Abstract
The tumor suppressor p53 locates at the key point of cell growth or apoptosis balance, and the expression level of p53 is tightly controlled by ubiquitin ligases including MDM2. Upon DNA damage stresses, p53 was accumulated and activated, leading to cell cycle arrest or apoptosis. We previously showed that Smad ubiquitylation regulatory factor 1/2 (Smurf1/2) promotes p53 degradation by interacting with and stabilizing MDM2, and consequently enhancing MDM2-mediated ubiquitylation of p53. However, it is unclear how the Smurf1-MDM2 interaction is regulated in response to DNA damage stress. Here, we show that in response to etoposide treatment Smurf1 dissociates from MDM2, resulting in MDM2 destabilization and p53 accumulation. The negative regulation of Smurf1 on apoptosis is released. Notably, this dissociation is a slow process rather than a rapid response, implicating high expression of Smurf1 might confer the resistance against p53 activation. Consistent with this notion, we observed that Smurf1/2 ligases are highly expressed in colon cancer, esophageal squamous cell carcinoma and pancreatic cancer tissues, suggesting the oncogenic tendency of Smurf1/2.
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References
Rotin D, Kumar S. Physiological functions of the HECT family of ubiquitin ligases. Nat Rev Mol Cell Biol, 2009, 10: 398–409
Pickart C M. Mechanisms underlying ubiquitylation. Annu Rev Biochem, 2001, 70: 503–533
Bernassola F, Karin M, Ciechanover A, et al. The HECT family of E3 ubiquitin ligases: Multiple players in cancer development. Cancer Cell, 2008, 14: 10–20
Kavsak P, Rasmussen R K, Causing C G, et al. Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGF beta receptor for degradation. Mol Cell, 2000, 6: 1365–1375
Wang H R, Zhang Y, Ozdamar B, et al. Regulation of cell polarity and protrusion formation by targeting RhoA for degradation. Science, 2003, 302: 1775–1779
Yamashita M, Ying S X, Zhang G, et al. Ubiquitin ligase Smurf1 controls osteoblast activity and bone homeostasis by targeting MEKK2 for degradation. Cell, 2005, 121: 101–113
Ozdamar B, Bose R, Barrios-Rodiles M, et al. Regulation of the polarity protein Par6 by TGFbeta receptors controls epithelial cell plasticity. Science, 2005, 307: 1603–1609
Yamashita M, Ying S X, Zhang G M, et al. Ubiquitin ligase Smurf1 controls osteoblast activity and bone homeostasis by targeting MEKK2 for degradation. Cell, 2005, 121: 101–113
Zhu H, Kavsak P, Abdollah S, et al. A SMAD ubiquitin ligase targets the BMP pathway and affects embryonic pattern formation. Nature, 1999, 400: 687–693
Nie J, Xie P, Liu L, et al. Smad ubiquitylation regulatory factor 1/2 (Smurf1/2) promotes p53 degradation by stabilizing the E3 ligase MDM2. J Biol Chem, 2010, 285: 22818–22830
Ryan K M, Phillips A C, Vousden K H. Regulation and function of the p53 tumor suppressor protein. Curr Opin Cell Biol, 2001, 13: 332–337
Micheau O, Solary E, Hammann A, et al. Dimanche-Boitrel, sensitization of cancer cells treated with cytotoxic drugs to Fas-mediated cytotoxicity. J Natl Cancer Inst, 1997, 89: 783–789
Wu X X, Mizutani Y, Kakehi Y, et al. Enhancement of Fas mediated apoptosis in renal cell carcinoma cells by adriamycin. Cancer Res, 2000, 60: 2912–2918
Piccart M. The role of taxanes in the adjuvant treatment of early stage breast cancer. Breast Cancer Res Treat, 2003, 79: 25–34
Hao X P, Pretlow T G, Rao J S, et al. Beta-catenin expression is altered in human colonic aberrant crypt foci. Cancer Res, 2001, 61: 8085–8088
Khosravi R, Maya R, Gottlieb T, et al. Rapid ATM-dependent phosphorylation of Mdm2 precedes p53 accumulation in response to DNA damage. Proc Natl Acad Sci USA, 1999, 96: 4973–4977
Blattner C, Tobiasch E, Litfen M, et al. DNA damage induced p53 stabilization: No indication for an involvement of p53 phosphorylation. Oncogene, 1999, 18: 1723–1732
Haupt Y, Maya R, Kazaz A, et al. Mdm2 promotes the rapid degradation of p53. Nature, 1997, 387: 296–299
Dornan D, Wertz I, Shimizu H, et al. The ubiquitin ligase COP1 is a critical negative regulator of p53. Nature, 2004, 429: 86–92
Sun L, Shi L, Li W, et al. JFK, a Kelch domain-containing F-box protein, links the SCF complex to p53 regulation. Proc Natl Acad Sci USA, 2009, 106: 10195–10200
Ciliberto A, Novak B, Tyson J J. Steady state and oscillations in the p53/Mdm2 network. Cell Cycle, 2005, 4: 488–493
Guo X, Shen S, Song S, et al. The E3 ligase Smurf1 regulates Wolfram syndrome protein stability at the endoplasmic reticulum. J Biol Chem, 2011, 286: 18037–18047
Franck T, Geoffrey M W. MDM2 and MDM4: p53 regulators as targets in anticancer therapy. Int J Biochem Cell Biol, 2007, 39: 1476–1482
Francesca B, Michael K, Aaron C, et al. The HECT family of E3 ubiquitin ligases: Multiple players in Cancer development. Cell, 2008, 14: 10–21
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Nie, J., Liu, L., Zhao, X. et al. DNA damage stress induces the dissociation of Smurf1/2 from MDM2 in a slow manner. Chin. Sci. Bull. 56, 3155–3161 (2011). https://doi.org/10.1007/s11434-011-4703-9
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DOI: https://doi.org/10.1007/s11434-011-4703-9