Abstract
The familial cancer syndrome, von Hippel–Lindau (VHL) disease, characterized by a predisposition to renal cell carcinoma and certain other tumor types, is caused by mutational inactivation of the VHL tumor suppressor gene. Loss of VHL gene function is detected also in the vast majority of sporadic renal cell carcinomas. Previous reports have determined a protective role for VHL in response to serum withdrawal and glucose deprivation. In this study, the effect of UV irradiation on VHL-negative and VHL-positive renal carcinoma cells was examined. VHL-negative 786-O renal carcinoma cells underwent apoptosis following UV irradiation. In contrast, reintroduction of wild-type VHL expression protected 786-O cells from UV-mediated cell death. p53 and Bax levels were equivalent in VHL-negative and VHL-positive 786-O cells. Strikingly, cyclin-dependent kinase inhibitors p21 and p27 underwent proteasome-dependent degradation in VHL-negative 786-O cells following UV treatment. However, p21 and p27 protein levels were stable in VHL-positive cells. Also, levels of the anti-apoptotic proteins, Bcl-2 and Bcl-xL were elevated in VHL-positive cells, consistent with the protection from apoptotic stimuli. UV treatment led to increased S phase in VHL-negative, but not VHL-positive cells. Thus, following UV irradiation, diminution of p21 and p27 levels resulted in a hyperproliferative state in VHL-negative cells, leading to apoptosis. These results suggest that loss of VHL function promotes apoptosis and may provide selective pressure toward cells that are able to escape apoptosis, leading to tumorigenesis.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Agarwal ML, Taylor WR, Chernov MV, Chernova OB and Stark GR. . 1998 J. Biol. Chem. 273: 1–4.
Blagosklonny MV, Wu GS, Omura S and el-Deiry WS. . 1996 Biochem. Biophys. Res. Commun. 227: 564–569.
Blankenship C, Naglich JG, Whaley JM, Seizinger B and Kley N. . 1999 Oncogene 18: 1529–1535.
Di Cristofano A and Pandolfi PP. . 2000 Cell 100: 387–390.
Duan DR, Humphrey JS, Chen DY, Weng Y, Sukegawa J, Lee S, Gnarra JR, Linehan WM and Klausner RD. . 1995 Proc. Natl. Acad. Sci. USA 92: 6459–6463.
Gorospe M, Egan JM, Zbar B, Lerman M, Geil L, Kuzmin I and Holbrook NJ. . 1999 Mol. Cell. Biol. 19: 1289–1300.
Iliopoulos O, Kibel A, Gray S and Kaelin WG. . 1995 Nat. Med. 1: 822–826.
Iliopoulos O, Levy AP, Jiang C, Kaelin WG and Goldberg MA. . 1996 Proc. Natl. Acad. Sci. USA 93: 10595–10599.
Iliopoulos O, Ohh M and Kaelin Jr WG. . 1998 Proc. Natl. Acad. Sci. USA 95: 11661–11666.
Iwai K, Yamanaka K, Kamura T, Minato N, Conaway RC, Conaway JW, Klausner RD and Pause A. . 1999 Proc. Natl. Acad. Sci. USA 96: 12436–12441.
Latif F, Tory K, Gnarra J, Yao M, Duh FM, Orcutt ML, Stackhouse T, Kuzmin I, Modi W, Geil L, Schmidt L, Zhou F, Li H, Wei MH, Chen F, Glenn G, Choyke P, Walther MM, Weng Y, Duan DR, Dean M, Glavac D, Richards F, Crossey PA, Ferguson-Smith MA, Paslier DL, Chumakov I, Cohen D, Chinault AC, Maher ER, Linehan WM, Zbar B and Lerman MI. . 1993 Science 260: 1317–1320.
Levine AJ. . 1997 Cell 88: 323–331.
Lieubeau-Teillet B, Rak J, Jothy S, Iliopoulos O, Kaelin W and Kerbel RS. . 1998 Cancer Res. 58: 4957–4962.
Linehan WM, Lerman MI and Zbar B. . 1995 J. Am. Med. Assoc. 273: 564–570.
Lisztwan J, Imbert G, Wirbelauer C, Gstaiger M and Krek W. . 1999 Genes Dev. 13: 1822–1833.
Lowe SW and Lin AW. . 2000 Carcinogenesis 21: 485–495.
Lu X, Burbidge SA, Griffin S and Smith HM. . 1996 Oncogene 13: 413–418.
Lubensky IA, Gnarra JR, Bertheau P, Walther MM, Linehan WM and Zhuang Z. . 1996 Am. J. Pathol. 149: 2089–2094.
Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, Wykoff CC, Pugh CW, Maher ER and Ratcliffe PJ. . 1999 Nature 399: 271–275.
Morimoto M, Nishida T, Honda R and Yasuda H. . 2000 Biochem Biophys Res Commun 270: 1093–1096.
Ohh M, Park CW, Ivan M, Hoffman MA, Kim TY, Huang LE, Pavletich N, Chau V and Kaelin WG. . 2000 Nat. Cell Biol. 2: 423–427.
Pagano M, Tam SW, Theodoras AM, Beer-Romero P, Del Sal G, Chau V, Yew PR, Draetta GF and Rolfe M. . 1995 Science 269: 682–685.
Pause A, Lee S, Lonergan KM and Klausner RD. . 1998 Proc. Natl. Acad. Sci. USA 95: 993–998.
Ramaswamy S, Nakamura N, Vazquez F, Batt DB, Perera S, Roberts TM and Sellers WR. . 1999 Proc. Natl. Acad. Sci. USA 96: 2110–2115.
Schoenfeld A, Davidowitz EJ and Burk RD. . 1998 Proc. Natl. Acad. Sci. USA 95: 8817–8822.
Shieh SY, Ikeda M, Taya Y and Prives C. . 1997 Cell 91: 325–334.
Shieh SY, Taya Y and Prives C. . 1999 EMBO J. 18: 1815–1823.
Siliciano JD, Canman CE, Taya Y, Sakaguchi K, Appella E and Kastan MB. . 1997 Genes Dev. 11: 3471–3481.
Acknowledgements
This work was supported in part by a grant from the VHL Family Alliance. AR Schoenfeld was supported by a National Institutes of Health training grant (CA 09060). EJ Davidowitz was supported by a National Institutes of Health training grant (DK 07218).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Schoenfeld, A., Parris, T., Eisenberger, A. et al. The von Hippel-Lindau tumor suppressor gene protects cells from UV-mediated apoptosis. Oncogene 19, 5851–5857 (2000). https://doi.org/10.1038/sj.onc.1203985
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1203985
Keywords
This article is cited by
-
The uremic toxin p-cresyl sulfate induces proliferation and migration of clear cell renal cell carcinoma via microRNA-21/ HIF-1α axis signals
Scientific Reports (2019)
-
RalBP1 and p19-VHL play an oncogenic role, and p30-VHL plays a tumor suppressor role during the blebbishield emergency program
Cell Death Discovery (2017)
-
Differential effects of HIF-α isoforms on apoptosis in renal carcinoma cell lines
Cancer Cell International (2015)
-
Von Hippel-Lindau syndrome: molecular mechanisms of the disease
Clinical and Translational Oncology (2010)
-
Differences in regulation of tight junctions and cell morphology between VHL mutations from disease subtypes
BMC Cancer (2009)