Regulation of the p53 homolog p73 by adenoviral oncogene E1A.
p73 is a p53 homolog, as they are similar structurally and functionally. Unlike p53, p73 is not inactivated by the products of viral oncogenes such as SV40 T antigen and human papilloma virus E6. Here we show that the product of adenoviral oncogene E1A inhibits the transcriptional activation by both p73alpha and p73beta. Electrophoretic mobility shift assays revealed that E1A does not inhibit the sequence-specific DNA binding by p73. Transcriptional activation by a fusion protein containing the Gal4 DNA-binding domain and either of the activation domains of p73 was inhibited by wild-type (WT) E1A, but not by the N-terminal deletion mutant E1A(Delta2-36). E1A(Delta2-36), which does not bind to the p300/CBP family of coactivators, failed to inhibit p73-mediated transcription, whereas E1A(DeltaCR2), a deletion mutant that does not bind to the pRb family of proteins, inhibited p73-mediated transcription as efficiently as WT E1A. Consistent with these observations, growth arrest induced by p73 expressed from a recombinant adenovirus was abrogated by WT E1A, which correlated with inhibition of p73-mediated induction of p21(WAF1/CIP1) by E1A. However, p73 was able to induce p21(WAF1/CIP1) and to mediate growth arrest in the presence of E1A(Delta2-36). Furthermore, the expression of either wild-type E1A or E1A(Delta2-36) resulted in the stabilization of endogenous p73. However, p73 stabilized in response to the expression of E1A(Delta2-36), but not WT E1A, was able to activate the expression of p21(WAF1/CIP1). These results suggest that the transcriptional activation function of p73 is specifically targeted by E1A through a mechanism involving p300/CBP proteins during the process of transformation and that p73 may have a role to play as a tumor suppressor.
Das
Sanjeev
S
Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560 012, India.
El-Deiry
Wafik S
WS
Somasundaram
Kumaravel
K
D000256:Adenoviridae / Q000235:genetics; D017500:Adenovirus E1A Proteins / Q000378:metabolism*; D015153:Blotting, Western; D001973:Bromodeoxyuridine / Q000494:pharmacology; D002453:Cell Cycle; D002455:Cell Division; D002460:Cell Line; D002469:Cell Separation; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D016147:Genes, Tumor Suppressor; D006801:Humans; D007150:Immunohistochemistry; D009687:Nuclear Proteins / Q000378:metabolism*; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013997:Time Factors; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins
D017500:Adenovirus E1A Proteins; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D004247:DNA; D001973:Bromodeoxyuridine