The retinoblastoma gene family members pRB and p107 coactivate the AP-1-dependent mouse tissue factor promoter in fibroblasts

被引:18
作者
Liu, SL [1 ]
Rand, A [1 ]
Kelm, RJ [1 ]
Getz, MJ [1 ]
机构
[1] Mayo Clin & Mayo Fdn, Dept Biochem & Mol Biol, Program Tumor Biol, Rochester, MN 55905 USA
关键词
tissue factor; adenovirus EIA; retinoblastoma tumor suppressor; pRB; p107; AP-1;
D O I
10.1038/sj.onc.1203675
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Serum-stimulation of quiescent mouse fibroblasts results in transcriptional activation of tissue factor (TF), the cellular initiator of blood coagulation. This requires the rapid entry of c-Fos into specific AP-1 DNA-binding complexes and can be strongly inhibited by the adenovirus E1A 12S gene product. In this study, we utilized a panel of E1A mutants deficient in cellular protein binding to analyse the molecular basis for E1A inhibition of a minimal, c-Fos-dependent TF promoter/reporter construct in mouse AKR-2B fibroblasts, Mutations which impaired binding of the retinoblastoma tumor suppressor protein family members pRB, p107, and p130 relieved E1A-mediated inhibition of transcription in response to serum-stimulation or c-Fos overexpression. Inhibition was restricted to the G(0) to G(1) transition, consistent with the specificity of E1A for hypophosphorylated forms of RE proteins. Although E1A mutants deficient in CBP/p300 binding retained the ability to inhibit TF transcription, deletion of the aminoterminal portion of the CBP/p300 interaction domain was required to permit rescue of TF promoter activity by coexpression of pRB, Moreover, ectopic p107 could effectively substitute for pRB in relieving E1A-mediated repression. In primary mouse embryo fibroblasts, activity of the minimal AP(-/-) dependent TF promoter was suppressed in Rb-/- cells compared to parallel Rb+/- and Rh+/+ transfectants, Ectopic expression of either PRB or p107 markedly enhanced TF promoter activity in Rh-/- fibroblasts. Collectively, these data imply that pRB and p107 can cooperate with c-Fos to activate TF gene transcription in fibroblasts and suggest a requirement for another, as yet unidentified, E1A-binding protein.
引用
收藏
页码:3352 / 3362
页数:11
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