Signal Transduction Laboratory 

Director
John S. Davis, Ph.D.

Role of the Early Growth Response Factor 1 (Egr-1) Transcription Factor in the Corpus Luteum 

Secretion of progesterone is a primary function of the corpus luteum (CL) and a prerequisite for normal maintenance of pregnancy in all mammals.  The CL is a transient endocrine gland that develops from ovarian follicular cells, secrets progesterone for a period of time characteristic of the species and then undergoes luteolysis (disruption of progesterone synthesis and induction of cell death through apoptosis) unless pregnancy ensues.  While it is generally accepted that prostaglandin F_2a (PGF_2a) is the natural luteolysin in most mammals, the cellular and molecular mechanisms of PGF_2a-induced luteolysis remain poorly understood.

In humans, monkeys and ruminants the CL is largely dependent on pituitary-derived luteinizing hormone (LH).  Despite the acknowledged role of LH, the CL is unique with respect to regulation in that luteal progesterone production occurs relatively autonomously.  The classic-negative feedback system observed in the other endocrine tissues does not operate in the CL and at the end of the luteal phase, in spite of pituitary-support, the CL undergoes regression and progesterone secretion declines.  The uniqueness of CL regulation is also evident by the different mechanisms whereby luteal regression occurs and by the species specific mechanisms employed to maintain luteal progesterone secretion if a pregnancy ensues. This concept is clearly evident comparing the trophoblastic production of chorionic gonadotropin (hCG) in primates to the mechanisms employed in ungulates, which modulate uterine PGF_2a production and/or secretion.  Thus, the changing capacity for steroidogenesis by the CL is a critical aspect of luteal physiology.  In species where luteolysis is well established as being driven by uterine PGF_2a, exogenous administration of this luteolytic compound has been shown to cause a pronounced decline in progesterone secretion. 

The early growth response-1 gene (egr-1)  belongs to a group of immediate-early response genes and encodes a zinc finger-containing DNA-binding transcription factor. Egr-1 knock out mice have a reduced body size and are infertile. A recent report  suggests that egr-1 may mediate molecular programs of differentiation and lutienization in granulosa cells. Studies in various cell lines have shown that Egr-1 protein can induce the up-regulation and activation of various pro-apoptotic proteins, suggesting that Egr-1 is an active part of the apoptotic-signaling cascade. Our preliminary data demonstrate that Egr-1 mRNA and protein are up-regulated in the CL during PGF_2a-induced luteolysis in vivo and in PGF_2a-treated luteal cells in vitro. Ongoing studies are evaluating the mechanisms that regulate Egr-1 action and the role of Egr-1 in the function and fate of the CL.

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