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Identification and Pharmacological Characterization of SRBP-2

A Novel SR31747A-binding Protein

Immunology-Oncology Department, SanofiSynthelabo, F-34184 Montpellier cedex 04 [H. V., S. G., D. C., P. C., T. C., E. B., P. C.]; Molecular and Functional Genomics Department, SanofiSynthelabo, F-31676 Labège Innopole cedex [G. M., P-H. D., G. L.]; and Departments of Pathology [J. S-L.] and Biostatistics [A. K.], Montpellier Cancer Institute, Montpellier cedex, France

SR31747A is a ligand with potent antiproliferative activity against tumor cells and for which three binding proteins have been identified to date: (a) SRBP-1 (also called 1); (b) HIS; and (c) 2. In this study, we characterized an additional SR31747A binding site, i.e., SRBP-2 (SR31747A-binding protein 2). Using an in silico screening approach, we identified this novel sequence, which exhibits 41% homology with HSI. The 1142-bp cDNA was found to encode a 206 amino acid protein not related to SRBP-1. Northern blot analysis of SRBP-2 mRNA expression revealed a single 1.1-kb transcript that was widely expressed in organs; the liver was particularly enriched, and the brain showed the lowest abundance. A murine homologue that exhibited a similar expression pattern was also characterized. Subcellular localization analysis using specific polyclonal antibodies revealed that SRBP-2 had the same nuclear membrane and endoplasmic reticulum localization as other members of the SR31747A-binding protein family. Considering SRBP-2-binding properties, pharmacological analysis clearly highlighted that SRBP-2 was distinct from 2. Scatchard plot analysis revealed K_d values of 10 and 3 nM for SR31747A and Tamoxifen, respectively. In contrast with HSI, the protein also did not exhibit detectable isomerase activity. When analyzing SRBP-2 expression in human breast cancer biopsies, we obtained evidence that SRBP-2 expression, together with SRBP-1 and HSI, may be of interest as a prognostic marker. These findings demonstrated that SRBP-2 represents an additional molecular target for SR31747A, which could help to understand the immunosuppressive and antiproliferative effects of the molecule.