Current data from my laboratory on the activation of steroidogenesis in a clonal strain of cultured Leydig tumor cells (MA-10 cells) show that mouse epidermal growth factor (mEGF) is capable of activating steroid biosynthesis without affecting cAMP levels and that it potentiates the activation of steroidogenesis by hCG and cAMP analogues. These data suggest that steroid biosynthesis can be activated by a """"""""cAMP independent"""""""" pathway(s), and that the activation of this pathway9s) along with the cAMP signalling system leads to the synergistic activation of steroidogenesis. The overall aim of this proposal is to characterize the mechanisms by which LH/CG, mEGF, and other growth factors and hormones activate steroid biosynthesis and modulate the actions of LH/CG in the MA-10 cells.
The specific aims are as follows: (1) Characterize the actions of mEGF, alone and in combination with hCG or cAMP analogues, on the pathway for steroid biosynthesis. (2) Characterize the effects of mEGF on other actions of hCG and cAMP analogues on the MA-10 cells. (3) Characterize the mechanisms by which mEGF modulates the actions of hCG and cAMP analogues. (4) Define the signalling system(s) activated by mEGF in the MA-10 cells and determine if this signalling system(s) is also activated by LH/CG. (5) Determine if the signalling system(s) identified under growth factors and certain hormones (insulin, angiotensin II, and arginine vasopressin) activate steroid biosynthesis and modulate the actions of hCG and cAMP analogues. These studies will allow us a much better understanding of the interaction of different horomones and growth factors in the endocrine, paracrine, and/or autocrine regulation of Leydig cell steroidogenesis. From a more general point of view, these studies will contribute to our understanding of whether a given hormone regulates cellular functions by activating one or more signalling systems, and how different signalling systems lead to the activation of the same cellular function.

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National Cancer Institute (NCI)
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Matzkin, Maria Eugenia; Yamashita, Soichi; Ascoli, Mario (2013) The ERK1/2 pathway regulates testosterone synthesis by coordinately regulating the expression of steroidogenic genes in Leydig cells. Mol Cell Endocrinol 370:130-7
Tai, Ping; Ascoli, Mario (2011) Reactive oxygen species (ROS) play a critical role in the cAMP-induced activation of Ras and the phosphorylation of ERK1/2 in Leydig cells. Mol Endocrinol 25:885-93
Yamashita, Soichi; Tai, Ping; Charron, Jean et al. (2011) The Leydig cell MEK/ERK pathway is critical for maintaining a functional population of adult Leydig cells and for fertility. Mol Endocrinol 25:1211-22
Tai, Ping; Shiraishi, Koji; Ascoli, Mario (2009) Activation of the lutropin/choriogonadotropin receptor inhibits apoptosis of immature Leydig cells in primary culture. Endocrinology 150:3766-73
Galet, Colette; Ascoli, Mario (2008) Arrestin-3 is essential for the activation of Fyn by the luteinizing hormone receptor (LHR) in MA-10 cells. Cell Signal 20:1822-9
Shiraishi, Koji; Ascoli, Mario (2008) A co-culture system reveals the involvement of intercellular pathways as mediators of the lutropin receptor (LHR)-stimulated ERK1/2 phosphorylation in Leydig cells. Exp Cell Res 314:25-37
Shiraishi, Koji; Ascoli, Mario (2007) Lutropin/choriogonadotropin stimulate the proliferation of primary cultures of rat Leydig cells through a pathway that involves activation of the extracellularly regulated kinase 1/2 cascade. Endocrinology 148:3214-25
Ascoli, Mario (2007) Potential Leydig cell mitogenic signals generated by the wild-type and constitutively active mutants of the lutropin/choriogonadotropin receptor (LHR). Mol Cell Endocrinol 260-262:244-8
Galet, Colette; Ascoli, Mario (2006) A constitutively active mutant of the human lutropin receptor (hLHR-L457R) escapes lysosomal targeting and degradation. Mol Endocrinol 20:2931-45
Shiraishi, Koji; Ascoli, Mario (2006) Activation of the lutropin/choriogonadotropin receptor in MA-10 cells stimulates tyrosine kinase cascades that activate ras and the extracellular signal regulated kinases (ERK1/2). Endocrinology 147:3419-27

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