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PAPA-1 Is a Nuclear Binding Partner of IGFBP-2 and Modulates Its Growth-Promoting Actions

Pediatric Endocrinology (K.M., L.J.C., M.F., A.H., P.C.), David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California 90095; Department of Neuroscience and Cell Biology (B.P., J.E.P.), University of Medicine and Dentistry of New Jersey, Piscataway, New Jersey 08854; and Molecular Biology (H.A.), Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan

Address all correspondence and requests for reprints to: Pinchas Cohen, M.D., Pediatric Endocrinology, David Geffen School of Medicine at University of California, Los Angeles, 10833 Le Conte Avenue MDCC 22-315, Los Angeles, California 90095-1752. E-mail: hassy{at}mednet.ucla.edu.

IGF-binding proteins (IGFBPs) have multiple cellular effects, which occur by both IGF-dependent and -independent mechanisms. IGFBP-2 is involved in the regulation of both normal and carcinogenic cell growth. To further understand the actions of IGFBP-2, we carried out a yeast two-hybrid screen to search for intracellular partner proteins using a human prostate cDNA library. We isolated Pim-1-associated protein-1 (PAP-1)-associated protein-1 (PAPA-1) as an IGFBP-2-binding protein, whose expression and subcellular localization is regulated by both IGFBP-2 and androgens. Coimmunoprecipitation and glutathione S-transferase pull-down assay confirmed the interaction in vitro, and confocal microscopy showed the colocalization of IGFBP-2 and PAPA-1 in the nucleus. Suppression of PAPA-1 by small interfering RNA treatment enhanced the growth-promoting effect of IGFBP-2. Conversely, IGFBP-2-promoted bromodeoxyuridine incorporation into LNCaP cells was abrogated by the simultaneous overexpression of myc-hPAPA-1. Mouse embryonic fibroblasts from IGFBP-2 knockout mouse showed diminished growth activity compared with wild type, and expression of FLAG-mPAPA-1 decreased cell proliferation in IGFBP-2 knockout, but not control mouse embryonic fibroblasts. These studies suggest that the growth-promoting role of IGFBP-2 in prostate cancer is inhibited by its intracellular interaction with PAPA-1.