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Inhibition of ER-Mediated Trans-Activation of Human Coagulation Factor XII Gene by Heteromeric Transcription Factor NF-Y

Istituto di Neurobiologia e Medicina Molecolare, Consiglio Nazionale delle Ricerche (A.F., F.M.); Cattedra di Endocrinologia, Università di Roma La Sapienza (M.N.); Dipartimento Biologia Animale, Università di Modena e Reggio (R.M.); Istituto di Patologia Medica, Università Cattolica del Sacro Cuore (A.P.); and Laboratorio di Oncogenesi Molecolare, Istituto Tumori Regina Elena (A.F., M.N., F.M., S.N., A.S., A.P.), 00158 Rome, Italy

Address all correspondence and requests for reprints to: Dr. Alfredo Pontecorvi, Laboratorio di Oncogenesi Molecolare, Istituto Tumori Regina Elena, via delle Messi d’Oro No. 156, 00158 Rome, Italy. E-mail: pontecorvi{at}ifo.it

Human coagulation factor XII promoter contains an estrogen response element that mediates ligand-activated ER induction of coagulation factor XII gene expression. The 3'-half of coagulation factor XII-estrogen response element overlaps a putative CCAAT box, the widespread regulatory element specifically recognized by the heteromeric transcription factor NF-Y. Transient cotransfection of NF-Y and ER results in strong inhibition of estrogen stimulation of coagulation factor XII promoter activity. NF-Y antagonism is primarily exerted by the NF-YA subunit and does not require binding to the CCAAT element, as NF-YA mutants with impaired DNA binding capacity retain the ability to inhibit ER trans-activation. EMSAs with increasing concentrations of recombinant NF-Y do not detect the formation of NF-Y-DNA complexes or show impairment of ER binding to estrogen response element. Immunoprecipitation of whole cell extracts with anti-ER antibody reveals an in vivo association between the two transcription factors, which is abolished by deletion of the NF-YA carboxyl-terminus. In functional experiments with sequential NF-YA deletion mutants the HAP2-homology region appears essential in eliciting NF-YA antagonistic activity. In conclusion, our results demonstrate that heteromeric transcription factor NF-Y inhibits estrogen induction of coagulation factor XII promoter in a DNA binding-independent fashion and suggest a novel role for NF-Y as a partner for the ER transcription complex.

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