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UFD2a mediates the proteasomal turnover of p73 without promoting p73 ubiquitination

Abstract

p73 protein level is kept extremely low in mammalian cultured cells and its stability may be regulated by not only the ubiquitin/proteasome-dependent proteolysis but also through other unidentified mechanisms. Here, we found for the first time that p73 is physically as well as functionally associated with the U-box-type E3/E4 ubiquitin ligase UFD2a. The immunoprecipitation experiments demonstrated that this interaction is mediated by the COOH-terminal region of p73α containing SAM domain. During the cisplatin-induced apoptosis in SH-SY5Y neuroblastoma cells, p73α accumulated at a protein level, whereas the endogenous UFD2a was significantly reduced in response to cisplatin. Ectopic expression of UFD2a decreased the half-life of p73α in association with a significant inhibition of the p73α-mediated transactivation as well as proapoptotic activity. Downregulation of endogenous UFD2a by antisense strategy resulted in a remarkable accumulation of p73α. Unexpectedly, UFD2a-mediated degradation of p73α was sensitive to the proteasomal inhibitor, however, UFD2a did not affect the ubiquitination levels of p73α. Taken together, our present findings imply that UFD2a might promote the proteasomal turnover of p73 in a ubiquitination-independent manner, and also suggest that UFD2a might play an important role in the regulation of cisplatin-induced apoptosis mediated by p73.

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References

  • Agami R, Blandino G, Oren M and Shaul Y . (1999). Nature, 399, 809–813.

  • Balint E, Bates S and Vousden KH . (1999). Oncogene, 18, 3923–3929.

  • Bernassola F, Salomoni P, Oberst A, Di Como CJ, Pagano M, Melino G and Pandolfi PP . (2004). J. Exp. Med., 199, 1545–1557.

  • Chi SM, Ayed A and Arrowsmith OH . (1999). EMBO J., 16, 4438–4445.

  • Coffino P . (2001). Nat. Rev. Mol. Cell Biol., 2, 188–194.

  • De Laurenzi V, Costanzo A, Barcaroli D, Torrinoni A, Falcico M, Annicchiarico-Petruzzelli M, Levrero M and Melino G . (1998). J. Exp. Med., 188, 1763–1768.

  • Gong J, Costanzo A, Yang HQ, Melino G, Kaelin WG, Levrero M and Wang JYJ . (1999). Nature, 399, 806–809.

  • Grob TJ, Novak U, Maisse C, Barcaroli D, Luthi AU, Pirnia F, Hugh B, Graber HU, De Laurenzi V, Fey MF, Mehino G and Tobler A . (2001). Cell Death Differ., 8, 1213–1223.

  • Hatakeyama H, Yada M, Matsumoto M, Ishida N and Nakayama KI . (2001). J. Biol. Chem., 276, 33111–33120.

  • Jin Y, Lee H, Zeng SX, Dai MS and Lu H . (2003). EMBO J., 22, 6365–6377.

  • Jost CA, Mann MC and Kaehin WG . (1997). Nature, 389, 191–194.

  • Kaghad M, Bonnet H, Yang A, Creancier L, Biscan JC, Valent A, Minty A, Chalon P, Lehias JM, Dumont X, Ferrara P, McKeon F and Caput D . (1997). Cell, 90, 809–819.

  • Kaneko C, Hatakeyama S, Matsumoto M, Yada M, Nakayama K and Nakayama KI . (2003). Biochem.Biophys. Res. Commun., 300, 297–304.

  • Koegl M, Hoppe T, Schlenker S, Ulrich HD, Mayer TU and Jentsch S . (1999). Cell, 96, 635–644.

  • Lee OW and La Thangue NB . (1999). Oncogene, 18, 4171–4181.

  • Leng RP, Lin Y, Ma W, Wu H, Lemmers B, Chung S, Parant JM, Lozano G, Hakem R and Benchimol S . (2003). Cell, 112, 779–791.

  • Mahoney JA, Odin JA, White SM, Shaffer D, Koff A, Casciola-Rosen L and Rosen A . (2002). Biochem. J., 361, 587–595.

  • Melino G, De Laurenzi V and Vousden KH . (2002). Nat. Rev. Cancer, 2, 605–615.

  • Murakami Y, Matsufuji S, Kameji T, Hayashi S, Igarashi K, Tamura T, Tanaka K and Ichihara A . (1992). Nature, 360, 597–599.

  • Nakagawa T, Takahashi M, Ozaki T, Watanabe K, Todo S, Mizuguchi H, Hayakawa T and Nakagawara A . (2002). Mol.Cell.Biol., 22, 2575–2585.

  • Nakamura Y, Ozaki T, Nakagawara A and Sakiyama S . (1997). Eur. J. Cancer, 33, 1986–1990.

  • Ohira M, Kageyama H, Mihara M, Furuta S, Machida T, Shishikura T, Takayasa H, Islam A, Nakamura Y, Takahashi M, Tomioka M, Sakiyama S, Kaneko Y, Toyoda A, Hattori M, Sakaki Y, Ohki M, Horii A, Soeda E, Inazawa J, Seki N, Kuma H, Nozawa I and Nakagawara A . (2000). Oncogene, 19, 4302–4307.

  • Ohtsuka T, Ryu H, Minamishima YA, Ryo A and Lee SW . (2003). Oncogene, 22, 1678–1687.

  • Osada M, Inaba R, Shinohara H, Hagiwara M, Nakamura M and Ikawa Y . (2001). Biochem. Biophys. Res. Commun., 283, 1135–1141.

  • Ozaki T, Naka M, Takada N, Tada M, Sakiyama S and Nakagawara A . (1999). Cancer Res., 59, 5902–5907.

  • Pozniak CD, Radinovic S, Yang A, McKeon F, Kaplan DR and Miller FD . (2000). Science, 289, 304–306.

  • Ren J, Datta R, Shioya H, Li Y, Oki E, Biedermann V, Bharti A and Kufe D . (2002). J. Biol. Chem., 277, 33758–33765.

  • Rossi M, De Laurenzi V, Munarriz E, Green DR, Liu YC, Vousden KH, Cesareni G and Melino G . (2005). EMBO J., 24, 836–848.

  • Schultz J, Ponting CP, Hofmann K and Bork P . (1997). Protein Sci., 6, 249–253.

  • Serber Z, Lai HC, Yang A, Ou HD, Sigal MS, Kelly AE, Darimont BD, Duijf PHG, van Bokhoven H, McKeon F and Dotsch V . (2002). Mol. Cell. Biol., 22, 8601–8611.

  • Sheaff RJ, Singer JD, Swanger J, Smitherman M, Roberts JM and Clurman BE . (2000). Mol. Cell, 5, 403–410.

  • Stiewe T, Zimmermann S, Frilling A, Esche H and Putzer BM . (2002). Cancer Res., 62, 3598–3602.

  • Thanos CD and Bowie JU . (1999). Protein Sci., 8, 1708–1710.

  • Thanos CD, Goodwilll KE and Bowie JU . (1999). Science, 283, 833–836.

  • Tsai KKC and Yuan ZM . (2003). Cancer Res., 63, 3418–3424.

  • Ueda Y, Hijikata M, Takagi S, Chiba T and Shimotohno K . (1999). Oncogene, 18, 4993–4998.

  • Vousden KH . (2000). Cell, 103, 691–694.

  • Wu L, Zhu H, Nie L and Maki OG . (2004). Oncogene, 23, 4032–4036.

  • Xie Y and Varshavsky A . (2002). Nat. Cell Biol., 4, 1003–1007.

  • Yang A, Walker N, Bronson R, Kaghad M, Oosterwegel M, Bonnin J, Vagner C, Bonnet H, Dikkens P, Sharpe A, McKeon F and Caput D . (2000). Nature, 404, 99–103.

  • Yuan ZM, Shioya H, Ishiko T, Sun X, Gu J, Huang YY, Lu H, Kharbanda S, Weichselbaum R and Kufe D . (1999). Nature, 399, 814–817.

  • Zeng X, Chen L, Jost CA, Maya R, Keller D, Wang X, Kaelin WG, Oren M, Chen J and Lu H . (1999). Mol. Cell. Biol., 19, 3257–3266.

  • Zaika Al, Slade N, Erster SH, Sansome C, Joseph T, Pearl M, Chalas E and Moll UM . (2002). J. Exp. Med., 196, 765–780.

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Acknowledgements

We are grateful to Dr KI Nakayama for providing us with mammalian expression plasmid for FLAG-tagged mouse UFD2a and Ms Y Nakamura for assistance with DNA sequencing. This work was supported in part by a Grant-in-Aid from the Ministry of Health, Labour and Welfare for Third Term Comprehensive Control Research for Cancer, a Grant-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Culture, Sports, Science and Technology, Japan, and a Grant-in-Aid for Scientific Research from Japan Society for the Promotion of Science.

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Correspondence to Akira Nakagawara.

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Hosoda, M., Ozaki, T., Miyazaki, K. et al. UFD2a mediates the proteasomal turnover of p73 without promoting p73 ubiquitination. Oncogene 24, 7156–7169 (2005). https://doi.org/10.1038/sj.onc.1208872

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Keywords

  • E3 ligase
  • p53
  • p73
  • ubiquitin
  • UFD2a

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