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Submitted on August 15, 2006
Accepted on November 21, 2006
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030 ; Garvan Institute of Medical Research, Cancer Research Program, Darlinghurst NSW, 2010, Australia , University of Colorado Health Sciences Center Cancer Center, Aurora, CO 80045 , Wyeth Womens Health Research Institute, Collegeville, PA 19426
* To whom correspondence should be addressed. E-mail: deane{at}bcm.tmc.edu.
Human progesterone receptor (PR) contains a motif that interacts with the SH3 domain of Src and mediates rapid activation of Src and down stream MAP kinase (Erk-1/-2) without relying on the transcriptional activity of the receptor. Here we investigated the role and intracellular location of this non-transcriptional activity of PR. Progestin activation of Src/MAPK occurred outside the nucleus with the B isoform of PR that was distributed between the cytoplasm and nucleus, but not with PR-A that was predominantly nuclear. Breast cancer cells stably expressing wild type PR-B or PR-B with disrupting point mutations in the SH3 domain binding motif (PR-B
SH3) that do not affect the transcriptional activity of PR, were compared for effects of progestin on endogenous target gene expression and cell proliferation. Progestin induction of the cyclin D1 gene, that lacks a progesterone response element (PRE), was dependent on PR activation of the Src/MAPK pathway whereas induction of the Sgk (serum and glucocorticoid regulated kinase) gene that contains a functional PRE was unaffected by mutations that interfere with PR activation of Src. Progestin induction of cell cycle progression was also abrogated in cells expressing PR-BSH3, and no effect of progestin on cyclin D1 expression and cell cycle was observed in the presence of PR-A. These results highlight the importance of PR activation of the Src/MAPK signaling pathway for progesterone induced transcription of select target genes and cell cycle progression.
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