A cellular repressor of E1A-stimulated genes that inhibits activation by E2F.
The adenovirus E1A protein both activates and represses gene expression to promote cellular proliferation and inhibit differentiation. Here we report the identification and characterization of a cellular protein that antagonizes transcriptional activation and cellular transformation by E1A. This protein, termed CREG for cellular repressor of E1A-stimulated genes, shares limited sequence similarity with E1A and binds both the general transcription factor TBP and the tumor suppressor pRb in vitro. In transfection assays, CREG represses transcription and antagonizes 12SE1A-mediated activation of both the adenovirus E2 and cellular hsp70 promoters. CREG also antagonizes E1A-mediated transformation, as expression of CREG reduces the efficiency with which E1A and the oncogene ras cooperate to transform primary cells. Binding sites for E2F, a key transcriptional regulator of cell cycle progression, were found to be required for repression of the adenovirus E2 promoter by CREG, and CREG was shown to inhibit activation by E2F. Since both the adenovirus E1A protein and transcriptional activation by E2F function to promote cellular proliferation, the results presented here suggest that CREG activity may contribute to the transcriptional control of cell growth and differentiation.
Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA.
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E
Veal
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Eisenstein
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ZH
Tseng
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Gill
D000256:Adenoviridae / Q000235:genetics; D017500:Adenovirus E1A Proteins / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins; D002453:Cell Cycle; D018797:Cell Cycle Proteins; D002455:Cell Division; D002460:Cell Line; D002472:Cell Transformation, Viral; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins; D004330:Drosophila; D029721:Drosophila Proteins; D050684:E2F Transcription Factors; D017930:Genes, Reporter; D011905:Genes, ras; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000502:physiology*; D051379:Mice; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D012097:Repressor Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000378:metabolism; D056465:Retinoblastoma-Binding Protein 1; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D015534:Trans-Activators; D050680:Transcription Factor DP1; D035362:Transcription Factor TFIID; D014157:Transcription Factors / Q000378:metabolism*; D019473:Transcription Factors, TFII / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection
D017500:Adenovirus E1A Proteins; C533431:Arid4a protein, mouse; C485247:CREG protein, Drosophila; C114068:CREG1 protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C485248:Creg protein, mouse; D004268:DNA-Binding Proteins; C088053:Dp transcription factor, Drosophila; D029721:Drosophila Proteins; D050684:E2F Transcription Factors; D018840:HSP70 Heat-Shock Proteins; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D016160:Retinoblastoma Protein; D056465:Retinoblastoma-Binding Protein 1; D015534:Trans-Activators; D050680:Transcription Factor DP1; D035362:Transcription Factor TFIID; D014157:Transcription Factors; D019473:Transcription Factors, TFII