title: Inhibition of p53-mediated transactivation and cell cycle arrest by E1A through its p300/CBP-interacting region.
abstract: Cellular transformation by the adenovirus E1A oncoprotein requires its p300/CBP- and Rb-binding domains. We mapped inhibition of p53-mediated transactivation to the p300/CBP-binding region of E1A. An E1A mutant incapable of physically interacting with Rb retained the capacity to inhibit transactivation by p53, whereas E1A mutants of the p300/CBP-interacting domain failed to inhibit p53. The inhibitory effect of the p300/CBP-binding region of E1A on p53 was demonstrated with p53-activated reporters and endogenous p53 targets such as p21(WAF1/CIP1) or MDM2. E1A lacking the capacity to interact with Rb, but capable of p300/CBP interaction, was competent in suppression of a DNA-damage activated p53-dependent cell cycle checkpoint. Exogenous CBP and p300 were able to individually relieve E1A's inhibitory effect on p53-mediated transcription. Mutants of E1A that are not capable of interacting with p300 or CBP were found to efficiently stabilize endogenous p53 but were not competent in repression of p21 expression thus dissociating these two effects of E1A. Our results suggest that the p300/CBP-binding domain of E1A inhibits a p53-dependent cellular response which normally inhibits DNA replication following Adenovirus infection.
authors.affiliation: Department of Medicine and Genetics, University of Pennsylvania School of Medicine and Comprehensive Cancer Center, Philadelphia 19104, USA.
authors.forename: K
authors.initials: K
authors.lastname: Somasundaram
authors.forename: W S
authors.initials: WS
authors.lastname: El-Deiry
mesh_terms: D000123:Acetyltransferases; D017500:Adenovirus E1A Proteins / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics; D018797:Cell Cycle Proteins / Q000502:physiology*; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000187:drug effects / Q000378:metabolism; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000378:metabolism; D005047:Etoposide / Q000494:pharmacology; D051548:Histone Acetyltransferases; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism; D012175:Retinoblastoma / Q000378:metabolism; D014157:Transcription Factors; D015533:Transcriptional Activation / Q000235:genetics*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism*; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
chemical_list: D000123:Acetyltransferases; D017500:Adenovirus E1A Proteins; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004273:DNA, Neoplasm; D004317:Doxorubicin; D004791:Enzyme Inhibitors; D005047:Etoposide; D051548:Histone Acetyltransferases; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C493956:CDKN1A protein, human