Adenovirus E1A downregulates cJun- and JunB-mediated transcription by targeting their coactivator p300.
Transcription factors and cofactors play critical roles in cell growth and differentiation. Alterations of their activities either through genetic mutations or by viral oncoproteins often result in aberrant cell growth and tumorigenesis. The transcriptional cofactor p300 has recently been shown to be complexed with transcription factors YY1 and CREB. Adenovirus E1A oncoproteins target these transcription complexes via physical interactions with p300, resulting in alterations of transcription mediated by these transcription factors. Here we show that p300 is also critical for repression by E1A of the activities of cJun and JunB, two members of the AP-1 transcriptional complexes. This repressive effect of E1A is dependent on the p300-binding domain of E1A and can be relieved by overexpression of p300. These results suggest that p300 serves as a mediator protein for downregulation of AP-1 activity by E1A. This hypothesis was further supported by the following observations: (i) in the absence of E1A, overexpression of p300 stimulated transcription both through an AP-1 site present in the collagenase promoter and through Jun proteins in GAL4 fusion protein-based assays; and (ii) overexpression of a mutant p300 lacking the E1A-interacting domain reduced the responsiveness of Jun-dependent transcription to E1A repression. As predicted from the functional results, p300 physically interacted with the Jun proteins. These findings thus established that p300 is a cofactor for cJun and JunB. We propose that p300 is a common mediator protein through which E1A gains control over multiple transcriptional regulatory pathways in the host cells.
Lee
J S
JS
Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA.
See
R H
RH
Deng
T
T
Shi
Y
Y
D017500:Adenovirus E1A Proteins / Q000502:physiology*; D000260:Adenoviruses, Human / Q000235:genetics; D001665:Binding Sites; D015536:Down-Regulation; D015967:Gene Expression Regulation, Viral; D006367:HeLa Cells; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D013329:Structure-Activity Relationship; D015534:Trans-Activators; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic; D015533:Transcriptional Activation
D017500:Adenovirus E1A Proteins; D009687:Nuclear Proteins; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D015534:Trans-Activators; D018808:Transcription Factor AP-1; D014157:Transcription Factors