Renal cell carcinoma pathophysiology: Difference between revisions
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==Pathophysiology== | ==Pathophysiology== | ||
===Sporadic Clear Cell Renal Carcinoma=== | ===Sporadic Forms of Clear Cell Renal Carcinoma=== | ||
Although Von Hippel-Lindau (VHL), an autosomal dominant disorder, is characterized by the mutation of the ''VHL'' gene - a tumor suppressor gene - and the consequential development of renal clear cell carcinomas following the silencing of the remaining normal ''VHL'' gene, the gene itself has been identified to be similarly responsible of the development of sporadic forms of renal clear cell carcinomas.<ref name="pmid16339096">{{cite journal| author=Cohen HT, McGovern FJ| title=Renal-cell carcinoma. | journal=N Engl J Med | year= 2005 | volume= 353 | issue= 23 | pages= 2477-90 | pmid=16339096 | doi=10.1056/NEJMra043172 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16339096 }} </ref> | Although Von Hippel-Lindau (VHL), an autosomal dominant disorder, is characterized by the mutation of the ''VHL'' gene - a tumor suppressor gene - and the consequential development of renal clear cell carcinomas following the silencing of the remaining normal ''VHL'' gene, the gene itself has been identified to be similarly responsible of the development of sporadic forms of renal clear cell carcinomas.<ref name="pmid16339096">{{cite journal| author=Cohen HT, McGovern FJ| title=Renal-cell carcinoma. | journal=N Engl J Med | year= 2005 | volume= 353 | issue= 23 | pages= 2477-90 | pmid=16339096 | doi=10.1056/NEJMra043172 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16339096 }} </ref> | ||
Revision as of 19:37, 28 December 2013
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Overview
Pathophysiology
Sporadic Forms of Clear Cell Renal Carcinoma
Although Von Hippel-Lindau (VHL), an autosomal dominant disorder, is characterized by the mutation of the VHL gene - a tumor suppressor gene - and the consequential development of renal clear cell carcinomas following the silencing of the remaining normal VHL gene, the gene itself has been identified to be similarly responsible of the development of sporadic forms of renal clear cell carcinomas.[1]
VHL protein is an oxygen sensing regulator of hypoxic responses. It has a major role in binding and inhibiting transciptional activators hypoxia-induced factor (HIF) 1-alpha and 2-alpha via ubiquination and destruction using elongin proteins C and B that bind to cul2 protein of the ubiquitin ligase protein (cullin) family.[2][3][4][5][6][7][8][9] Normally, inhibition of HIF by VHL prevents the encoding of proteins that promote angiogenesis, such as vascular endothelial growth factor (VEGF), transforming growth factor alpha (TGF-alpha), glucose receptors such as GLUT-1 glucose transporter, and carbonic anhydrase IX (CA9) which ensures acid-base balance.[1][2][3] Inhibition of VHL induces the overexpression of these proteins, mimicking hypoxemia, and facilitates the development of clear cell carcinoma.[1] The disease process is not believed to be due to the simple interaction between VHL protein and HIF. Other proteins are also thought to be involved in the process, including fibronectin[10], chaperonin TRiC/CCT[11], microtubules[12], and transcription factor Jade-1[13][14][15].
Familial Forms of Clear Cell Renal Carcinoma
The translocation and loss of chromosome 3p at the site 3p14 is hypothesized to be responsible for the development of renal clear cell carcinomas in other familial forms not related to VHL disease.[16]
References
- ↑ 1.0 1.1 1.2 Cohen HT, McGovern FJ (2005). "Renal-cell carcinoma". N Engl J Med. 353 (23): 2477–90. doi:10.1056/NEJMra043172. PMID 16339096.
- ↑ 2.0 2.1 Iliopoulos O, Kibel A, Gray S, Kaelin WG (1995). "Tumour suppression by the human von Hippel-Lindau gene product". Nat Med. 1 (8): 822–6. PMID 7585187.
- ↑ 3.0 3.1 Chen F, Kishida T, Duh FM, Renbaum P, Orcutt ML, Schmidt L; et al. (1995). "Suppression of growth of renal carcinoma cells by the von Hippel-Lindau tumor suppressor gene". Cancer Res. 55 (21): 4804–7. PMID 7585510.
- ↑ Iliopoulos O, Levy AP, Jiang C, Kaelin WG, Goldberg MA (1996). "Negative regulation of hypoxia-inducible genes by the von Hippel-Lindau protein". Proc Natl Acad Sci U S A. 93 (20): 10595–9. PMC 38198. PMID 8855223.
- ↑ Pause A, Lee S, Worrell RA, Chen DY, Burgess WH, Linehan WM; et al. (1997). "The von Hippel-Lindau tumor-suppressor gene product forms a stable complex with human CUL-2, a member of the Cdc53 family of proteins". Proc Natl Acad Sci U S A. 94 (6): 2156–61. PMC 20057. PMID 9122164.
- ↑ Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME; et al. (1999). "The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis". Nature. 399 (6733): 271–5. doi:10.1038/20459. PMID 10353251.
- ↑ Cockman ME, Masson N, Mole DR, Jaakkola P, Chang GW, Clifford SC; et al. (2000). "Hypoxia inducible factor-alpha binding and ubiquitylation by the von Hippel-Lindau tumor suppressor protein". J Biol Chem. 275 (33): 25733–41. doi:10.1074/jbc.M002740200. PMID 10823831.
- ↑ Ohh M, Park CW, Ivan M, Hoffman MA, Kim TY, Huang LE; et al. (2000). "Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein". Nat Cell Biol. 2 (7): 423–7. doi:10.1038/35017054. PMID 10878807.
- ↑ Tanimoto K, Makino Y, Pereira T, Poellinger L (2000). "Mechanism of regulation of the hypoxia-inducible factor-1 alpha by the von Hippel-Lindau tumor suppressor protein". EMBO J. 19 (16): 4298–309. doi:10.1093/emboj/19.16.4298. PMC 302039. PMID 10944113.
- ↑ Ohh M, Yauch RL, Lonergan KM, Whaley JM, Stemmer-Rachamimov AO, Louis DN; et al. (1998). "The von Hippel-Lindau tumor suppressor protein is required for proper assembly of an extracellular fibronectin matrix". Mol Cell. 1 (7): 959–68. PMID 9651579.
- ↑ Feldman DE, Spiess C, Howard DE, Frydman J (2003). "Tumorigenic mutations in VHL disrupt folding in vivo by interfering with chaperonin binding". Mol Cell. 12 (5): 1213–24. PMID 14636579.
- ↑ Hergovich A, Lisztwan J, Barry R, Ballschmieter P, Krek W (2003). "Regulation of microtubule stability by the von Hippel-Lindau tumour suppressor protein pVHL". Nat Cell Biol. 5 (1): 64–70. doi:10.1038/ncb899. PMID 12510195.
- ↑ Zhou MI, Wang H, Ross JJ, Kuzmin I, Xu C, Cohen HT (2002). "The von Hippel-Lindau tumor suppressor stabilizes novel plant homeodomain protein Jade-1". J Biol Chem. 277 (42): 39887–98. doi:10.1074/jbc.M205040200. PMID 12169691.
- ↑ Zhou MI, Wang H, Foy RL, Ross JJ, Cohen HT (2004). "Tumor suppressor von Hippel-Lindau (VHL) stabilization of Jade-1 protein occurs through plant homeodomains and is VHL mutation dependent". Cancer Res. 64 (4): 1278–86. PMID 14973063.
- ↑ Zhou MI, Foy RL, Chitalia VC, Zhao J, Panchenko MV, Wang H; et al. (2005). "Jade-1, a candidate renal tumor suppressor that promotes apoptosis". Proc Natl Acad Sci U S A. 102 (31): 11035–40. doi:10.1073/pnas.0500757102. PMC 1182408. PMID 16046545.
- ↑ Cohen AJ, Li FP, Berg S, Marchetto DJ, Tsai S, Jacobs SC; et al. (1979). "Hereditary renal-cell carcinoma associated with a chromosomal translocation". N Engl J Med. 301 (11): 592–5. doi:10.1056/NEJM197909133011107. PMID 470981.