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• W2085317811 abstract "p73 shares high sequence homology with the tumor suppressor p53. Like p53, ectopic overexpression of p73 induces cell cycle arrest and/or apoptosis, and these biological activities are linked to its sequence-specific transactivation function. The COOH-terminal region of p73 is unique and has a function to modulate DNA-binding ability and transactivation activity. To identify and characterize cellular proteins that interact with the COOH-terminal region of p73α and regulate its activity, we employed a yeast-based two-hybrid screen with a human fetal brain cDNA library. We found MM1, a nuclear c-Myc-binding protein, was associated with p73α in both yeast two-hybrid and in vitro pull-down assays. In mammalian cells, MM1 co-immunoprecipitated with p73α, whereas p73β and tumor suppressor p53 did not interact with MM1. Overexpression of MM1 in p53-deficient osteosarcoma SAOS-2 cells enhanced the p73α-dependent transcription from the p53/p73-responsiveBax and PG13 promoters, whereas p73β- and p53-mediated transcriptional activation was unaffected in the presence of MM1. MM1 also stimulated the p73α-mediated growth suppression in SAOS-2 cells. More importantly, we found that c-Myc was physically associated with p73α and significantly impaired the transcriptional activity of p73α on Bax and p21 waf1promoters. Expression of MM1 strongly reduced the c-Myc-mediated inhibitory activity on p73α. These results suggest that MM1 may act as a molecular partner for p73 to prevent the c-Myc-mediated inhibitory effect on its activity. p73 shares high sequence homology with the tumor suppressor p53. Like p53, ectopic overexpression of p73 induces cell cycle arrest and/or apoptosis, and these biological activities are linked to its sequence-specific transactivation function. The COOH-terminal region of p73 is unique and has a function to modulate DNA-binding ability and transactivation activity. To identify and characterize cellular proteins that interact with the COOH-terminal region of p73α and regulate its activity, we employed a yeast-based two-hybrid screen with a human fetal brain cDNA library. We found MM1, a nuclear c-Myc-binding protein, was associated with p73α in both yeast two-hybrid and in vitro pull-down assays. In mammalian cells, MM1 co-immunoprecipitated with p73α, whereas p73β and tumor suppressor p53 did not interact with MM1. Overexpression of MM1 in p53-deficient osteosarcoma SAOS-2 cells enhanced the p73α-dependent transcription from the p53/p73-responsiveBax and PG13 promoters, whereas p73β- and p53-mediated transcriptional activation was unaffected in the presence of MM1. MM1 also stimulated the p73α-mediated growth suppression in SAOS-2 cells. More importantly, we found that c-Myc was physically associated with p73α and significantly impaired the transcriptional activity of p73α on Bax and p21 waf1promoters. Expression of MM1 strongly reduced the c-Myc-mediated inhibitory activity on p73α. These results suggest that MM1 may act as a molecular partner for p73 to prevent the c-Myc-mediated inhibitory effect on its activity. p73 is a new member of the p53 gene family (1.Kaghad 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 (1533) Google Scholar). Like p53, p73 is a nuclear transcription factor, which carries an NH2-terminal transactivation domain, sequence-specific DNA-binding domain, and oligomerization domain. As expected from the significant amino acid sequence homology in the sequence-specific DNA-binding domain between p73 and p53, p73 recognizes and binds to the p53-responsive elements found within the promoter regions of the various p53-target genes. In transiently transfected mammalian cells, p73 transactivates the transcription from a variety of p53-responsive promoters to various degrees (1.Kaghad 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 (1533) Google Scholar, 2.Jost C.A. Marin M.C. Kaelin Jr., W.G. Nature. 1997; 389: 191-194Crossref PubMed Scopus (897) Google Scholar, 3.De Laurenzi V. Costanzo A. Barcaroli D. Torrinoni A. Falclco M. Annicchiarico-Petruzzelli M. Levrero M. Melino G. J. Exp. Med. 1998; 188: 1763-1768Crossref PubMed Scopus (361) Google Scholar, 4.Zhu J. Jiang J. Zhou W. Chen X. Cancer Res. 1998; 58: 5061-5065PubMed Google Scholar, 5.Di Como C.J. Gaiddon C. Prives C. Mol. Cell. Biol. 1999; 19: 1438-1449Crossref PubMed Scopus (380) Google Scholar, 6.Steegenga W.T. Shvarts A. Riteco N. Bos J.L. Jochemsen A.G. Mol. Cell. Biol. 1999; 19: 3885-3894Crossref PubMed Scopus (82) Google Scholar, 7.Fang L. Lee S.W. Aaronson S.A. J. Cell Biol. 1999; 147: 823-830Crossref PubMed Scopus (66) Google Scholar, 8.Ueda Y. Hijikata M. Takagi S. Chiba T. Shimotohno K. Oncogene. 1999; 18: 4993-4998Crossref PubMed Scopus (131) Google Scholar). Artificially introduced mutation within the DNA-binding domain has significantly reduced the transactivation activity of p73, suggesting that the structural integrity of this domain is required for this activity (1.Kaghad 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 (1533) Google Scholar, 2.Jost C.A. Marin M.C. Kaelin Jr., W.G. Nature. 1997; 389: 191-194Crossref PubMed Scopus (897) Google Scholar). Similarly to p53, the cellular transcriptional coactivator p300/CBP interacts with the NH2-terminal transactivation domain of p73, resulting in stimulation of its activity (9.Zeng X. Li X. Miller A. Yuan Z. Yuan W. Kwok R.P. Goodman R. Lu H. Mol. Cell. Biol. 2000; 20: 1299-1310Crossref PubMed Scopus (82) Google Scholar). Furthermore, ectopic overproduction of p73 induces the cell cycle arrest and/or apoptosis in p53-deficient cultured cells (1.Kaghad 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 (1533) Google Scholar, 2.Jost C.A. Marin M.C. Kaelin Jr., W.G. Nature. 1997; 389: 191-194Crossref PubMed Scopus (897) Google Scholar, 3.De Laurenzi V. Costanzo A. Barcaroli D. Torrinoni A. Falclco M. Annicchiarico-Petruzzelli M. Levrero M. Melino G. J. Exp. Med. 1998; 188: 1763-1768Crossref PubMed Scopus (361) Google Scholar, 4.Zhu J. Jiang J. Zhou W. Chen X. Cancer Res. 1998; 58: 5061-5065PubMed Google Scholar, 5.Di Como C.J. Gaiddon C. Prives C. Mol. Cell. Biol. 1999; 19: 1438-1449Crossref PubMed Scopus (380) Google Scholar, 6.Steegenga W.T. Shvarts A. Riteco N. Bos J.L. Jochemsen A.G. Mol. Cell. Biol. 1999; 19: 3885-3894Crossref PubMed Scopus (82) Google Scholar,10.Zeng X. Chen L. Jost C.A. Maya R. Keller D. Wang X. Kaelin Jr., W.G. Oren M. Chen J. Lu H. Mol. Cell. Biol. 1999; 19: 3257-3266Crossref PubMed Scopus (303) Google Scholar). Recently, it has been shown that p73 is stabilized and its apoptotic activity is enhanced in response to ionizing radiation or genotoxic agents such as cisplatin in a pathway depending on c-Abl (11.Gong J. Costanzo A. Yang H.Q. Melino G. Kaelin Jr., W.G. Levrero M. Wang J.Y.J. Nature. 1999; 399: 806-809Crossref PubMed Scopus (830) Google Scholar, 12.Agami R. Blandino G. Oren M. Shaul Y. Nature. 1999; 399: 809-813Crossref PubMed Scopus (504) Google Scholar, 13.Yuan Z.M. Shioya H. Ishiko T. Sun X. Gu J. Huang Y.Y. Lu H. Kharbanda S. Weichselbaum R. Kufe D. Nature. 1999; 399: 814-817Crossref PubMed Scopus (539) Google Scholar). In addition, the endogenous level of p73 is increased during retinoic acid-induced differentiation in cultured neuroblastoma cells, and overexpression of p73 but not p53 caused neuronal differentiation (14.De Laurenzi V. Raschella G. Barcaroli D. Annicchiarico-Petruzzelli M. Ranalli M. Catani M.V. Tanno B. Costanzo A. Levrero M. Melino G. J. Biol. Chem. 2000; 275: 15226-15231Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar). Fang et al. (7.Fang L. Lee S.W. Aaronson S.A. J. Cell Biol. 1999; 147: 823-830Crossref PubMed Scopus (66) Google Scholar) have found that overexpression of p73 induces the growth arrest and the senescence-like phenotypes in human bladder carcinoma cells.p73 is assigned to chromosome 1p36.3, which is a candidate tumor suppressor locus in a variety of human cancers (1.Kaghad 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 (1533) Google Scholar). Although p73 mimics p53 in transcriptional activation as well as induction of apoptosis, p73 is infrequently mutated in many human tumors (15.Ikawa S. Nakagawara A. Ikawa Y. Cell Death Differ. 1999; 6: 1154-1161Crossref PubMed Scopus (135) Google Scholar). In contrast to p53-knockout mice, p73 deficiency in mice did not lead to an increased susceptibility to spontaneous tumorigenesis (16.Yang 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 (878) Google Scholar). In addition, the elevated level of p73expression was detected in some primary tumors, including breast and ovarian cancers (17.Zaika A.I. Kovalev S. Marchenko N. Moll U.M. Cancer Res. 1999; 59: 3257-3263PubMed Google Scholar, 18.Chen C.L. Ip S.M. Cheng D. Wong L.C. Ngan H.Y. Clin. Cancer Res. 2000; 6: 3910-3915PubMed Google Scholar). Subsequent work from several laboratories has shown that forced expression of cellular and viral oncogenes, such as E2F-1, c-Myc, and E1A, stimulated expression of the p73 gene (19.Lissy N.A. Davis P.K. Irwin M. Kaelin Jr., W.G. Dowdy S.F. Nature. 2000; 407: 642-645Crossref PubMed Scopus (288) Google Scholar, 20.Irwin M. Marin M.C. Phillips A.C. Seelan R.S. Smith D.I. Liu W. Flores E.R. Tsai K.Y. Jacks T. Vousden K.H. Kaelin Jr., W.G. Nature. 2000; 407: 645-648Crossref PubMed Scopus (533) Google Scholar, 21.Stiewe T. Putzer B.M. Nat. Genet. 2000; 26: 464-469Crossref PubMed Scopus (307) Google Scholar, 22.Zaika A. Irwin M. Sansome C. Moll U.M. J. Biol. Chem. 2001; 276: 11310-11316Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar). Thus, there have been conflicting reports about the role of p73 in cellular function, although the reasons remain unclear.Unlike p53, p73 encodes at least six distinct isoforms (α, β, γ, δ, ε, and ζ) that are generated as a result of the alternative splicing of the primary p73transcript (1.Kaghad 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 (1533) Google Scholar, 3.De Laurenzi V. Costanzo A. Barcaroli D. Torrinoni A. Falclco M. Annicchiarico-Petruzzelli M. Levrero M. Melino G. J. Exp. Med. 1998; 188: 1763-1768Crossref PubMed Scopus (361) Google Scholar, 8.Ueda Y. Hijikata M. Takagi S. Chiba T. Shimotohno K. Oncogene. 1999; 18: 4993-4998Crossref PubMed Scopus (131) Google Scholar, 23.De Laurenzi V. Catanl M.V. Teminoni A. Corazzari M. Melino G. Costanzo A. Levrero M. Knight R.A. Cell Death Differ. 1999; 6: 389-390Crossref PubMed Scopus (131) Google Scholar). These splicing isoforms possess different COOH-terminal extensions not found in p53, and their expression patterns vary among normal tissues (3.De Laurenzi V. Costanzo A. Barcaroli D. Torrinoni A. Falclco M. Annicchiarico-Petruzzelli M. Levrero M. Melino G. J. Exp. Med. 1998; 188: 1763-1768Crossref PubMed Scopus (361) Google Scholar, 8.Ueda Y. Hijikata M. Takagi S. Chiba T. Shimotohno K. Oncogene. 1999; 18: 4993-4998Crossref PubMed Scopus (131) Google Scholar, 23.De Laurenzi V. Catanl M.V. Teminoni A. Corazzari M. Melino G. Costanzo A. Levrero M. Knight R.A. Cell Death Differ. 1999; 6: 389-390Crossref PubMed Scopus (131) Google Scholar). Intriguingly, these COOH-terminal splicing isoforms show different transcriptional and biological properties (3.De Laurenzi V. Costanzo A. Barcaroli D. Torrinoni A. Falclco M. Annicchiarico-Petruzzelli M. Levrero M. Melino G. J. Exp. Med. 1998; 188: 1763-1768Crossref PubMed Scopus (361) Google Scholar, 4.Zhu J. Jiang J. Zhou W. Chen X. Cancer Res. 1998; 58: 5061-5065PubMed Google Scholar, 5.Di Como C.J. Gaiddon C. Prives C. Mol. Cell. Biol. 1999; 19: 1438-1449Crossref PubMed Scopus (380) Google Scholar, 8.Ueda Y. Hijikata M. Takagi S. Chiba T. Shimotohno K. Oncogene. 1999; 18: 4993-4998Crossref PubMed Scopus (131) Google Scholar). Indeed, p73β transactivated a variety of the p53-responsive promoters to a greater degree than p73α (2.Jost C.A. Marin M.C. Kaelin Jr., W.G. Nature. 1997; 389: 191-194Crossref PubMed Scopus (897) Google Scholar, 3.De Laurenzi V. Costanzo A. Barcaroli D. Torrinoni A. Falclco M. Annicchiarico-Petruzzelli M. Levrero M. Melino G. J. Exp. Med. 1998; 188: 1763-1768Crossref PubMed Scopus (361) Google Scholar, 7.Fang L. Lee S.W. Aaronson S.A. J. Cell Biol. 1999; 147: 823-830Crossref PubMed Scopus (66) Google Scholar, 8.Ueda Y. Hijikata M. Takagi S. Chiba T. Shimotohno K. Oncogene. 1999; 18: 4993-4998Crossref PubMed Scopus (131) Google Scholar, 24.Dobbelstein M. Wienzek S. Konig C. Roth J. Oncogene. 1999; 18: 2101-2106Crossref PubMed Scopus (144) Google Scholar, 25.Lee C.-W. La Thangue N.B. Oncogene. 1999; 18: 4171-4181Crossref PubMed Scopus (128) Google Scholar). Similarly, the ability of p73β to inhibit cell growth in p53-deficient cells was stronger than p73α (3.De Laurenzi V. Costanzo A. Barcaroli D. Torrinoni A. Falclco M. Annicchiarico-Petruzzelli M. Levrero M. Melino G. J. Exp. Med. 1998; 188: 1763-1768Crossref PubMed Scopus (361) Google Scholar). These observations suggest that the COOH-terminal region of p73 may possess a regulatory role, which modulates its transactivation ability as well as its biological activity.Accumulating evidence indicates that homotypic and heterotypic interactions among p53 family members regulate their activities. The various p73 splicing isoforms interacted with each other with various efficiency (1.Kaghad 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 (1533) Google Scholar, 3.De Laurenzi V. Costanzo A. Barcaroli D. Torrinoni A. Falclco M. Annicchiarico-Petruzzelli M. Levrero M. Melino G. J. Exp. Med. 1998; 188: 1763-1768Crossref PubMed Scopus (361) Google Scholar). Di Como et al. (5.Di Como C.J. Gaiddon C. Prives C. Mol. Cell. Biol. 1999; 19: 1438-1449Crossref PubMed Scopus (380) Google Scholar) found that tumor-derived p53 mutants but not wild-type p53 were associated with p73α and thereby reduced its transactivation and pro-apoptotic function. Likewise, p53 mutant also interacted with the remaining p73 splicing isoforms (β, γ, and δ) through its DNA-binding domain, and abrogated their transcriptional activities (26.Strano S. Munarriz E. Rossi M. Cristofanelli B. Shaul Y. Castagnoli L. Levine A.J. Sacchi A. Cesareni G. Oren M. Blandino G. J. Biol. Chem. 2000; 275: 29503-29512Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar). The ability of mutant p53 to interact with p73 was regulated by the status of a common p53 polymorphism at codon 72 (27.Marin M.C. Jost C.A. Brooks L.A. Irwin M.S. O'Nions J. Tidy J.A. James N. McGregor J.M. Harwood C.A. Yulug I.G. Vousden K.H. Allday M.J. Gusterson B. Ikawa S. Hinds P.W. Crook T. Kaelin Jr., W.G. Nat. Genet. 2000; 25: 47-54Crossref PubMed Scopus (466) Google Scholar). Recently, Yang et al. (16.Yang 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 (878) Google Scholar) discovered the truncated p73 isoform (ΔNp73), 1The abbreviations used are: ΔNp73truncated p73 isoform lacking the NH2-terminal transactivation domainCOS7 cellsSV40-transformed kidney cells from African green monkeyFITCfluorescein isothiocyanateHAhemagglutininHDAChistone deacetylaseMBPmaltose-binding proteinMM1Myc modulator 1PBSphosphate-buffered salinePMSFphenylmethylsulfonyl fluorideTBSTris-buffered salineTKthymidine kinaseX-gal5-bromo-4-chloro-3-indolyl-β-d-galactopyranosideGSTglutathione S-transferaseRTreverse transcriptase1The abbreviations used are: ΔNp73truncated p73 isoform lacking the NH2-terminal transactivation domainCOS7 cellsSV40-transformed kidney cells from African green monkeyFITCfluorescein isothiocyanateHAhemagglutininHDAChistone deacetylaseMBPmaltose-binding proteinMM1Myc modulator 1PBSphosphate-buffered salinePMSFphenylmethylsulfonyl fluorideTBSTris-buffered salineTKthymidine kinaseX-gal5-bromo-4-chloro-3-indolyl-β-d-galactopyranosideGSTglutathione S-transferaseRTreverse transcriptase which lacks the NH2-terminal transactivation domain. ΔNp73 was generated from an alternative promoter located within the intron 3 of the p73 gene and lost the transactivation ability toward the p53-responsive promoter. Of note, ΔNp73 was predominantly expressed in the developing brain and sympathetic neurons, and inhibited the pro-apoptotic function of p53 by hetero-oligomerization (29.Pozniak C.D. Radinovic S. Yang A. McKeon F. Kaplan D.R. Miller F.D. Science. 2000; 289: 304-306Crossref PubMed Scopus (405) Google Scholar). These homotypic and heterotypic interactions among p53 family members give a complexity to the understanding of the p73 signaling in vivo.Various lines of evidence suggest that the extreme COOH-terminal region of p53 has a function of negative regulator. The COOH terminus of p53 directly binds and masks its central DNA-binding domain (30.Hupp T.R. Lane D.P. Cold Spring Harbor Symp. Quant. Biol. 1994; 59: 195-206Crossref PubMed Scopus (106) Google Scholar, 31.Hupp T.R. Sparks A. Lane D.P. Cell. 1995; 83: 237-245Abstract Full Text PDF PubMed Scopus (448) Google Scholar). Indeed, its inhibitory effect was removed by structural modifications such as phosphorylation, glycosylation, acetylation, or deletions (32.Hupp T.R. Meek D.W. Midgley C.A. Lane D.P. Cell. 1992; 71: 875-886Abstract Full Text PDF PubMed Scopus (859) Google Scholar, 33.Shaw P. Freeman J. Bovey R. Iggo R. Oncogene. 1996; 12: 921-930PubMed Google Scholar, 34.Gu W. Roeder R.G. Cell. 1997; 90: 595-606Abstract Full Text Full Text PDF PubMed Scopus (2152) Google Scholar, 35.Anderson M.E. Woelker B. Reed M. Wang P. Tegtmeyer P. Mol. Cell. Biol. 1997; 17: 6255-6264Crossref PubMed Scopus (104) Google Scholar, 36.Nie Y. Li H.-H. Bula C.M. Liu X. Mol. Cell. Biol. 2000; 20: 741-748Crossref PubMed Scopus (68) Google Scholar). Additionally, physical interaction of Ref-1 (previously identified as the AP-1-stimulating protein (37.Xanthoudakis S. Curran T. EMBO J. 1992; 11: 653-665Crossref PubMed Scopus (596) Google Scholar)) or 14-3-3 with the COOH-terminal region of p53 stimulated its DNA-binding activity (38.Jayaraman L. Murthy K.G.K. Zhu C. Curran T. Xanthoudakis S. Prives C. Genes Dev. 1997; 11: 558-570Crossref PubMed Scopus (442) Google Scholar,39.Waterman M.J.F. Stavridi E.S. Waterman J.L.F. Halazonetis T.D. Nat. Genet. 1998; 19: 175-178Crossref PubMed Scopus (402) Google Scholar). Like p53, the COOH-terminal deletion of p73α caused the significant increase in its DNA-binding and transactivation activities (8.Ueda Y. Hijikata M. Takagi S. Chiba T. Shimotohno K. Oncogene. 1999; 18: 4993-4998Crossref PubMed Scopus (131) Google Scholar, 25.Lee C.-W. La Thangue N.B. Oncogene. 1999; 18: 4171-4181Crossref PubMed Scopus (128) Google Scholar, 40.Ozaki T. Naka M. Takada N. Tada M. Sakiyama S. Nakagawara A. Cancer Res. 1999; 59: 5902-5907PubMed Google Scholar). These observations suggest that the p73-DNA crystal structure might be similar to that of p53, although the COOH-terminal region of p73 does not share amino acid sequence similarity with that of p53.The purpose of this study was initially to isolate and characterize cellular protein(s) that could associate with the COOH-terminal region of p73α. By using a yeast-based two-hybrid screening, we identified MM1, which had been reported to be a c-Myc-binding protein (41.Mori K. Maeda Y. Kitaura H. Taira T. Iguchi-Ariga S.M. Ariga H. J. Biol. Chem. 1998; 273: 29794-29800Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar), as a p73α COOH-terminal region-binding protein. We found that overexpression of MM1 stimulated the p73α-mediated transcription from some p53/p73-responsive promoters as well as growth suppression. Moreover, c-Myc bound to p73α and inhibited the p73α-dependent transactivation. Of interest, overexpression of MM1 antagonized the inhibitory effect of c-Myc on p73α.DISCUSSIONOur present results have revealed for the first time that p73 is directly associated with c-Myc and its repressor MM1. However, the functional interactions among them appear to be finely regulated. MM1 is able to bind only to p73α but not to p73β and stimulates transactivation ability of the former. Only c-Myc but not N-Myc binds to p73α and inhibits its transcriptional activity. In addition, the regulatory effect of MM1 on p73α function seems to be dependent on each target gene promoter. Nevertheless, our finding of a direct link through forming a complex among c-Myc oncogene product, p73 tumor suppressor, and MM1 should give a new insight into better understanding of molecular and cellular mechanism of cell cycle control and apoptosis.MM1 has bound to p73α at the extreme COOH-terminal region, which regulates its transactivation activity and DNA-binding ability. Like p53, p73-mediated transcription and apoptosis are reported to be markedly enhanced by binding to p300/CBP (9.Zeng X. Li X. Miller A. Yuan Z. Yuan W. Kwok R.P. Goodman R. Lu H. Mol. Cell. Biol. 2000; 20: 1299-1310Crossref PubMed Scopus (82) Google Scholar), or the COOH-terminal deletions (8.Ueda Y. Hijikata M. Takagi S. Chiba T. Shimotohno K. Oncogene. 1999; 18: 4993-4998Crossref PubMed Scopus (131) Google Scholar, 25.Lee C.-W. La Thangue N.B. Oncogene. 1999; 18: 4171-4181Crossref PubMed Scopus (128) Google Scholar, 40.Ozaki T. Naka M. Takada N. Tada M. Sakiyama S. Nakagawara A. Cancer Res. 1999; 59: 5902-5907PubMed Google Scholar). The importance of the COOH-terminal region of p53 has so far been insisted. The extreme COOH-terminal region of p53 is closely involved in its pro-apoptotic function by protein·protein interactions (48.Wang X.W. Vermeulen W. Coursen J.D. Gibson M. Lupold S.E. Forrester K. Xu G. Elmore L. Yeh H. Hoeijmakers J.H.J. Harris C.C. Genes Dev. 1996; 10: 1219-1232Crossref PubMed Scopus (309) Google Scholar). The physical interaction of the NH2-terminal region of p53 with the components of RNA polymerase II transcriptional machinery or with the transcriptional coactivators such as p300/CBP enhanced its transcriptional activity (49.Thut C.J. Chen J.L. Klemin R. Tjian R. Science. 1995; 267: 100-104Crossref PubMed Scopus (406) Google Scholar, 50.Lu H. Levine A.J. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 5154-5158Crossref PubMed Scopus (280) Google Scholar, 51.Avantaggiati M.L. Ogryzko V. Gardner K. Giordano A. Levine A.S. Kelly K. Cell. 1997; 89: 1175-1184Abstract Full Text Full Text PDF PubMed Scopus (588) Google Scholar). Similarly, the structural modifications within the COOH-terminal region of p53 significantly facilitated its sequence-specific DNA binding (32.Hupp T.R. Meek D.W. Midgley C.A. Lane D.P. Cell. 1992; 71: 875-886Abstract Full Text PDF PubMed Scopus (859) Google Scholar, 33.Shaw P. Freeman J. Bovey R. Iggo R. Oncogene. 1996; 12: 921-930PubMed Google Scholar, 34.Gu W. Roeder R.G. Cell. 1997; 90: 595-606Abstract Full Text Full Text PDF PubMed Scopus (2152) Google Scholar, 35.Anderson M.E. Woelker B. Reed M. Wang P. Tegtmeyer P. Mol. Cell. Biol. 1997; 17: 6255-6264Crossref PubMed Scopus (104) Google Scholar, 36.Nie Y. Li H.-H. Bula C.M. Liu X. Mol. Cell. Biol. 2000; 20: 741-748Crossref PubMed Scopus (68) Google Scholar, 37.Xanthoudakis S. Curran T. EMBO J. 1992; 11: 653-665Crossref PubMed Scopus (596) Google Scholar, 38.Jayaraman L. Murthy K.G.K. Zhu C. Curran T. Xanthoudakis S. Prives C. Genes Dev. 1997; 11: 558-570Crossref PubMed Scopus (442) Google Scholar, 39.Waterman M.J.F. Stavridi E.S. Waterman J.L.F. Halazonetis T.D. Nat. Genet. 1998; 19: 175-178Crossref PubMed Scopus (402) Google Scholar). In relation to these observations on p53, the importance of the COOH-terminal extension of p73α has also been implicated. There exist various functional motifs, including a PPPPY motif (amino acid residues 482–488) and a SAM domain (amino acid residues 484–549) within that region. The SAM domain seems to be a protein·protein interaction module found in a variety of proteins involved in developmental regulation (52.Chi S.-M. Ayed A. Arrowsmith C.H. EMBO J. 1999; 16: 4438-4445Crossref Scopus (149) Google Scholar). Recently, it has been shown that Yes-associated protein is associated with p73α via its PPPPY motif and enhances the transcriptional activity of p73α (53.Strano S. Munarriz E. Rossi M. Castagnoli L. Shaul Y. Sacchi A. Oren M. Sudol M. Cesareni G. Blandino G. J. Biol. Chem. 2001; 276: 15164-15173Abstract Full Text Full Text PDF PubMed Scopus (349) Google Scholar). In addition, Minty et al. (54.Minty A. Dumont X. Kaghad M. Caput D. J. Biol. Chem. 2000; 275: 36316-36323Abstract Full Text Full Text PDF PubMed Scopus (326) Google Scholar) have found that p73α but not p73β bound to SUMO-1, and the extreme COOH-terminal Lys residue of p73α (at position 627) is the major site for SUMO-1 modification. SUMO-1 modification alters the subcellular distribution of p73, although it did not affect the transcriptional activity of p73. Furthermore, the extreme COOH-terminal region of p73α is suggested to act as a negative regulator of its own function (8.Ueda Y. Hijikata M. Takagi S. Chiba T. Shimotohno K. Oncogene. 1999; 18: 4993-4998Crossref PubMed Scopus (131) Google Scholar, 40.Ozaki T. Naka M. Takada N. Tada M. Sakiyama S. Nakagawara A. Cancer Res. 1999; 59: 5902-5907PubMed Google Scholar). In conjunction with those observations reported, our data suggest that the interaction of MM1 with the extreme COOH-terminal region allows p73α to take the conformation competent to express its activity, although the precise mechanism remains to be clarified.Our present data have shown that the ability of p73α to drive the transcription from the Bax and the PG13 promoter is enhanced by overexpression of MM1. However, the effect of MM1 on the p73α-mediated transcription from the MDM2 andp21 waf1 promoter is barely detectable. The similar pattern of target gene induction is also observed in some other cases. Mts1, which is associated with the extreme COOH-terminal region of p53, differentially regulates the transactivation function of p53 (55.Grigorian M. Andresen S. Tulchinsky E. Kriajevska M. Carlberg C. Kruse C. Cohn M. Ambartsumian N. Christensen A. Selivanova G. Lukanidin E. J. Biol. Chem. 2001; 276: 22699-22708Abstract Full Text Full Text PDF PubMed Scopus (262) Google Scholar). Mts1 significantly inhibited the p53-dependent transcription from the p21 waf1 promoter as measured in transient reporter assays, whereas its effect on the Bax promoter was negligible. Similarly, WT1 exhibited an inhibitory effect on the p53-regulated activation of the MDM2 promoter, whereas the repression of the Bax promoter by WT1 was not significant (56.Scharnhorst V. Dekker P. van der Eb A.J. Jochemsen A.G. J. Biol. Chem. 2000; 275: 10202-10211Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar). Recently, Thornborrow and Manfredi (57.Thornborrow E.C. Manfredi J.J. J. Biol. Chem. 2001; 276: 15598-15608Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar) have reported that there exists an Sp1-binding site immediately adjacent to the p53-responsive element of the Bax promoter, and p53 may require the cooperation of Sp1 to activate the Bax promoter. In contrast, the p53·Sp1 complex may function in an antagonistic manner for other promoters (58.Wang Q. Beck W.T. Cancer Res. 1998; 58: 5762-5769PubMed Google Scholar). These findings suggest that MM1-mediated differential regulation of the p53/p73-responsive promoters is due to a requirement for additional cofactors specific to each promoter, although this requires further elucidation.Recently, Ceballos et al. (45.Ceballos E. Delgado M.D. Gutierrez P. Richard C. Muller D. Eilers M. Ehinger M. Gullberg U. Leon J. Oncogene. 2000; 19: 2194-2204Crossref PubMed Scopus (59) Google Scholar) have found that c-Myc significantly inhibits the transactivation and pro-apoptotic function of p53. Consistent with their report, our data have shown that co-expression of p53 with c-Myc results in a remarkable reduction of the p53-mediated transcriptional activation of the Bax andp21 waf1 promoter. Using the immunoprecipitation and the luciferase reporter assays, we have demonstrated that c-Myc physically interacts with p73α and thereby inhibits its transactivation function. In contrast, N-Myc, the other member of myc family, is unable to affect the p73α- or p53-dependent transcriptional activation. As reported previously, targeted homozygous disruption of the c-myc or N-myc gene resulted in embryonic lethality (59.Stanton B.R. Perkins A.S. Tessarollo L. Sassoon D.A. Parada L.F. Genes Dev. 1992; 6: 2235-2247Crossref PubMed Scopus (305) Google Scholar, 60.Charron J. Malynn B.A. Fisher P. Stewart V. Jeannotte L. Goff S.P. Robertson E.J. Alt F.W. Genes Dev. 1992; 6: 2248-2257Crossref PubMed Scopus (263) Google Scholar, 61.Davis A.C. Wims M. Spotts G.D. Hann S.R. Bradley A. Genes Dev. 1993; 7: 671-682Crossref PubMed Scopus (426) Google Scholar). When c-myc was replaced by N-myc, mice did" @default.
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• W2085317811 title "Physical Interaction of p73 with c-Myc and MM1, a c-Myc-binding Protein, and Modulation of the p73 Function" @default.
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