The THAP–zinc finger protein THAP1 regulates endothelial cell proliferation through modulation of pRB/E2F cell-cycle target genes

Author:

Cayrol Corinne1,Lacroix Chrystelle1,Mathe Catherine1,Ecochard Vincent1,Ceribelli Michele2,Loreau Emilie3,Lazar Vladimir4,Dessen Philippe4,Mantovani Roberto2,Aguilar Luc3,Girard Jean-Philippe1

Affiliation:

1. Laboratoire de Biologie Vasculaire, Equipe labellisée ‘La Ligue 2006,’ Institut de Pharmacologie et de Biologie Structurale (IPBS), Centre National de la Recherche Scientifique (CNRS) Unité mixte de recherche (UMR) 5089, Toulouse, France;

2. Dipartimento di Scienze Biomolecolari e Biotecnologie, Università di Milano, Milan, Italy;

3. ENDOCUBE, Prologue Biotech, Labège, France;

4. Unité de Génomique Fonctionnelle et Bioinformatique, Institut Gustave Roussy, Villejuif, France

Abstract

AbstractWe recently cloned a novel human nuclear factor (designated THAP1) from postcapillary venule endothelial cells (ECs) that contains a DNA-binding THAP domain, shared with zebrafish E2F6 and several Caenorhabditis elegans proteins interacting genetically with retinoblastoma gene product (pRB). Here, we show that THAP1 is a physiologic regulator of EC proliferation and cell-cycle progression, 2 essential processes for angiogenesis. Retroviral-mediated gene transfer of THAP1 into primary human ECs inhibited proliferation, and large-scale expression profiling with microarrays revealed that THAP1-mediated growth inhibition is due to coordinated repression of pRB/E2F cell-cycle target genes. Silencing of endogenous THAP1 through RNA interference similarly inhibited EC proliferation and G1/S cell-cycle progression, and resulted in down-regulation of several pRB/E2F cell-cycle target genes, including RRM1, a gene required for S-phase DNA synthesis. Chromatin immunoprecipitation assays in proliferating ECs showed that endogenous THAP1 associates in vivo with a consensus THAP1-binding site found in the RRM1 promoter, indicating that RRM1 is a direct transcriptional target of THAP1. The similar phenotypes observed after THAP1 overexpression and silencing suggest that an optimal range of THAP1 expression is essential for EC proliferation. Together, these data provide the first links in mammals among THAP proteins, cell proliferation, and pRB/E2F cell-cycle pathways.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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