.[13] One specific point mutation of CDK4 (R24C) was first identified in melanoma patients. This mutation was introduced also in animal models and its role as a cancer driver oncogene was studied thoroughly.[13] Nowadays, deregulated CDK4 is considered to be a potential therapeutic target in some cancer types and various CDK4 inhibitors are being tested for cancer treatment in clinical trials. Multiple polyadenylation sites of this gene have been reported.

Cyclin D and CDK4/6 activities are observed to be up-regulated in certain cancers, sparking interest in the development of small-molecule inhibitors of CDK4/6. Ribociclib are US FDA approved CDK4 and CDK6 inhibitors for the treatment of estrogen receptor positive/ HER2 negative advanced breast cancer.[14]

HIV

[edit]

There is some evidence that CDK4 plays a role in the HIV-1 restriction pathway in primary microphages. Cell cycle control plays a major role in determining susceptibility to HIV-1 infection. Active CDKs phosphorylate SAMHD1, deactivating the enzyme which usually can restrict HIV-1 replication. A complex formed by cyclin D2-CDK4-p21 lowers the amount of active CDK in the cell, allowing SAMHD1 to exist in its active, dephosphorylated form that restricts HIV-1 replication.[15]

Interactions

[edit]

Cyclin-dependent kinase 4 has been shown to interact with:

Overview of signal transduction pathways involved in apoptosis. (CDK4 in the (pink) nucleus)

References

[edit]
  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000135446 – Ensembl, May 2017
  2. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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  22. ^ a b Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, et al. (October 2005). "Towards a proteome-scale map of the human protein-protein interaction network". Nature. 437 (7062): 1173–1178. Bibcode:2005Natur.437.1173R. doi:10.1038/nature04209. PMID 16189514. S2CID 4427026.
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  26. ^ a b c Sugimoto M, Nakamura T, Ohtani N, Hampson L, Hampson IN, Shimamoto A, et al. (November 1999). "Regulation of CDK4 activity by a novel CDK4-binding protein, p34(SEI-1)". Genes & Development. 13 (22): 3027–3033. doi:10.1101/gad.13.22.3027. PMC 317153. PMID 10580009.
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Further reading

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[edit]
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