UCSF DIABETES, ENDOCRINOLOGY & METABOLISM TRAINING PROGRAM FACULTY RESEARCH SUMMARIES

Neuroendocrine Control of Reproduction and Signaling Pathways for the Antiangiogenic Factor 16K PRL

My laboratory works on the neuroendocrine mechanisms which control ovulation in mammals. Reproductive function is driven by the pulsatile release of the hypothalamic hormone GnRH. We showed that pulsatile release of GnRH was an intrinsic property of the GnRH neurons. We are currently studying the molecular basis for the biological clock timing the release of GnRH every 25 minutes. Current findings suggest that the clock consists of the generation of cAMP and the activation of downstream signaling pathways, including cAMP-gated cation channels and protein kinase A. We use genetic approaches to alter the cAMP signaling pathway (e.g., expressing a phosphodiesterase to hydrolyze cAMP). We have now shown that lowering cAMP levels in GT1 cells or transgenic rats by expressing a phosphodiesterase results in the inhibition of pulsatile GnRH release. The lowered gonadotropin levels in the transgenic rats results in the formation of polycystic ovaries.

A second research focus is to develop therapeutic agents that inhibit the formation of a new blood supply (angiogenesis) to tumors. We showed that the 16 kDa N-terminal fragment of prolactin (16K PRL) is a potent anti-angiogenic factor. In capillary endothelial cells, 16K PRL inhibits VEGF-induced cell proliferation, activates PAI-1 expression, and induces apoptosis. We are studying the signaling pathways involved in mediating these responses. We are utilizing fluorescence resonance energy transfer to understand how these complex signaling events are integrated at the level of the plasma membrane. We also showed that 16K PRL through its anti-angiogenic action inhibits the growth of human colon cancer cells in a mouse model. We are now developing adenovirus vectors for testing in tumor models.

Selected References

El Majdoubi, M., S. Paruthiyil and R. I. Weiner. 2003. Pulsatile LH and FSH Secretion and Gonadotropin Subunit mRNA levels in the Ovariectomized GPR-4 Transgenic Rat. Neuroendocrinology 78:287-293.

Tsai, P. S., S. M. Moenter, H. R. Postigo, M. El Majdoubi, T. R. Pak, J. C. Gill, S. Paruthiyil. S. Werner, R. I. Weiner. 2004. Targeted expression of a dominant negative FGF receptor in GnRH neurons reduces FGF responsiveness and the size of GnRH neuronal population. Mol. Endocrinol. 19:225-236.

Gomez, F., S. E. La Fleur, R.I. Weiner, M.F. Dallman and M. El Majdoubi. 2005. Decreased gonadotropin-releasing hormone neuronal activity is associated with decreased fertility and dysregulation of food intake in the female GPR-4 transgenic rat. Endocrinology 146(9):3800-8.

Website : http://obgyn-nw.ucsf.edu/page.cfm?id=265

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