Receptors and Signal Transduction / Cellular and Molecular Endocrinology

The lutropin/choriogonadotropin (LHR) and follitropin (FSHR) receptors are the principal regulators of reproduction in humans.  Loss-of-function and gain-of-function mutations of these receptors are known to be associated with a number of disorders of the reproductive system such as ovarian dysgenesis, ovarian hyperstimulation syndrome, Leydig cell hypoplasia, male-limited precocious puberty and Leydig cell tumors.  The cognate hormones, lutropin/choriogonadotropin (LH/CG) and follitropin are widely used in the treatment of infertility.

Research in my laboratory is driven by the hypothesis that the binding of agonist to the LHR and the FSHR result in the activation of multiple signaling pathways, and that these pathways, either alone or in combination, stimulate the proliferation and differentiated functions of their respective target cells (Leydig and Granulosa cells).

Some of the projects that we are currently working on are as follows.  (1) Examine the involvement of G protein-dependent and G protein-independent pathways on the LHR and FSHR-induced activation of mitogenic signaling cascades.  (2) Examine the involvement of the Src-family of kinases and other tyrosine kinase cascades on the proliferative and differentiating functions of the LHR and FSHR. (3) Determine how the activation of two homologous receptors (LHR and FSHR) results in the expression of different phenotypes in granulosa cells

Experimental systems used in my laboratory include a Leydig tumor cell line that can be readily manipulated using standard transfection protocols, primary cultures of granulosa or Leydig cells that can be readily manipulated using adenoviral vectors and intact rats or genetically-modified mouse models.

Representative Publications:

K. Shiraishi and M. Ascoli: 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. doi:10.1016/j.yexcr.2007.06.025, 2007.

K. Shiraishi and M. Ascoli:  Lutropin choriogonadotropin (LH/CG) stimulate the proliferation of primary cultures of rat Leydig cells through a pathway that involves activation of the ERK1/2 cascade.  Endocrinology 148:3214-3225, 2007.

C. Galet and M. Ascoli: A constitutively active mutant of the human lutropin receptor (hLHR-L457R) escapes lysosomal targeting and degrada tion. Mol. Endocrinol 20:2931-2945, 2006.

N. Andric and M. Ascoli. A delayed, gonadotropin-dependent and growth-factor mediated activation of the ERK1/2 cascade negatively regulates aromatase expression in granulosa cells. Mol. Endocrinol. 20:3308-3320, 2006.

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