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

Oncogene volume 19, pages 3352–3362 (2000)Cite this article

Abstract

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 G0 to G1 transition, consistent with the specificity of E1A for hypophosphorylated forms of RB proteins. Although E1A mutants deficient in CBP/p300 binding retained the ability to inhibit TF transcription, deletion of the amino-terminal 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-1-dependent TF promoter was suppressed in Rb−/− cells compared to parallel Rb+/− and Rb+/+ transfectants. Ectopic expression of either pRB or p107 markedly enhanced TF promoter activity in Rb−/− 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.

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Acknowledgements

We would like to thank J Nevins, WG Kaelin, Jr, B Dynlacht and H Iba for sharing expression plasmids and T Jacks for providing us with Rb+/+, Rb+/− and Rb−/− mouse embryo fibroblasts. We also thank Sara Felts for helpful discussions and Brenda Birch for assistance in preparing the manuscript. This paper is dedicated in memory of our friend and mentor, Dr Michael John Getz. This work was supported by National Institutes of Health grant CA76083 to MJ Getz and by the Mayo Foundation. S-L, Liu was supported by NIH postdoctoral training grant T32 CA09441.

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  1. Michael J Getz: Deceased

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  1. Department of Biochemistry and Molecular Biology, Program in Tumor Biology, Mayo Clinic/Foundation, Rochester, 55905, Minnesota, MN, USA

    Su-Ling Liu, Arlymae Rand, Robert J Kelm Jr & Michael J Getz

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  1. Su-Ling Liu
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  2. Arlymae Rand
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Liu, SL., Rand, A., Kelm, R. et al. The retinoblastoma gene family members pRB and p107 coactivate the AP-1-dependent mouse tissue factor promoter in fibroblasts. Oncogene 19, 3352–3362 (2000). https://doi.org/10.1038/sj.onc.1203675

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