Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

TAp63γ (p51A) and dNp63α (p73L), two major isoforms of the p63 gene, exert opposite effects on the vascular endothelial growth factor (VEGF) gene expression

Oncogene volume 21, pages 2455–2465 (2002)Cite this article

Abstract

Tumor suppressor p53 has been shown to repress expression of vascular endothelial growth factor (VEGF), an endothelial cell-specific mitogen and a key mediator of tumor angiogenesis. The p63 gene, recently identified as a p53-relative, encodes multiple isoforms with structural and functional similarities and differences from p53. In this study, we show the evidence that the two major isoforms of the p63 gene, TAp63γ (p51A) and dNp63α (p73L), represses and upregulates VEGF expression, respectively, on transcription and protein levels. Transient transfection assays show that a hypoxia-inducible factor (HIF) 1 binding site within the VEGF promoter region is responsible for both upregulation and repression by dNp63α and by TAp63γ, respectively, of the VEGF promoter activity. We also show that TAp63γ targets HIF1α for promoting proteasomal degradation but that dNp63α targets HIF1α for stabilization. Mammalian two-hybrid assays show that HIF1α-dependent transcription is repressed by TAp63γ as well as by p53, whereas it is upregulated by dNp63α in collaboration with a transcription coactivator p300. Our data also show that dNp63α acts as a dominant-negative reagent toward both p53- and TAp63γ-mediated degradation of HIF1α and repression of HIF1α-dependent transcription. These results suggest that p63 is involved in the regulation of the VEGF gene expression and that modulation of VEGF expression by TAp63γ and dNp63α is closely correlated with their distinct roles on the regulation of HIF1α stability.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8

Similar content being viewed by others

References

  • Arany Z, Huang LE, Eckner R, Bhattacharya S, Jiang C, Goldberg MA, Bunn HF, Livingston DM . 1996 Proc. Natl. Acad. Sci. USA 93: 12969–12973

  • Blagosklonny MV, An WG, Romanova LY, Trepel J, Fojo T, Neckers L . 1998 J. Biol. Chem. 273: 11995–11998

  • Bunn HF, Poyton RO . 1996 Physiol. Rev. 76: 839–885

  • Bouvet M, Ellis LM, Nishizaki M, Fujiwara T, Liu W, Bucana CD, Fang B, Lee JJ, Roth JA . 1998 Cancer Res. 58: 2288–2292

  • Crook T, Nicholls JM, Brooks L, O'Nions J, Allday MJ . 2000 Oncogene 19: 3439–3444

  • Dohn M, Zhang S, Chen X . 2001 Oncogene 20: 3193–3205

  • Ema M, Hirota K, Mimura J, Abe H, Yodoi J, Sogawa K, Poellinger L, Fujii-Kuriyama Y . 1999 EMBO J. 18: 1905–1914

  • Finkenzeller G, Technau A, Marme D . 1995 Biochem. Biophys. Res. Commun. 208: 432–439

  • Folkman J . 1997 Tumor angiogenesis In Cancer Medicine pp 181–204 Baltimore, MD: Williams & Wilkins

    Google Scholar 

  • Fontanini G, Boldrini L, Vignati S, Chine S, Basolo F, Silvestri V, Lucchi M, Mussi A, Angeletti CA, Bevilacqua G . 1998 Eur. J. Cancer 34: 718–723

  • Forsythe JA, Jiang BH, Iyer NV, Agani F, Leung SW, Koos RD, Semenza GL . 1996 Mol. Cell. Biol. 16: 4604–4613

  • Gleadle JM, Ebert BL, Firth JD, Ratcliffe PJ . 1995 Am. J. Physiol. 268: C1362–C1368

  • Goldberg MA, Schneider TJ . 1994 J. Biol. Chem. 269: 4355–4359

  • Hibi K, Trink B, Patturajan M, Westra WH, Caballero OL, Hill DE, Ratovitski EA, Jen J, Sidransky D . 2000 Proc. Natl. Acad. Sci. USA 97: 5462–5467

  • Huang EL, Gu J, Schau M, Bunn HF . 1998 Proc. Natl. Acad. Sci. USA 95: 7987–7992

  • Ikeda E, Achen MG, Breier G, Risau W . 1995 J. Biol. Chem. 270: 19761–19766

  • Iyer NV, Kotch LE, Agani F, Leung SW, Laughner E, Wenger RH, Gassmann M, Gearhart JD, Lawler AM, Yu AY, Semenza GL . 1998 Genes Dev. 12: 149–162

  • Kallio PJ, Okamoto K, O'Brien S, Carrero P, Makino Y, Tanaka H, Pollinger L . 1998 EMBO J. 17: 6573–6586

  • Kallio PJ, Wilson WJ, O'Brien S, Makino Y, Poellinger L . 1999 J. Biol. Chem. 274: 6519–6525

  • Kanegae Y, Lee G, Sato Y, Tanaka M, Nakai M, Sakaki T, Sugano S, Saito I . 1995 Nucleic Acids Res. 23: 3816–3821

  • Kanegae Y, Takamori K, Sato Y, Lee G, Nakai M, Saito I . 1996 Gene 181: 207–212

  • Kotch LE, Iyer NV, Laughner E, Semenza GL . 1999 Dev. Biol. 209: 254–267

  • Levy AP, Levy NS, Wegner S, Goldberg MA . 1995 J. Biol. Chem. 270: 13333–13340

  • Liu Y, Cox SR, Morita T, Kourembanas S . 1995 Circ. Res. 77: 638–643

  • Martiny-Baron G, Marme D . 1995 Curr. Opin. Biotechnol. 6: 675–680

  • Mitsudomi T, Steinberg SM, Nau MM, Carbone D, D'Amico D, Bodner S, Oie HK, Linnoila RI, Mulshine JL, Minna JD, Gazdar AF . 1992 Oncogene 7: 171–180

  • Mukhopadhyay D, Tsiokas L, Sukhatme VP . 1995 Cancer Res. 55: 6161–6165

  • Nishi H, Isaka K, Sagawa Y, Usuda S, Fujito A, Ito H, Senoo M, Kato H, Takayama M . 1999 Int. J. Oncol. 15: 1149–1153

  • Nishi H, Senoo M, Nishi KH, Murphy B, Rikiyama T, Matsumura Y, Habu S, Johnson AC . 2001 J. Biol. Chem. 276: 41717–41724

  • Niwa H, Yamamura K, Miyazaki J . 1991 Gene 108: 193–200

  • Nylander K, Coates PJ, Hall PA . 2000 Int. J. Cancer 87: 368–372

  • Osada M, Ohba M, Kawahara C, Ishioka C, Kanamaru R, Katoh I, Ikawa Y, Nimura Y, Nakagawara A, Obinata M, Ikawa S . 1998 Nature Med. 4: 839–843

  • Park BJ, Lee SJ, Kim JI, Lee SJ, Lee CH, Chang SG, Park JH, Chi SG . 2000 Cancer Res. 60: 3370–3374

  • Ravi R, Mookerjee B, Bhujwalla ZM, Sutter CH, Artemov D, Zung Q, Dillehay LE, Madan A, Semenza GL, Bedi A . 2000 Genes Dev. 14: 34–44

  • Salimath B, Marme D, Finkenzeller G . 2000 Oncogene 19: 3470–3476

  • Salceda S, Caro J . 1997 J. Biol. Chem. 272: 22642–22647

  • Schmale H, Bamberger C . 1997 Oncogene 15: 1363–1367

  • Semenza GL . 1998 Curr. Opin. Genet. Dev. 8: 588–594

  • Semenza GL . 1999 Annu. Rev. Cell Dev. Biol. 15: 551–578

  • Senoo M, Seki N, Ohira M, Sugano S, Watanabe M, Inuzuka S, Okamoto T, Tachibana M, Tanaka T, Shinkai Y, Kato H . 1998 Biochem. Biophys. Res. Commun. 248: 603–607

  • Senoo M, Tsuchiya I, Matsumura Y, Mori T, Saito Y, Kato H, Okamoto H, Habu S . 2001a Br. J. Cancer 84: 1235–1241

  • Senoo M, Matsumura Y, Habu S . 2001b Biochem. Biophys. Res. Commun. 286: 628–634

  • Shima DT, Kuroki M, Deutsch U, Ng YS, Adamis AP, D'Amore PA . 1996 J. Biol. Chem. 271: 3877–3883

  • Shimada A, Kato S, Enjo K, Osada M, Ikawa Y, Kohno K, Obinata M, Kanamaru R, Ikawa S, Ishioka C . 1999 Cancer Res. 59: 2781–2786

  • Shweiki D, Itin A, Soffer D, Keshet E . 1992 Nature 359: 843–845

  • Sunahara M, Shishikura T, Takahashi M, Todo S, Yamamoto N, Kimura H, Kato S, Ishioka C, Ikawa S, Ikawa Y, Nakagawara A . 1999 Oncogene 18: 3761–3765

  • Suzuki K, Hayashi N, Miyamoto Y, Yamamoto M, Ohkawa K, Ito Y, Sasaki Y, Yamaguchi Y, Nakase H, Noda K, Enomoto K, Arai Y, Yamada H, Yoshihara T, Tujimura K, Kawano K, Yoshikawa N, Kamada T . 1996 Cancer Res. 56: 3004–3009

  • Trink B, Okami K, Wu L, Sriuranpong V, Jen J, Sidransky D . 1998 Nature Med. 4: 747–

  • Wang GL, Jiang BH, Rue EA, Semenza GL . 1995 Proc. Natl. Acad. Sci. USA 92: 5510–5154

  • Wenger RH, Gassmann M . 1997 Biol. Chem. 378: 609–616

  • Yang A, Kaghad M, Wang Y, Gillett E, Fleming MD, Dotsch V, Andrews NC, Caput D, McKeon F . 1998 Mol. Cell 2: 305–316

  • Zong H, DeMarzo AM, Laughner E, Lim M, Hilton A, Zagzag D, Buechler P, Isaacs WB, Semenza GL, Simons JW . 1999 Cancer Res. 59: 5830–5835

Download references

Acknowledgements

We thank Drs GL Semenza, PA D'Amore and S Ishii for providing the plasmids. We also thank T Matsumura for help in establishing the inducible H1299 cell lines. This work was partially supported by 2001 Tokai University School of Medicine Research Aid.

Author information

Authors and Affiliations

  1. Department of Immunology, Tokai University School of Medicine, Bouseidai, Isehara-city, Kanagawa, 259-1193, Japan

    Makoto Senoo, Yasuko Matsumura & Sonoko Habu

Authors
  1. Makoto Senoo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yasuko Matsumura
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sonoko Habu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sonoko Habu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Senoo, M., Matsumura, Y. & Habu, S. TAp63γ (p51A) and dNp63α (p73L), two major isoforms of the p63 gene, exert opposite effects on the vascular endothelial growth factor (VEGF) gene expression. Oncogene 21, 2455–2465 (2002). https://doi.org/10.1038/sj.onc.1205330

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1205330

Keywords

This article is cited by

Search

Advanced search

Quick links