Regulation of ovarian and placental steroidogenesis

University Of Pennsylvania, Philadelphia PA

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): Steroid biosynthesis requires the efficient movement of substrate to the cholesterol side-chain cleavage system. Although progress has been made with respect to the identification of proteins participating in the translocation of cholesterol in steroidogenic cells, fundamental questions remain regarding their mechanism of action, and regulation of their expression and functional activity. Four Specific Aims are proposed: 1) To identify chromatin modifications associated with induction of StAR gene transcription during granulosa cell luteinization. The hypothesis to be tested is that an ordered sequence of transcription factor binding, histone modification, and chromatin remodeling at the StAR locus occurs during the process of luteinization. These chromatin alterations are proposed to convert the virtually silent StAR gene in preovulatory granulosa cells into one capable of undergoing rapid increases in transcription in response to LH; 2) To define the role of StAR posttranslational modifications in controlling protein turnover and mitochondrial protein importation. The hypotheses to be tested are that the short-lived cytoplasmic StAR preprotein, believed to be the biologically active form of the molecule, is degraded by proteasomes; and that the half-life of the StAR preprotein is regulated by a phosphorylation code that determines susceptibility to proteasomal degradation; that a phosphorylation code influences the rate of preprotein binding and/or importation into mitochondria, and consequently the duration/magnitude of the steroidogenic response. 3) To elucidate the roles of the StAR-related protein, MLN64, in intracellular sterol trafficking. We will determine whether MLN64 participates in the vesicular intracellular trafficking of sterols and if the MLN64 START domain, released by proteolytic cleavage, stimulates movement of cholesterol to the inner mitochondrial membrane of placental mitochondria. 4) To determine the specificity and mechanism of START domain action. The hypotheses to be tested are that START domains act on specific membrane configurations; that their sterol transfer activity is dependent upon a molten globule configuration; and that the ability of the START domain to bind cholesterol is critical to its sterol transfer activity.