Inhibition of crystallin expression and induction of apoptosis by lens-specific E1A expression in transgenic mice.
Previous studies have shown that the adenovirus E1A oncoprotein can bind to and inactivate the retinoblastoma tumor suppressor protein (pRb) and the transcriptional coactivators CBP/p300. In this study, wild-type E1A12S or two deletion mutants (delN, which binds pRb but not CBP/p300; delCR2, which binds to CBP/p300 but not pRb) were linked to the lens-specific alphaA-crystallin promoter, and used to generate transgenic mice. Lens fiber cells expressing E1A12S or delCR2, both of which bind to CBP/p300, failed to upregulate beta-crystallin and gamma-crystallin expression. In contrast, lens fiber cells expressing delN showed significant expression of beta- and gamma-crystallins. Lens fiber cells expressing delN showed cell cycle entry, marked apoptosis, and evidence for p53 activation, while cells expressing either 12S or delCR2 showed limited apoptosis and no evidence for upregulation of the p53-inducible gene p21. Our results suggest that the transcriptional coactivators CBP and/or p300 are required for the dramatic increases in crystallin expression that accompany terminal differentiation in the lens, and also for activation of p53 in response to inactivation of pRb in the lens.
Chen
Qin
Q
Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Ash
John D
JD
Branton
Phil
P
Fromm
Larry
L
Overbeek
Paul A
PA
D000123:Acetyltransferases / Q000096:biosynthesis / Q000235:genetics; D017500:Adenovirus E1A Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis; D015415:Biomarkers / Q000032:analysis; D050882:CREB-Binding Protein; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics; D002454:Cell Differentiation; D003459:Crystallins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D015536:Down-Regulation; D051548:Histone Acetyltransferases; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007908:Lens, Crystalline / Q000033:anatomy & histology / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009154:Mutation; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D051257:Proto-Oncogene Proteins c-maf; D012333:RNA, Messenger / Q000378:metabolism; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics; D014157:Transcription Factors; D014158:Transcription, Genetic; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
D000123:Acetyltransferases; D017500:Adenovirus E1A Proteins; D015415:Biomarkers; D050882:CREB-Binding Protein; D018797:Cell Cycle Proteins; D003459:Crystallins; D004268:DNA-Binding Proteins; D051548:Histone Acetyltransferases; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D051257:Proto-Oncogene Proteins c-maf; D012333:RNA, Messenger; D015534:Trans-Activators; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C495608:Maf protein, mouse; C494364:Crebbp protein, mouse