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Identification, Localization, and Function in Steroidogenesis of PAP7: A Peripheral-Type Benzodiazepine Receptor- and PKA (RI)-Associated Protein

Division of Hormone Research (H.L., B.D., Z.-X.Y., V.P.), Departments of Cell Biology, Pharmacology, and Neuroscience, Georgetown University School of Medicine, Washington, DC 20007; and Institute of Medical Biochemistry (D.T., K.T.), University of Oslo, N-0317 Oslo, Norway

Address all correspondence and requests for reprints to: Dr. Vassilios Papadopoulos, Division of Hormone Research, Department of Cell Biology, Georgetown University School of Medicine, 3900 Reservoir Road, Washington, DC 20007. E-mail: papadopv{at}georgetown.edu

Peptide hormones and cAMP acutely stimulate steroid biosynthesis by accelerating the transport of cholesterol into the mitochondria. The peripheral-type benzodiazepine receptor (PBR) has been shown to be an indispensable element of the cholesterol transport machinery. Using the yeast two-hybrid system and PBR as bait, we identified a protein that interacts with PBR, the PBR-associated protein PAP7. Using the regulatory subunit RI of PKA as bait, we also isolated PAP7. Glutathione-S-transferase -PAP7 interacted with both the mitochondrial PBR and cytosolic PKA-RI in MA-10 Leydig cells. PAP7 is a novel 52-kDa protein present in mouse, rat, and human tissues, and it has a major 3-kb mRNA transcript in all tissues examined. Immunohistochemical and in situ hybridization studies indicated that PAP7 is highly expressed in the gonads, adrenal, hippocampus, and distinct brain neuronal and glial populations. Overexpression of the full length PAP7 increased the hCG-induced steroid production. However, overexpression of a partial PAP7, which includes the PBR- and PKA-RI-binding domains, inhibited the hormone-stimulated cholesterol transport and steroid synthesis. Treatment of MA-10 cells with oligonucleotides antisense to PAP7 also inhibited the hCG-stimulated steroid formation, suggesting that PAP7 is a functional element of the hormone-induced signal transduction cascade leading to steroidogenesis. PAP7 may function by targeting the PKA isoenzyme to organelles rich in PBR, i.e. mitochondria, where phosphorylation of specific protein substrates may induce the reorganization of PBR topography and function.

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