title: Double null cells reveal that CBP and p300 are dispensable for p53 targets p21 and Mdm2 but variably required for target genes of other signaling pathways.
abstract: The histone acetyltransferase coactivators CBP (CREBBP) and p300 (EP300) have more than 400 described protein interaction partners and are implicated in numerous transcriptional pathways. We have shown previously that CBP and p300 double knockout mutations in mouse embryonic fibroblasts (dKO MEFs) result in mixed effects on cAMP-inducible gene expression, with many CREB target genes requiring CBP/p300 for full expression, while others are unaffected or expressed better in their absence. Here we used CBP and p300 dKO MEFs to examine gene expression in response to four other signals: DNA damage (via p53), double-stranded RNA, serum, and retinoic acid. We found that while retinoic acid-inducible gene expression tends to be uniformly dependent on CBP/p300, dsRNA- and serum-inducible genes displayed non-uniform requirements for CBP/p300, with the dsRNA-inducible expression of Ifnb1 (interferon-β) being particularly dependent on CBP/p300. Surprisingly, the p53-dependent genes Cdkn1a (p21/CIP/WAF) and Mdm2 did not require CBP/p300 for their expression. As with cAMP-responsive CREB targets, we propose that the signal-responsive recruitment of CBP and p300 does not necessarily indicate a requirement for these coactivators at a locus. Rather, target gene context (e.g. DNA sequence) influences the extent to which transcription requires CBP/p300 versus other coactivators, which may not be HATs.
authors.affiliation: Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Lawryn H
authors.initials: LH
authors.lastname: Kasper
authors.forename: Mary C
authors.initials: MC
authors.lastname: Thomas
authors.forename: Gerard P
authors.initials: GP
authors.lastname: Zambetti
authors.forename: Paul K
authors.initials: PK
authors.lastname: Brindle
mesh_terms: D000818:Animals; D050882:CREB-Binding Protein / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D050881:E1A-Associated p300 Protein / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D005347:Fibroblasts / Q000378:metabolism; D015870:Gene Expression; D055786:Gene Knockout Techniques; D016899:Interferon-beta / Q000378:metabolism; D051379:Mice; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D012330:RNA, Double-Stranded / Q000378:metabolism; D015398:Signal Transduction; D014212:Tretinoin / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D012330:RNA, Double-Stranded; D016159:Tumor Suppressor Protein p53; D014212:Tretinoin; D016899:Interferon-beta; D050882:CREB-Binding Protein; C494364:Crebbp protein, mouse; D050881:E1A-Associated p300 Protein; C494361:Ep300 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2