Abstract
Loss of the von Hippel–Lindau gene (VHL) expression ca-uses deregulation of contact inhibition of cell growth, which might be one of the bases of the tumor suppressor function of VHL. Here we show that this function of the VHL gene product (pVHL) depends on cell autonomous events. To identify the target gene of pVHL, which is directly involved in the contact inhibition, we compared the gene expression profile between VHL-deficient renal carcinoma 786-O cells and those infected with an adenovirus vector encoding VHL. In addition to known pVHL-regulated genes, such as vascular endothelial growth factor and carbonic anhydrase, we found cyclinD1 as a new target of pVHL at a high cell density. In VHL-expressing cells (VHL (+) cells), the cyclinD1 mRNA expression level diminishes at a high cell density, while it remains at a relatively high level in VHL-deficient cells (VHL (−) cells). The cyclinD1 expression level was also abnormally high in VHL (−) cells at a high cell density. Consequently, the phosporylation level of the retinoblastoma (Rb) protein remained high in these cells, whereas there was no phosporylated Rb in VHL (+) cells under the contact inhibition. The abnormal expression of cyclinD1 at a high cell density was observed even in VHL (+) cells under the hypoxic state. Moreover, ectopic expression of a HIF mutant resistant to pVHL-mediated proteolysis causes the abnormal cyclinD1 expression in VHL (+) cells. Taken together, these observations indicate that VHL is required for the downregulation of cyclinD1 at a high cell density through HIF.
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Abbreviations
- VHL:
-
von Hippel–Lindau
- CCRCC:
-
clear cell renal cell carcinoma
- VEGF:
-
vascular endothelial growth factor
- SDS–PAGE:
-
sodium dodecyl sulfate–polyacrylamide gel electrophoresis
- HIF:
-
hypoxia-inducible-factor
- Glut-1:
-
glucose transporter-1
References
Baba M, Hirai S, Kawakami S, Kishida T, Sakai N, Kaneko S, Yao M, Shuin T, Kubota Y, Hosaka M and Ohno S . (2001). Oncogene, 20, 2727–2736.
Bindra RS, Vasselli JR, Stearman R, Linehan WM and Klausner RD . (2002). Cancer Res., 62, 3014–3019.
de Paulsen N, Brychzy A, Fournier MC, Klausner RD, Gnarra JR, Pause A and Lee S . (2001). Proc. Natl. Acad. Sci. USA, 98, 1387–1392.
Ferrara N . (2002). Nat. Rev. Cancer, 2, 795–803.
Hinds PW, Dowdy SF, Eaton EN, Arnold A and Weinberg RA . (1994). Proc. Natl. Acad. Sci. USA, 91, 709–713.
Hunter T and Pines J . (1991). Cell, 66, 1071–1074.
Iizuka N, Oka M, Yamada-Okabe H, Mori N, Tamesa T, Okada T, Takemoto N, Tangoku A, Hamada K, Nakayama H, Miyamoto T, Uchimura S and Hamamoto Y . (2002). Cancer Res., 62, 3939–3944.
Iliopoulos O, Kibel A, Gray S and Kaelin Jr WG . (1995). Nat. Med., 1, 822–826.
Iliopoulos O, Levy AP, Jiang C, Kaelin Jr WG and Goldberg MA . (1996). Proc. Natl. Acad. Sci. USA, 93, 10595–10599.
Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, Salic A, Asara JM, Lane WS and Kaelin Jr WG . (2001). Science, 292, 464–468.
Ivanov SV, Kuzmin I, Wei MH, Pack S, Geil L, Johnson BE, Stanbridge EJ and Lerman MI . (1998). Proc. Natl. Acad. Sci. USA, 95, 12596–12601.
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.
Izumi Y, Hirai S, Tamai Y, Fujise-Matsuoka A, Nishimura Y and Ohno S . (1997). J. Biol. Chem., 212, 7381–7389.
Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, Kriegsheim A, Hebestreit HF, Mukherji M, Schofield CJ, Maxwell PH, Pugh CW and Ratcliffe PJ . (2001). Science, 292, 468–472.
Jacobsen K, Groth A and Willumsen BM . (2002). Oncogene, 21, 3058–3067.
Jiang W, Kahn SM, Zhou P, Zhang YJ, Cacace AM, Infante AS, Doi S, Santella RM and Weinstein IB . (1993). Oncogene, 8, 3447–3457.
Kamura T, Koepp DM, Conrad MN, Skowyra D, Moreland RJ, Iliopoulos O, Lane WS, Kaelin Jr WG, Elledge SJ, Conaway RC, Harper JW and Conaway JW . (1999). Science, 284, 657–661.
Knebelmann B, Ananth S, Cohen HT and Sukhatme VP . (1998). Cancer Res., 58, 226–231.
Kondo K and Kaelin Jr WG . (2001). Exp. Cell Res., 264, 117–125.
Kondo K, Klco J, Nakamura E, Lechpammer M and Kaelin Jr WG . (2002a). Cancer Cell, 1, 237–246.
Kondo K, Yao M, Yoshida M, Kishida T, Shuin T, Miura T, Moriyama M, Kobayashi K, Sakai N, Kaneko S, Kawakami S, Baba M, Nakaigawa N, Nagashima Y, Nakatani Y and, Hosaka M . (2002b). Genes Chromosomes Cancer, 34, 58–68.
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, Wong Y, Duan DR, Dean M, Glavao D, Richards FM, Crossey PA, Ferguson-Smith MA, Paslier DL, Chumakov I, Cohen D, Chinault C, Maher ER, Linohan WM, Zbar B and, Lerman MI . (1993). Science, 260, 1317–1320.
Lavoie JN, L'Allemain G, Brunet A, Muller R and Pouyssegur J . (1996). J. Biol. Chem., 271, 20608–20616.
Maher ER and Kaelin Jr WG . (1997). Medicine (Baltimore), 76, 381–391.
Mandriota SJ, Turner KJ, Davies DR, Murray PG, Morgan NV, Sowter HM, Wykoff CC, Maher ER, Harris AL, Ratcliffe PJ and Maxwell PH . (2002). Cancer Cell, 1, 459–468.
Matsushime H, Roussel MF, Ashmun RA and Sherr CJ . (1991). Cell, 65, 701–713.
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.
Miyake S, Makimura M, Kanegae Y, Harada S, Sato Y, Takamori K, Tokuda C and Saito I . (1996). Proc. Natl. Acad. Sci. USA, 93, 1320–1324.
Papadimitriou E and Lelkes PI . (1993). J. Immunol. Methods, 162, 41–45.
Pause A, Lee S, Worrell RA, Chen DY, Burgess WH, Linehan WM and Klausner RD . (1997). Proc. Natl. Acad. Sci. USA, 94, 2156–2161.
Quelle DE, Ashmun RA, Shurtleff SA, Kato JY, Bar-Sagi D, Roussel MF and Sherr CJ . (1993). Genes Dev., 7, 1559–1571.
Robles AI, Rodriguez-Puebla ML, Glick AB, Trempus C, Hansen L, Sicinski P, Tennant RW, Weinberg RA, Yuspa SH and Conti CJ . (1998). Genes Dev., 12, 2469–2474.
Roovers K and Assoian RK . (2000). Bioessays, 22, 818–826.
Sellers WR and Kaelin WG . (1996). Biochim. Biophys. Acta, 1288, M1–M5.
Semenza GL . (2001). Cell, 107, 1–3.
Sherr CJ . (1995). Trends Biochem. Sci., 20, 187–190.
Shuin T, Kondo K, Torigoe S, Kishida T, Kubota Y, Hosaka M, Nagashima Y, Kitamura H, Latif F, Zbar B, Lerman MI and, Yao M . (1994). Cancer Res., 54, 2852–2855.
Siemeister G, Weindel K, Mohrs K, Barleon B, Martiny-Baron G and Marme D . (1996). Cancer Res., 56, 2299–2301.
Vinals F and Pouyssegur J . (1999). Mol. Cell. Biol., 19, 2763–2772.
Weinberg RA . (1995). Cell, 81, 323–330.
Won KA, Xiong Y, Beach D and Gilman MZ . (1992). Proc. Natl. Acad. Sci. USA, 89, 9910–9914.
Yao M, Yoshida M, Kishida T, Nakaigawa N, Baba M, Kobayashi K, Miura T, Moriyama M, Nagashima Y, Nakatani Y, Kubota Y and Kondo K . (2002). J. Natl. Cancer Inst., 94, 1569–1575.
Zatyka M, da Silva NF, Clifford SC, Morris MR, Wiesener MS, Eckardt KU, Houlston RS, Richards FM, Latif F and Maher ER . (2002). Cancer Res., 62, 3803–3811.
Acknowledgements
We thank Dr William G Kaelin for 786-O cells and their VHL-expressing subclones. We also thank Y Amano for the excellent technical support.
This work was supported in part by Grants in Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture of Japan and Grants from the Japan Society for the Promotion of Science. MB received support from the Yokohama Foundation for Advancement of Medical Science, Yokohama Academic Foundation and Public Trust Haraguchi Memorial Cancer Research Fund.
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Baba, M., Hirai, S., Yamada-Okabe, H. et al. Loss of von Hippel-Lindau protein causes cell density dependent deregulation of CyclinD1 expression through Hypoxia-inducible factor. Oncogene 22, 2728–2738 (2003). https://doi.org/10.1038/sj.onc.1206373
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DOI: https://doi.org/10.1038/sj.onc.1206373
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