Geminin
Template:PBB Geminin, DNA replication inhibitor, also known as GMNN, is a protein in humans encoded by the GMNN gene.[1]maintains DNA fidelity by preventing chromosomal polyploidy during the metazoan cell cycle while also contributing to progression of the cell cycle and cell proliferation. Geminin also appears influence cellular differentiation.
Structure
Geminin is a nuclear protein made up of about 200 amino acids, with a molecular weight of approximately 25 kDa.[2]
Function
Geminin is multi-functional with roles in metazoan cell cycle, early cell lineage commitment, and neural differentiation.[3] Geminin was originally identified as an inhibitor of DNA replication and substrate of the anaphase promoting complex (APC).[2] Coincidentally, Geminin was also shown to have a role in the disappears to play important roles in the progression of the cell cycle and cell proliferation. [4]
Cell Cycle Control
Geminin is absent during G1 phase and accumulates through S, G2 phase and M phases of the cell cycle. Geminin levels drop at the metaphase / anaphase transition of mitosis when it is degraded by the Anaphase Promoting Complex (APC).[2]
S phase
During S phase, geminin is a negative regulator of DNA replication. In many cancer cell lines, inhibition of geminin by RNAi results in re-replication of portions of the genome, which leads to aneuploidy. In these cell lines, geminin knockdown leads to markedly slowed growth and apoptosis within several days.[5] However, the same is not true for primary and immortalized human cell lines, where other mechanisms exists to prevent re-replication.[5] Since geminin knockdown leads to cell death in many cancer cell lines but not primary cell lines, it has been proposed as a potential therapeutic target for cancer treatment.[5]
M phase
During M phase, or mitosis, geminin stabilizes the replication factor Cdt1 by protecting it from ubiquitination and therefore subsequence proteolysis, thereby potentially promoting DNA replication during the following cell cycle. Although inhibition of geminin by RNAi leads to destabilization of Cdt1 protein and impairment of DNA replication during the following cell cycle in many cancer cell lines, no such cell cycle defect is seen in primary and immortalized cell lines (although Cdt1 levels are still reduced in these cells).[5]
Geminin therefore is an important player in ensuring that one and only one round of replication occurs during each cell cycle.
Developmental Control
Clinical significance
Recently, geminin has been found to be overexpressed in several malignancies and cancer cell lines.[6]
References
- ^ "Entrez Gene: GMNN geminin, DNA replication inhibitor".
- ^ a b c McGarry TJ; Depamphilis, ML (1998). "Geminin, an inhibitor of DNA replication, is degraded during mitosis". Cell. 93 (11): 1043–1053. doi:10.1016/S0092-8674(00)81209-X. PMID 9635433.
- ^ Kroll, KL (2007). "Geminin in embryonic development: coordinating transcription and the cell cycle during differentiation". Front Biosci. 12 (4): 1395–409. PMID 17127390.
- ^ Wohlschlegel JA, Kutok JL, Weng AP, Dutta A (2002). "Expression of geminin as a marker of cell proliferation in normal tissues and malignancies". Am J Pathol. 161 (1): 267–73. PMC 1850683. PMID 12107111.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ a b c d Zhu W, Depamphilis ML (2009). "Selective killing of cancer cells by suppression of geminin activity". Cancer Res. 69 (11): 4870–4877. doi:10.1158/0008-5472.CAN-08-4559. PMC 2749580. PMID 19487297.
{{cite journal}}: Unknown parameter|month=ignored (help) - ^ Montanari M, Boninsegna A, Faraglia B, Coco C, Giordano A, Cittadini A, Sgambato A (2005). "Increased expression of geminin stimulates the growth of mammary epithelial cells and is a frequent event in human tumors". J Cell Physiol. 202 (1): 215–22. doi:10.1002/jcp.20120. PMID 15389519.
{{cite journal}}: CS1 maint: multiple names: authors list (link)
Further reading
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External links
- GMNN+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)