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BRAF (gene)

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Template:PBB B-Raf proto-oncogene serine/threonine-protein kinase (B-RAF), also known as V-raf murine sarcoma viral oncogene homolog B1, is a protein that in humans is encoded by the BRAF gene.[1][2] The B-RAF protein is involved in sending signals in cells and in cell growth. The BRAF gene may be mutated,[3] and the B-RAF protein altered, as an inherited mutation which causes birth defects, or as an acquired mutation (oncogene) in adults which causes cancer. Drugs that treat those cancers by inhibiting B-RAF are being studied, and one, PLX4032, has started phase III clinical trials.[4]

Function

This gene encodes a protein belonging to the raf/mil family of serine/threonine protein kinases. This protein plays a role in regulating the MAP kinase / ERKs signaling pathway, which affects cell division, differentiation, and secretion.[5]

Clinical significance

Mutations in the BRAF gene can cause disease in two ways. First, mutations can be inherited and cause birth defects. Second, mutations can appear later in life and cause cancer, as an oncogene.

Inherited mutations in this gene cause cardiofaciocutaneous syndrome, a disease characterized by heart defects, mental retardation and a distinctive facial appearance.

Acquired mutations in this gene have also been found in cancers, including non-Hodgkin lymphoma, colorectal cancer, malignant melanoma, papillary thyroid carcinoma, non-small cell lung carcinoma, and adenocarcinoma of lung.[5] Some pharmaceutical firms are developing specific inhibitors of B-raf protein for anticancer use.[6][7]

BRAF Mutants

More than 30 mutations of the BRAF gene associated with human cancers have been identified. The frequency of BRAF mutations varies widely in human cancers from more than 80% in melanomas and nevi, to as little as 0-18% in other tumors, such as 1-3% in lung cancers and 5% in colorectal cancer.[8] In 90% of the cases, a Glu for Val substitution at residue 599(now referred to as V600E) in the activation segment has been found in human cancers. This mutation has been widely observed in papillary thyroid carcinoma, colorectal cancer and melanomas.[9][10][11][12][13][14][15]

Other mutations which have been found are R461I, I462S, G463E, G463V, G465A, G465E, G465V, G468A, G468E, N580S, E585K, D593V, F594L, G595R, L596V, T598I, V599D, V599E, V599K, V599R, K600E, A727V, etc and most of these mutations are clustered to two regions: the glycine-rich P loop of the N lobe and the activation segment and flanking regions.[16] These mutations change the activation segment from inactive state to active state, for example in the previous cited paper it has been reported that the aliphatic side chain of Val599 interacts with the phenyl ring of Phe467 in the P loop. Replacing the medium sized hydrophobic Val side chain with a larger and charged residue as found in human cancer(Glu, Asp, Lys, or Arg) would be expected to destabilize the interactions that maintain the DFG motif in an inactive conformation, so flipping the activation segment into the active position. Depending on the type of mutation the kinase activity towards MEK may also vary. In the same paper it has been reported that most of the mutants stimulate enhanced B-RAF kinase activity toward MEK. However, a few mutants act through a different mechanism because although their activity toward MEK is reduced, they adopt a conformation that activates wild-type C-RAF, which then signals to ERK.

PLX4032

A B-RAG inhibitor, PLX4032 (RO5185426), has been shown to cause programmed cell death in melanoma cell lines.[17] PLX4032 interrupts the B-Raf/MEK step on the B-Raf/MEK/ERK pathway − if the B-Raf has a common mutation.

In a phase I clinical study, PLX4032 was able to reduce numbers of cancer cells in over half of a group of 16 patients with advanced melanoma, and the treated group had a median increased survival time of 6 months over the control group.[18][19][20][21] PLX4032 only works in melanoma patients whose cancer has a V600E BRAF mutation (that is, at amino acid position number 600 on the B-RAF protein, the normal valine is replaced by glutamic acid). About 60% of melanomas have the V600E mutation. Melanoma cells without this mutation are not inhibited by PLX4032; PLX4032 paradoxically stimulates normal BRAF and may promote tumor growth.[22][23] Phase I[24] and phase II studies are ongoing,[25] and a phase III trial has been started.[4]

In vitro, a melanoma cell line A375 is inhibited by silencing the BRAF gene by short hairpin RNA.[17]

Interactions

BRAF (gene) has been shown to interact with YWHAB,[26][27] C-Raf,[28] AKT1[29] and HRAS.[30][31]

References

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  2. ^ Sithanandam G, Druck T, Cannizzaro LA, Leuzzi G, Huebner K, Rapp UR (1992). "B-raf and a B-raf pseudogene are located on 7q in man". Oncogene. 7 (4): 795–9. PMID 1565476. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
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  14. ^ Puxeddu E, Moretti S, Elisei R, Romei C, Pascucci R, Martinelli M, Marino C, Avenia N, Rossi ED, Fadda G, Cavaliere A, Ribacchi R, Falorni A, Pontecorvi A, Pacini F, Pinchera A, Santeusanio F (2004). "BRAF(V599E) mutation is the leading genetic event in adult sporadic papillary thyroid carcinomas". J. Clin. Endocrinol. Metab. 89 (5): 2414–20. doi:10.1210/jc.2003-031425. PMID 15126572. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  15. ^ Elisei R, Ugolini C, Viola D, Lupi C, Biagini A, Giannini R, Romei C, Miccoli P, Pinchera A, Basolo F (2008). "BRAF(V600E) mutation and outcome of patients with papillary thyroid carcinoma: a 15-year median follow-up study". J. Clin. Endocrinol. Metab. 93 (10): 3943–9. doi:10.1210/jc.2008-0607. PMID 18682506. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  16. ^ Wan PT, Garnett MJ, Roe SM, Lee S, Niculescu-Duvaz D, Good VM, Jones CM, Marshall CJ, Springer CJ, Barford D, Marais R (2004). "Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF". Cell. 116 (6): 855–67. doi:10.1016/S0092-8674(04)00215-6. PMID 15035987. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  17. ^ a b Sala E, Mologni L, Truffa S, Gaetano C, Bollag GE, Gambacorti-Passerini C (2008). "BRAF silencing by short hairpin RNA or chemical blockade by PLX4032 leads to different responses in melanoma and thyroid carcinoma cells". Mol. Cancer Res. 6 (5): 751–9. doi:10.1158/1541-7786.MCR-07-2001. PMID 18458053. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  18. ^ "Drug hope for advanced melanoma". BBC News. 2009-06-02. Retrieved 2009-06-07.
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  21. ^ Flaherty K, Puzanov I, Sosman J, Kim K, Ribas A, McArthur G, Lee RJ, Grippo JF, Nolop K, Chapman P. "Phase I study of PLX4032: Proof of concept for V600E BRAF mutation as a therapeutic target in human cancer. - ASCO". 2009 ASCO Annual Meeting Abstract, J Clin Oncol 27:15s, 2009 (suppl; abstr 9000). {{cite web}}: Cite has empty unknown parameter: |coauthors= (help)CS1 maint: multiple names: authors list (link)
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  23. ^ Halaban R, Zhang W, Bacchiocchi A, Cheng E, Parisi F, Ariyan S, Krauthammer M, McCusker JP, Kluger Y, Sznol M (2010). "PLX4032, a Selective BRAF(V600E) Kinase Inhibitor, Activates the ERK Pathway and Enhances Cell Migration and Proliferation of BRAF(WT) Melanoma Cells". Pigment Cell Melanoma Res. doi:10.1111/j.1755-148X.2010.00685.x. PMID 20149136. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
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Further reading

Template:PBB Further reading

  • "BRAF gene". NCI Dictionary of Cancer Terms. Retrieved 2007-11-25.

Template:PBB Controls

Public Domain This article incorporates public domain material from Dictionary of Cancer Terms. U.S. National Cancer Institute. This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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