Year: 2004
Type: article
Abstract: Rb (retinoblastoma protein) inhibits E2F-1-induced cell death. We now show that the ability of Rb to inhibit E2F-1-induced cell death is dependent on a functional LXCXE-binding site in Rb, thereby suggesting that proteins that bind the LXCXE-binding site in Rb may regulate the anti-apoptotic activity of Rb. HDAC1, an LXCXE protein that plays a critical role in Rb-mediated transcription repression, abrogates the effect of Rb on E2F-1-induced cell death. In contrast, RF-Cp145, another LXCXE protein, cooperates with Rb to inhibit E2F-1-induced cell death. Both proteins exert their effect in an LXCXE-dependent manner. Rb regulates E2F-induced cell death by acting upstream of p73. Rb represses the p73 promoter. Our results further suggest a model in which Rb-E2F-1 complexes mediate the anti-apoptotic activity of Rb through active repression of target genes without recruiting HDAC1. Rb (retinoblastoma protein) inhibits E2F-1-induced cell death. We now show that the ability of Rb to inhibit E2F-1-induced cell death is dependent on a functional LXCXE-binding site in Rb, thereby suggesting that proteins that bind the LXCXE-binding site in Rb may regulate the anti-apoptotic activity of Rb. HDAC1, an LXCXE protein that plays a critical role in Rb-mediated transcription repression, abrogates the effect of Rb on E2F-1-induced cell death. In contrast, RF-Cp145, another LXCXE protein, cooperates with Rb to inhibit E2F-1-induced cell death. Both proteins exert their effect in an LXCXE-dependent manner. Rb regulates E2F-induced cell death by acting upstream of p73. Rb represses the p73 promoter. Our results further suggest a model in which Rb-E2F-1 complexes mediate the anti-apoptotic activity of Rb through active repression of target genes without recruiting HDAC1. The Rb tumor suppressor gene is frequently mutated in many kinds of tumors. Rb functions in part through interaction with E2F family of transcription factors. Rb represses the transcription of E2F-responsive genes by at least two mechanisms. Rb binds to E2F transcription factor family members such as E2F-1 and directly represses transcriptional activation by E2F. In addition, the Rb-E2F complex that forms at the promoter actively represses transcription by recruiting chromatin modeling enzymes (1Weintraub S.J. Prater C.A. Dean D.C. Nature. 1992; 358: 259-261Crossref PubMed Scopus (560) Google Scholar, 2Sellers W.R. Rodgers J.W. Kaelin Jr., W.G. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 11544-11548Crossref PubMed Scopus (230) Google Scholar, 3Weintraub S.J. Chow K.N. Luo R.X. Zhang S.H. He S. Dean D.C. Nature. 1995; 375: 812-815Crossref PubMed Scopus (458) Google Scholar, 4Zhang H.S. Gavin M. Dahiya A. Postigo A.A. Ma D. Luo R.X. Harbour J.W. Dean D.C. Cell. 2000; 101: 79-89Abstract Full Text Full Text PDF PubMed Scopus (541) Google Scholar). The second mechanism is termed active repression and is invoked to explain transcriptional repression of activator proteins bound to the proximal promoter. Rb can repress transcription by recruiting class I histone deacteylases such as HDAC1 (4Zhang H.S. Gavin M. Dahiya A. Postigo A.A. Ma D. Luo R.X. Harbour J.W. Dean D.C. Cell. 2000; 101: 79-89Abstract Full Text Full Text PDF PubMed Scopus (541) Google Scholar, 5Brehm A. Miska E.A. McCance D.J. Reid J.L. Bannister A.J. Kouzarides T. Nature. 1998; 391: 597-601Crossref PubMed Scopus (1078) Google Scholar, 6Luo R.X. Postigo A.A. Dean D.C. Cell. 1998; 92: 463-473Abstract Full Text Full Text PDF PubMed Scopus (838) Google Scholar, 7Magnaghi-Jaulin L. Groisman R. Naguibneva I. Robin P. Lorain S. Le Villain J.P. Troalen F. Trouche D. Harel-Bellan A. Nature. 1998; 391: 601-605Crossref PubMed Scopus (804) Google Scholar) and other proteins like RBP1 (8Lai A. Lee J.M. Yang W.M. DeCaprio J.A. Kaelin Jr., W.G. Seto E. Branton P.E. Mol. Cell. Biol. 1999; 19: 6632-6641Crossref PubMed Scopus (142) Google Scholar, 9Lai A. Kennedy B.K. Barbie D.A. Bertos N.R. Yang X.J. Theberge M.C. Tsai S.C. Seto E. Zhang Y. Kuzmichev A. Lane W.S. Reinberg D. Harlow E. Branton P.E. Mol. Cell. Biol. 2001; 21: 2918-2932Crossref PubMed Scopus (165) Google Scholar). Histone deacetylases facilitate condensation of chromatin, thereby conferring transcriptional repression. Rb regulates cell cycle progression from the G1 to S phase and in the S phase (Refs. 10Knudsen E.S. Buckmaster C. Chen T.T. Feramisco J.R. Wang J.Y. Genes Dev. 1998; 12: 2278-2292Crossref PubMed Scopus (190) Google Scholar and 11Niculescu III, A.B. Chen X. Smeets M. Hengst L. Prives C. Reed S.I. Mol. Cell. Biol. 1998; 18: 629-643Crossref PubMed Google Scholar; and reviewed in Ref. 12Weinberg R.A. Cell. 1995; 81: 323-330Abstract Full Text PDF PubMed Scopus (4319) Google Scholar). In addition, Rb inhibits cell death induced by DNA-damaging agents (13Haas-Kogan D.A. Kogan S.C. 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Dick F. Dyson N. Chen T.T. Wang J.Y. Fotedar R. Fotedar A. Mol. Cell. 2001; 7: 715-727Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar). The of in the of the by the of in in the or of We the of in the or of E2F-1 to the of The from at and and a Rb Wang J.Y. Cell. Full Text PDF PubMed Scopus Google Scholar) cell in and The proteins on and by the The LXCXE-binding in Rb Rb-mediated of E2F-1-induced the role of the LXCXE-binding site in Rb in regulating cell the V. Salles-Passador I. Munshi A. Brickner H. Regazzoni K. Dick F. Dyson N. Chen T.T. Wang J.Y. Fotedar R. Fotedar A. Mol. Cell. 2001; 7: 715-727Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar). In the with a and the of is We the of in the or of E2F-1 to the of The from at of the cell with E2F-1 cell death. of Rb inhibit E2F-1-induced cell death in a In contrast, the LXCXE Rb to as Rb to inhibit E2F-1-induced cell death of E2F-1 at cell death in the of Rb as with the Rb The of E2F-1-induced cell death by Rb the Rb is to an effect on E2F-1 protein Both Rb and the Rb E2F-1 protein with as Proc. Natl. Acad. Sci. U. S. A. 1997; PubMed Scopus Google Scholar, F. F. Wang Genes Dev. PubMed Scopus Google Scholar, A. R. Genes Dev. PubMed Scopus Google Scholar). Rb is an of cell death in many cell M. M.C. E.R. Tsai K.Y. Jacks T. Kaelin Jr., W.G. Nature. 2000; PubMed Scopus Google Scholar). that E2F-1-induced cell death in -/- is in a M. M.C. E.R. Tsai K.Y. Jacks T. Kaelin Jr., W.G. Nature. 2000; PubMed Scopus Google Scholar). Rb inhibits E2F-1-induced cell death by regulating the ability of p73 to cell death. We E2F-1-induced cell death in is We a of p73 that inhibits M. M.C. E.R. Tsai K.Y. Jacks T. Kaelin Jr., W.G. Nature. 2000; PubMed Scopus Google Scholar). p73 E2F-1-induced cell death in of the p73 effect on E2F-1-induced cell death in The of E2F-1-induced cell death by p73 is to effect on E2F-1 protein p73 to cell death M. M.C. E.R. Tsai K.Y. Jacks T. Kaelin Jr., W.G. Nature. 2000; PubMed Scopus Google Rb inhibits or cell death. Rb inhibit or cell death in Rb effect on p73 protein E2F-1 the p73 promoter M. M.C. E.R. Tsai K.Y. Jacks T. Kaelin Jr., W.G. Nature. 2000; PubMed Scopus Google Scholar and results suggest that Rb and E2F regulate cell death by acting upstream of p73. of HDAC1, and on Rb-mediated of E2F-induced demonstration that a functional LXCXE-binding site is Rb to inhibit E2F-1-induced cell death to LXCXE proteins such as HDAC1 L. Groisman R. Naguibneva I. Robin P. Lorain S. Le Villain J.P. Troalen F. Trouche D. Harel-Bellan A. Nature. 1998; 391: 601-605Crossref PubMed Scopus (804) Google C. E. M. EMBO J. PubMed Scopus Google or V. 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Cell. 2001; 7: 715-727Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar). in to Rb, and functional complexes and to the role of and HDAC1 in Rb (4Zhang H.S. Gavin M. Dahiya A. Postigo A.A. Ma D. Luo R.X. Harbour J.W. Dean D.C. Cell. 2000; 101: 79-89Abstract Full Text Full Text PDF PubMed Scopus (541) Google Scholar). RF-Cp145, the of the ability of Rb to inhibit E2F-1-induced cell death in a In the of Rb, by to inhibit E2F-1-induced cell death that cell in the of Rb. on the other effect in or the ability of Rb to inhibit E2F-1-induced cell death effect on E2F-1-induced cell death in the of Rb In contrast, HDAC1 abrogates the ability of Rb to inhibit E2F-1-induced cell death in a effect on E2F-1-induced cell death in the of Rb HDAC1, and effect on E2F-1 or Rb protein show that the LXCXE proteins on Rb-mediated of E2F-1-induced apoptosis. We of proteins on Rb-mediated of E2F-1-induced cell death to their effect on transcriptional repression. E2F-1-induced cell death is the p73 promoter to the of a to repression p73 promoter to show that E2F the p73 promoter M. M.C. E.R. Tsai K.Y. Jacks T. Kaelin Jr., W.G. Nature. 2000; PubMed Scopus Google Scholar). Rb p73 promoter activity We that cooperates with Rb to mediate transcriptional repression, HDAC1 We that effect on activity in the of Rb results suggest that the of HDAC1 and on cell death on Rb-mediated transcriptional repression. HDAC1 the of Rb to in a LXCXE further the effect of HDAC1 on cell the ability of HDAC1 and to Rb of E2F-1-induced cell death in The of from the of histone by HDAC1 condensation of chromatin, which in of transcription to gene repression. The of the HDAC1 active site J.R. A. R.A. R. Nature. 1999; PubMed Scopus Google Scholar). on the HDAC1 to activity C.A. J.K. T. Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google Scholar). We that HDAC1 and the HDAC1 at the ability of Rb to inhibit cell death in a The ability of HDAC1 to regulate Rb-mediated of cell death is dependent on We the in HDAC1 is HDAC1 to the ability of Rb to inhibit apoptosis. HDAC1 in which the HDAC1 a ability to bind Rb L. Groisman R. Naguibneva I. Robin P. Lorain S. Le Villain J.P. Troalen F. Trouche D. Harel-Bellan A. Nature. 1998; 391: 601-605Crossref PubMed Scopus (804) Google Scholar). We the ability of HDAC1 with the HDAC1 to Rb-mediated of E2F-1-induced cell death. We that HDAC1 abrogates the ability of Rb to inhibit E2F-1-induced cell the HDAC1 We show that cooperates with Rb to inhibit E2F-1-induced cell death We HDAC1 abrogates the ability of to inhibit E2F-1-induced cell death. HDAC1 and the HDAC1 the ability of to inhibit E2F-1-induced cell death in a In contrast, the HDAC1 cell by that the in HDAC1 is HDAC1 to the ability of Rb to inhibit E2F-1-induced cell death. Rb-mediated of E2F-induced in a LXCXE and that inhibit E2F-1-induced death in the of Rb in Rb -/- in a the ability of Rb to inhibit E2F-1-induced apoptosis with Rb inhibit E2F-1-induced cell death The in which the LXCXE mutated to to with Rb to inhibit E2F-1-induced cell death The as inhibit E2F-1-induced cell death in the of Rb or the Rb results suggest that the LXCXE in and the LXCXE-binding site in Rb of E2F-1-induced cell death. The complex to activity that is in the of other like J. E. F. N. M. J. J. Biol. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, J. N. E. J. M. J. Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google Scholar, N. R. E. J. Biol. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, V. J. Biol. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). The ability to in active complexes a of that activity of The which to the is the activity of the complex J. N. E. J. M. J. Proc. Natl. Acad. Sci. U. S. 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In show that the LXCXE-binding site in Rb is critical ability to inhibit E2F-1-induced cell death. suggests that proteins that bind the LXCXE-binding site in Rb regulate the of E2F-induced cell death by Rb. In the effect of HDAC1 on the anti-apoptotic activity of Rb. We that HDAC1 with Rb to inhibit E2F-1-induced cell death. In HDAC1 the of E2F-1-induced cell death by Rb. The activity of HDAC1 is the in HDAC1 is to the of E2F-1-induced cell death by Rb. In to HDAC1, another LXCXE protein RF-Cp145, the of cooperates with Rb to inhibit E2F-1-induced cell death. The ability of to Rb-mediated of E2F-1-induced cell death is dependent on a LXCXE in and the LXCXE-binding site in Rb as cell death V. Salles-Passador I. Munshi A. Brickner H. Regazzoni K. Dick F. Dyson N. Chen T.T. Wang J.Y. Fotedar R. Fotedar A. Mol. 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Source: Journal of Biological Chemistry
Institution: Institut de Biologie Structurale
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,430
OpenAlex ID: W2146612142