Abstract:
:The adenoviral E1A oncogene sensitizes mammalian cells to tumor necrosis factor-alpha (TNF-alpha), in part by repressing the nuclear factor-kappa B (NF-kappa B)-dependent defense against this cytokine. Other E1A activities involve binding to either p300/cyclic AMP response element-binding protein (CBP) or retinoblastoma (Rb)-family proteins, but the roles of E1A interactions with these transcriptional regulators in sensitizing cells to TNF-alpha are unclear. E1A expression did not block upstream events in TNF-alpha-induced activation of NF-kappa B in NIH 3T3 cells, including degradation of I kappa B-alpha, nuclear translocation of NF-kappa B subunits, and their dimeric binding to kappa B sequences in the nucleus. However, E1A markedly repressed NF-kappa B-dependent transcription and sensitized cells to TNF-alpha induced apoptosis. These E1A effects were selective for kappa B-dependent transcription and for the function of the NF-kappa B p65/RelA subunit. A four amino acid E1A deletion that eliminates binding to Rb-family proteins blocked both repression of TNF-alpha-induced transcription and sensitization to apoptosis. In contrast, mutations that eliminate E1A binding to p300/CBP (coactivators of p65/RelA) did not affect either E1A activity. These data suggest that E1A-Rb-binding blocks the NF-kappa B-dependent activation response to TNF-alpha by altering the function of p65/RelA at a stage after formation of the transcription factor-enhancer complex. These observations also open questions about the general role of Rb-family proteins in modulation of NF-kappa B-dependent transcription.
journal_name
Proc Natl Acad Sci U S Aauthors
Cook JL,Walker TA,Worthen GS,Radke JRdoi
10.1073/pnas.162082999keywords:
subject
Has Abstractpub_date
2002-07-23 00:00:00pages
9966-71issue
15eissn
0027-8424issn
1091-6490pii
162082999journal_volume
99pub_type
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