Mdm2-mediated NEDD8 Modification of TAp73 Regulates Its Transactivation Function

Mutations in p73 are rare in cancer. Emerging evidence suggests that the relative expression of various p73 isoforms may contribute to tumorigenesis. Alternative promoters and N-terminal splicing result in the transcription and processing of either full-length (TA) or N-terminally truncated (ΔN) p73 isoforms. TAp73 possesses pro-apoptotic functions, while ΔNp73 has anti-apoptotic properties via functional inhibition of TAp73 and p53. Here, we report that TAp73, but not ΔNp73, is covalently modified by NEDD8 under physiologic conditions in an Mdm2-dependent manner. Co-expression of NEDP1, a cysteine protease that specifically cleaves NEDD8 conjugates, was shown to deneddylate TAp73. In addition, blockage of the endogenous NEDD8 pathway increased TAp73-mediated transactivation of p53- and p73-responsive promoter-driven reporter activity, and in conjunction, neddylated TAp73 species were found preferentially in the cytoplasm. These results suggest that Mdm2 attenuates TAp73 transactivation function, at least in part, by promoting NEDD8-dependent TAp73 cytoplasmic localization and provide the first evidence of a covalent post-translational modification exclusively targeting the TA isoforms of p73. Mutations in p73 are rare in cancer. Emerging evidence suggests that the relative expression of various p73 isoforms may contribute to tumorigenesis. Alternative promoters and N-terminal splicing result in the transcription and processing of either full-length (TA) or N-terminally truncated (ΔN) p73 isoforms. TAp73 possesses pro-apoptotic functions, while ΔNp73 has anti-apoptotic properties via functional inhibition of TAp73 and p53. Here, we report that TAp73, but not ΔNp73, is covalently modified by NEDD8 under physiologic conditions in an Mdm2-dependent manner. Co-expression of NEDP1, a cysteine protease that specifically cleaves NEDD8 conjugates, was shown to deneddylate TAp73. In addition, blockage of the endogenous NEDD8 pathway increased TAp73-mediated transactivation of p53- and p73-responsive promoter-driven reporter activity, and in conjunction, neddylated TAp73 species were found preferentially in the cytoplasm. These results suggest that Mdm2 attenuates TAp73 transactivation function, at least in part, by promoting NEDD8-dependent TAp73 cytoplasmic localization and provide the first evidence of a covalent post-translational modification exclusively targeting the TA isoforms of p73. p73 is a member of the p53 family that binds p53 DNA-binding sites, transactivates p53-target genes, and induces apoptosis (1Jost C.A. Marin M.C. Kaelin Jr., W.G. Nature. 1997; 389: 191-194Crossref PubMed Scopus (903) Google Scholar, 2Kaghad M. Bonnet H. Yang A. Creancier L. Biscan J.-C. Valent A. Minty A. Chalon P. Lelias J.-M. Dumont X. Ferrara P. McKeon F. Caput D. Cell. 1997; 90: 809-819Abstract Full Text Full Text PDF PubMed Scopus (1539) Google Scholar, 3Marin M.C. Jost C. Irwin M.S. DeCaprio J.A. Caput D. Kaelin W.G. Mol. Cell. Biol. 1998; 18: 6316-6324Crossref PubMed Scopus (174) Google Scholar). p73 mutations are rarely observed in cancer (4Irwin M.S. Miller F.D. Cell Death Differ. 2004; 11: S17-S22Crossref PubMed Scopus (17) Google Scholar). However, p73 exists as multiple C-terminal (α, β, γ, δ, ϵ, and ζ) and N-terminal (TA and ΔN) isoforms, and accumulating evidence suggests that the relative expression and stability of the different N-terminal isoforms of p73 may play a role in tumorigenesis. Full-length TAp73 3The abbreviations used are: TAp73, full-length p73; ΔNp73, N-terminally truncated p73; Mdm2, murine double minute 2; Hdm2, human double minute 2; NEDD8, neural precursor cell-expressed developmentally downregulated 8; HEK293, human embryonic kidney 293; CHO, Chinese hamster ovary; HA, hemagglutinin; E1, activating enzyme; E2, conjugating protein; E3, protein isopeptide ligase. isoforms have pro-apoptotic properties, whereas the N-terminally truncated ΔNp73 isoforms, which lack the transactivation domain due to the use of a promoter within intron 3 and alternative N-terminal mRNA splicing, have anti-apoptotic properties. ΔNp73 acts as a negative inhibitor of both TAp73 and p53, either via hetero-oligomerization or through competition for DNA-binding sites (5Ishimoto O. Kawahara C. Enjo K. Obinata M. Nukiwa T. Ikawa S. Cancer Res. 2002; 62: 636-641PubMed Google Scholar, 6Nakagawa T. Takahashi M. Ozaki T. Watanabe Ki K. Todo S. Mizuguchi H. Hayakawa T. Nakagawara A. Mol. Cell. Biol. 2002; 22: 2575-2585Crossref PubMed Scopus (174) Google Scholar, 7Pozniak C.D. Radinovic S. Yang A. McKeon F. Kaplan D.R. Miller F.D. Science. 2000; 289: 304-306Crossref PubMed Scopus (416) Google Scholar, 8Stiewe T. Theseling C.C. Putzer B.M. J. Biol. Chem. 2002; 277: 14177-14185Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar, 9Yang A. Walker N. Bronson R. Kaghad M. Oosterwegel M. Bonnin J. Vagner C. Bonnet H. Dikkes P. Sharpe A. McKeon F. Caput D. Nature. 2000; 404: 99-103Crossref PubMed Scopus (888) Google Scholar, 10Zaika A.I. Slade N. Erster S.H. Sansome C. Joseph T.W. Pearl M. Chalas E. Moll U.M. J. Exp. Med. 2002; 196: 765-780Crossref PubMed Scopus (305) Google Scholar). Furthermore, ΔNp73 expression has been shown to be elevated in a number of human cancers, including breast, ovarian, hepatocellular, prostate, colon, and neuroblastoma tumors (11Concin N. Becker K. Slade N. Erster S. Mueller-Holzner E. Ulmer H. Daxenbichler G. Zeimet A. Zeillinger R. Marth C. Moll U.M. Cancer Res. 2004; 64: 2449-2460Crossref PubMed Scopus (132) Google Scholar, 12Dominguez G. Garcia J.M. Pena C. Silva J. Garcia V. Martinez L. Maximiano C. Gomez M.E. Rivera J.A. Garcia-Andrade C. Bonilla F. J. Clin. Oncol. 2006; 24: 805-815Crossref PubMed Scopus (112) Google Scholar, 13Douc-Rasy S. Barrois M. Echeynne M. Kaghad M. Blanc E. Raguenez G. Goldschneider D. Terrier-Lacombe M.J. Hartmann O. Moll U. Caput D. Benard J. Am. J. Pathol. 2002; 160: 631-639Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar, 14Guan M. Chen Y. J. Clin. Pathol. 2005; 58: 1175-1179Crossref PubMed Scopus (33) Google Scholar, 15Putzer B.M. Tuve S. Tannapfel A. Stiewe T. Cell Death Differ. 2003; 10: 612-614Crossref PubMed Scopus (40) Google Scholar). Increased ΔNp73 expression has been associated with poor prognosis in patients, and this finding has been attributed to ΔNp73 inhibition of p53 and TAp73 causing chemoresistance (10Zaika A.I. Slade N. Erster S.H. Sansome C. Joseph T.W. Pearl M. Chalas E. Moll U.M. J. Exp. Med. 2002; 196: 765-780Crossref PubMed Scopus (305) Google Scholar, 12Dominguez G. Garcia J.M. Pena C. Silva J. Garcia V. Martinez L. Maximiano C. Gomez M.E. Rivera J.A. Garcia-Andrade C. Bonilla F. J. Clin. Oncol. 2006; 24: 805-815Crossref PubMed Scopus (112) Google Scholar, 16Casciano I. Mazzocco K. Boni L. Pagnan G. Banelli B. Allemanni G. Ponzoni M. Tonini G.P. Romani M. Cell Death Differ. 2002; 9: 246-251Crossref PubMed Scopus (186) Google Scholar, 17Concin N. Hofstetter G. Berger A. Gehmacher A. Reimer D. Watrowski R. Tong D. Schuster E. Hefler L. Heim K. Mueller-Holzner E. Marth C. Moll U.M. Zeimet A.G. Zeillinger R. Clin. Cancer Res. 2005; 11: 8372-8383Crossref PubMed Scopus (90) Google Scholar). Conversely, a recent study demonstrated that aged p73 heterozygous mice develop spontaneous tumors, and in comparison with p53 heterozygous mice, mice heterozygous for both p53 and p73 have different tumor spectrums and higher tumor burden and incidence of metastasis, presumably due to the loss of function of the pro-apoptotic TAp73 isoforms (18Flores E.R. Sengupta S. Miller J.B. Newman J.J. Bronson R. Crowley D. Yang A. McKeon F. Jacks T. Cancer Cell. 2005; 7: 363-373Abstract Full Text Full Text PDF PubMed Scopus (425) Google Scholar). Studies have also established a role for TAp73 in chemotherapy-induced apoptosis and the status of TAp73 may be an important determinant of chemotherapeutic efficacy in humans (17Concin N. Hofstetter G. Berger A. Gehmacher A. Reimer D. Watrowski R. Tong D. Schuster E. Hefler L. Heim K. Mueller-Holzner E. Marth C. Moll U.M. Zeimet A.G. Zeillinger R. Clin. Cancer Res. 2005; 11: 8372-8383Crossref PubMed Scopus (90) Google Scholar, 19Irwin M.S. Kondo K.K. Marin M.C. Cheng L.S. Hahn W.C. Kaelin W.G. Cancer Cell. 2003; 3: 403-410Abstract Full Text Full Text PDF PubMed Scopus (366) Google Scholar, 20Muller M. Schilling T. Sayan A.E. Kairat A. Lorenz K. Schulze-Bergkamen H. Oren M. Koch A. Tannapfel A. Stremmel W. Melino G. Krammer P.H. Cell Death Differ. 2005; 12: 1564-1577Crossref PubMed Scopus (165) Google Scholar). Therefore, therapeutic modulation of the relative levels of TAp73 and ΔNp73 isoforms has potential therapeutic benefits in treating human cancers. The RING finger E3 ligase Mdm2 is one of the major regulators of p53. Mdm2 promotes ubiquitination of p53 on multiple C-terminal lysines resulting in its degradation via the 26S proteasome (21Haupt Y. Maya R. Kazaz A. Oren M. Nature. 1997; 387: 296-299Crossref PubMed Scopus (3750) Google Scholar, 22Honda R. Tanaka H. Yasuda H. FEBS Lett. 1997; 420: 25-27Crossref PubMed Scopus (1604) Google Scholar, 23Kubbutat M. Jones S. Vousden K. 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Cell. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). of the post-translational that p53 function, as and and regulators and p73 A. P. N. M. V. G. M. L. G. C. M. Mol. Cell. 2002; 9: Full Text Full Text PDF PubMed Scopus Google Scholar, S. C. C. Mol. Cell. Biol. 2003; 23: PubMed Scopus Google Scholar, E. D. A. C. A. Melino G. V. Mol. Cell. Biol. 2004; 24: PubMed Scopus Google Scholar). In addition, regulators of p73 have been as the E3 and K. Ozaki T. C. T. T. S. Watanabe K. T. Nakagawara A. Res. 2003; PubMed Scopus Google Scholar, M. V. E. D.R. Vousden G. Melino G. J. 2005; 24: PubMed Scopus Google Scholar). The role of Mdm2 in the of TAp73 is but also Mdm2 not the degradation of TAp73 but TAp73 E. S. Vousden Oncogene. 18: PubMed Scopus Google Scholar, K. L.S. Biol. 9: Full Text Full Text PDF PubMed Scopus Google Scholar, X. Chen L. Jost C.A. Maya R. D. X. Kaelin Jr., W.G. Oren M. Chen J. H. Mol. Cell. Biol. PubMed Scopus Google Scholar). The of TAp73 is TAp73 a functional and Mdm2 was shown to the of TAp73 J. L. H. Cancer Res. Google Scholar, T. J. R. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar, E. Vousden Mol. Cell. Biol. PubMed Scopus Google Scholar, X. T. A. K. FEBS Lett. PubMed Scopus Google Scholar). Mdm2 both TAp73-mediated transactivation and apoptosis E. S. Vousden Oncogene. 18: PubMed Scopus Google Scholar, X. Chen L. Jost C.A. Maya R. D. X. Kaelin Jr., W.G. Oren M. Chen J. H. Mol. Cell. Biol. PubMed Scopus Google Scholar, M. S. C. J. Oncogene. 18: PubMed Scopus Google Scholar). In Mdm2 was shown to the function of TAp73 by its with X. Chen L. Jost C.A. Maya R. D. X. Kaelin Jr., W.G. Oren M. Chen J. H. Mol. Cell. Biol. PubMed Scopus Google Scholar). However, the associated with the various properties of of p73 and post-translational that the TA and isoforms of p73 have been Here, we that TAp73 is covalently modified by NEDD8 in an Mdm2-dependent manner. The ΔNp73 which not the N-terminal to be modified by NEDD8 and the cysteine protease NEDP1, which specifically cleaves neddylated the of TAp73. an NEDD8 pathway TAp73 in Chinese hamster and Mdm2 cytoplasmic localization of provide a NEDD8-dependent of TAp73. In addition, to this is the first evidence of p73 via covalent post-translational modification exclusively targeting the TAp73 human embryonic kidney and were and in modified with at in a The and were as J. M. J. Cell. PubMed Scopus Google Scholar). and were and was was was M.C. Jost C. Irwin M.S. DeCaprio J.A. Caput D. Kaelin W.G. Mol. Cell. Biol. 1998; 18: 6316-6324Crossref PubMed Scopus (174) Google Scholar). was was was were a of the of murine p73. were and at and were and were J. J.M. Kaelin Jr., W.G. M. Mol. Cell. Biol. 2004; 24: PubMed Scopus Google Scholar). The was by The and were and by Melino V. A. D. A. M. M. M. Melino G. J. Exp. Med. 1998; PubMed Scopus Google and C.D. Radinovic S. Yang A. McKeon F. Kaplan D.R. Miller F.D. Science. 2000; 289: 304-306Crossref PubMed Scopus (416) Google Scholar). The and were T. Hay C. A. Chen J. B. Hay R.T. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). was by P. D.P. Hay R.T. Lane D.P. Cell. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). and reporter were M.C. Jost C.A. Irwin M.S. J. J.A. N. J.M. C.A. Vousden M.J. B. Ikawa S. T. Kaelin Jr., W.G. 2000; PubMed Scopus Google Scholar). The reporter that p53 DNA-binding sites of the and the reporter that p53 DNA-binding sites of the were by and in were by and by The were with in and in 3 3 and with protease The were at for by at for to were by and were with in for the and were as M.C. Jost C. Irwin M.S. DeCaprio J.A. Caput D. Kaelin W.G. Mol. Cell. Biol. 1998; 18: 6316-6324Crossref PubMed Scopus (174) Google Scholar). were with the for at with protein were with by in and by were to for were with and by at at for 3 were in of and with protease a on the was by at for at and the cytoplasmic was The was with The was in of 3 and on for while The was at for at were by and were as and were with of or of either or reporter and of In and were in the of was with either or of were at and were either at or to for an were with of or in with of and of by an of at The of was to an and were to the on a by NEDD8 via promotes NEDD8 conjugation of p53 to its D.P. Hay R.T. Lane D.P. Cell. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). p73 is to a similar NEDD8-dependent mediated by were with in with and human Mdm2 were with on and by with and were in with and and These modified were in with and As of and in the of not modified and Therefore, the forms of both and that covalently to in the of Hdm2, of and similar and under In a was by species both and were the that is modified by and were in the of not that the modified is by NEDD8, were with in with and were with on and by with and species both and NEDD8 were observed and with results suggest that Mdm2 promotes covalent modification by is a cysteine protease that specifically cleaves NEDD8 on which are the of E3 ligase C. A. Chen J. B. Hay R.T. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). In addition, NEDP1, but not enzymes was shown to specifically deneddylate p53 D.P. Hay R.T. Lane D.P. Cell. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). In a we the of were with Hdm2, or and or As shown in was modified by in the of However, of NEDP1, but not the the of and In addition, expression of which the C-terminal for the of the isopeptide in the loss of the modified results suggest is specifically modified by NEDD8 and by binds to the within the of p53. In and with and are for to Mdm2 A. V. C. P. W. K. Lane D.P. J. Mol. Biol. 1997; PubMed Scopus Google Scholar, P.H. S. V. B. J. Science. PubMed Scopus Google Scholar). These are in the of TA isoforms of p73 M. Bonnet H. Yang A. Creancier L. Biscan J.-C. Valent A. Minty A. Chalon P. Lelias J.-M. Dumont X. Ferrara P. McKeon F. Caput D. Cell. 1997; 90: 809-819Abstract Full Text Full Text PDF PubMed Scopus (1539) Google Scholar). Therefore, we the that the is of modified by were with or in with and were with an and with or was neddylated and was NEDD8 conjugation to the and These results suggest that of TAp73 is on its of p73 under of p73 in the of were under with an or a and with and As multiple endogenous p73 were the of various and C-terminal p73 isoforms a protein both and was observed and results were observed an the of TAp73 in with the the modified forms of p73 are most the full-length TA isoforms. In addition, a by an a protein species both NEDD8 and p73 not physiologic in the of a p73 protein NEDD8 was the for this is is due to the in the of the various of the NEDD8 and p73 under physiologic conditions and The results that Mdm2 promotes NEDD8 modification of the functional of we used a with a in the hamster of human a of the E1 to an NEDD8 pathway J. M. J. Cell. PubMed Scopus Google Scholar). The were with either p53 or with a reporter that multiple sites of the or a promoter-driven reporter were at either the or The to the increased the of as demonstrated by the elevated and reporter and but a on the which of the not of p53 was shown to its D.P. Hay R.T. Lane D.P. Cell. 2004; Full Text Full Text PDF PubMed Scopus Google and as a similar in the reporter was observed with p53 of the NEDD8 pathway Furthermore, we not a in the of in the and that the in in was not to the In a of in in a at the and expression of and in both and as by reporter These results suggest that an NEDD8 pathway attenuates TAp73 NEDD8 of the localization of neddylated as a potential by which of its transactivation were with in with and or As Mdm2 TAp73 via an K. L.S. Biol. 9: Full Text Full Text PDF PubMed Scopus Google Scholar, X. Chen L. Jost C.A. Maya R. D. X. Kaelin Jr., W.G. Oren M. Chen J. H. Mol. Cell. Biol. PubMed Scopus Google Scholar). Therefore, were with higher of as with with and to levels of The cytoplasmic and were and with an as as and for of of or in with and in the of neddylated and in the of and was and preferentially in the The of was also higher in the cytoplasmic In addition, the cytoplasmic expression of was neddylated was not in with and These results suggest that Mdm2 may its on activity, at least in part, by promoting cytoplasmic localization via NEDD8 conjugation of and the that the of is due to the higher expression of in the cytoplasm. we have also observed increased of in the of Hdm2, and is that of has a role in have demonstrated of Mdm2 on TAp73 Mdm2 the to the and expression of the protein was found in the X. T. A. K. FEBS Lett. PubMed Scopus Google Scholar). In addition, to the and was observed in the of Mdm2 expression J. L. H. Cancer Res. Google Scholar). However, were not in the of evidence suggests that relative expression and stability of the different isoforms of p73 may contribute to a role in tumor A. M. P. Oren M. Melino G. F. Res. 2005; PubMed Scopus Google Scholar). TAp73 isoforms an N-terminal transactivation domain that is in the isoforms to the use of an alternative promoter within intron 3 or alternative N-terminal both the TA and isoforms p53 DNA-binding sites, TA isoforms promoters of p53-target and apoptosis (1Jost C.A. Marin M.C. Kaelin Jr., W.G. Nature. 1997; 389: 191-194Crossref PubMed Scopus (903) Google Scholar, 3Marin M.C. Jost C. Irwin M.S. DeCaprio J.A. Caput D. Kaelin W.G. Mol. Cell. Biol. 1998; 18: 6316-6324Crossref PubMed Scopus (174) Google Scholar, 8Stiewe T. Theseling C.C. Putzer B.M. J. Biol. Chem. 2002; 277: 14177-14185Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar, 10Zaika A.I. Slade N. Erster S.H. Sansome C. Joseph T.W. Pearl M. Chalas E. Moll U.M. J. Exp. Med. 2002; 196: 765-780Crossref PubMed Scopus (305) Google Scholar). The isoforms as for TA isoforms of p53 family by that an or by for sites (5Ishimoto O. Kawahara C. Enjo K. Obinata M. Nukiwa T. Ikawa S. Cancer Res. 2002; 62: 636-641PubMed Google Scholar, 6Nakagawa T. Takahashi M. Ozaki T. Watanabe Ki K. Todo S. Mizuguchi H. Hayakawa T. Nakagawara A. Mol. Cell. Biol. 2002; 22: 2575-2585Crossref PubMed Scopus (174) Google Scholar, 7Pozniak C.D. Radinovic S. Yang A. McKeon F. Kaplan D.R. Miller F.D. Science. 2000; 289: 304-306Crossref PubMed Scopus (416) Google Scholar, 8Stiewe T. Theseling C.C. Putzer B.M. J. Biol. Chem. 2002; 277: 14177-14185Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar, 9Yang A. Walker N. Bronson R. Kaghad M. Oosterwegel M. Bonnin J. Vagner C. Bonnet H. Dikkes P. Sharpe A. McKeon F. Caput D. Nature. 2000; 404: 99-103Crossref PubMed Scopus (888) Google Scholar, 10Zaika A.I. Slade N. Erster S.H. Sansome C. Joseph T.W. Pearl M. Chalas E. Moll U.M. J. Exp. Med. 2002; 196: 765-780Crossref PubMed Scopus (305) Google Scholar). As a the anti-apoptotic isoforms chemotherapy-induced apoptosis in tumor that p53 T. Theseling C.C. Putzer B.M. J. Biol. Chem. 2002; 277: 14177-14185Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar, 10Zaika A.I. Slade N. Erster S.H. Sansome C. Joseph T.W. Pearl M. Chalas E. Moll U.M. J. Exp. Med. 2002; 196: 765-780Crossref PubMed Scopus (305) Google Scholar). In addition, elevated expression of isoforms have been associated with tumor poor and increased cancer (10Zaika A.I. Slade N. Erster S.H. Sansome C. Joseph T.W. Pearl M. Chalas E. Moll U.M. J. Exp. Med. 2002; 196: 765-780Crossref PubMed Scopus (305) Google Scholar, 12Dominguez G. Garcia J.M. Pena C. Silva J. Garcia V. Martinez L. Maximiano C. Gomez M.E. Rivera J.A. Garcia-Andrade C. Bonilla F. J. Clin. Oncol. 2006; 24: 805-815Crossref PubMed Scopus (112) Google Scholar, 16Casciano I. Mazzocco K. Boni L. Pagnan G. Banelli B. Allemanni G. Ponzoni M. Tonini G.P. Romani M. Cell Death Differ. 2002; 9: 246-251Crossref PubMed Scopus (186) Google Scholar, 17Concin N. Hofstetter G. Berger A. Gehmacher A. Reimer D. Watrowski R. Tong D. Schuster E. Hefler L. Heim K. Mueller-Holzner E. Marth C. Moll U.M. Zeimet A.G. Zeillinger R. Clin. Cancer Res. 2005; 11: 8372-8383Crossref PubMed Scopus (90) Google Scholar). The tumor role for TAp73 has been by the that TAp73 is by a of chemotherapeutic R. G. Oren M. Y. Nature. PubMed Scopus Google Scholar, J. A. Yang H. Melino G. Kaelin W.G. M. J. Nature. PubMed Scopus Google Scholar, H. T. X. J. Y. H. S. R. D. Nature. PubMed Scopus Google and that TAp73 function to chemoresistance M.S. Kondo K.K. Marin M.C. Cheng L.S. Hahn W.C. Kaelin W.G. Cancer Cell. 2003; 3: 403-410Abstract Full Text Full Text PDF PubMed Scopus (366) Google Scholar, D. M. L. A. N. G. I. M. G. A. M. O. B. V. M. P. X. T. Cancer Cell. 2003; 3: Full Text Full Text PDF PubMed Scopus Google and of N. Cancer Cell. 2006; 9: Full Text Full Text PDF PubMed Scopus Google Scholar). the role of p73 in may in the relative expression of TA and isoforms. However, post-translational the expression of TA and ΔNp73 isoforms have to be Here, we report the first evidence of a covalent post-translational exclusively targeting the TA of p73. have demonstrated that but not is covalently modified by NEDD8 in an Mdm2-dependent manner. The of is due to the of the domain within the In addition, a cysteine protease neddylated and an NEDD8 pathway in Furthermore, the expression of Mdm2 with NEDD8, but not with a of in the cytoplasm. These suggest that of via Mdm2 may its on activity, at least in part, by its Mdm2 is one of the major regulators of p53 stability via the Mdm2, promoting the degradation of TAp73, TAp73 E. S. Vousden Oncogene. 18: PubMed Scopus Google Scholar, K. L.S. Biol. 9: Full Text Full Text PDF PubMed Scopus Google Scholar, X. Chen L. Jost C.A. Maya R. D. X. Kaelin Jr., W.G. Oren M. Chen J. H. Mol. Cell. Biol. PubMed Scopus Google Scholar). The of TAp73 is have increased levels of expression of Mdm2 NEDD8 and not to that of TAp73 not in of TAp73 but also in its F. P. A. M. Melino G. J. Exp. Med. 2004; PubMed Scopus Google have shown that under the in a role of the NEDD8 pathway in the of In the of are to that may increased of TAp73 is associated with transactivation function of TAp73. The of Mdm2 to the N-terminal transactivation domain of to the N-terminal transactivation domain by Mdm2 may TAp73 X. Chen L. Jost C.A. Maya R. D. X. Kaelin Jr., W.G. Oren M. Chen J. H. Mol. Cell. Biol. PubMed Scopus Google Scholar). Furthermore, is that Mdm2 NEDD8 modification of lysyl and which are of by A. P. N. M. V. G. M. L. G. C. M. Mol. Cell. 2002; 9: Full Text Full Text PDF PubMed Scopus Google Scholar). are multiple of TAp73 mediated by The of the that the various post-translational and the that the function of TAp73 are that to be the of the Irwin and and and for and also in the of at the of for with

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