Regulation of AP1 (Jun/Fos) Factor Expression and Activation in Ovarian Granulosa Cells

Abstract

Growth of ovarian follicles involves regulated proliferation and differentiation of granulosa cells (1, 2). Exponential growth of granulosa cells in preovulatory follicles is followed by their terminal differentiation and formation of the corpus luteum, a transition initiated by the ovulatory surge of luteinizing hormone (LH).1 This transition of proliferating granulosa cells to non-dividing luteal cells is associated with specific changes in the expression of cell cycle regulatory molecules that control specific kinase cascades. The cell cycle activators, cyclin D2 and cyclin E, are increased by FSH and steroids in rapidly growing preovulatory follicles but are rapidly turned off by the surge of LH that terminates follicular growth (1, 2). Conversely, the cell cycle inhibitors, p27 KIP1 and p21 CIP1 , are induced by the LH surge (1, 2). Thus, the gonadotropins impact cell cycle progression at multiple steps depending on the stage of granulosa cell differentiation.The effects of the gonadotropins on ovarian cell proliferation and differentiation are mediated by changes in intracellular cAMP that activates cAMP-dependent protein kinases (protein kinase A) (3), as well as several other kinases (4, 5). Known targets of protein kinase A are the cAMP regulatory element (CRE)-binding protein CREB and the CREB-binding protein CBP (6). CREs are essential for transcriptional activation of aromatase (7) and inhibin ␣ (8), as well as the AP1 factors, c-fos (9) and fra2 (10). AP1 factors, in turn, mediate FSH-regulated expression of inhibin ␤A by binding to a variant CRE in the promoter of the ␤A gene (11). Members of the AP1 transcription factor superfamily are proto-oncogenes that regulate cell proliferation and transformation (12). They have also been associated with differentiation (13, 14). These observations suggest that specific AP1 factors or the combination of specific AP1 factors may regulate different sets of functions at specific stages of granulosa cell differentiation. Despite the intense research efforts that have analyzed the function of the Jun/Fos family in many different cell types, relatively few studies have analyzed how hormones regulate the expression of AP1 factors in granulosa cells or how these factors might impact FSH or LH activation of specific genes. Therefore, it becomes imperative to know which AP1 factors are present in granulosa cells and which might be regulated or activated by FSH and LH.

Analyses of p53 Target Genes in the Human Genome by Bioinformatic and Microarray Approaches

“…The results demonstrated that endogenous p53 protein interacts directly with predicted p53 binding sequences in these 5 genes, and that in silico prediction can greatly assist us in focusing on regions likely to confer p53-mediated expression. The biological properties of these genes are consistent with the functions that have been attributed to p53, such as, cell cycle checkpoints, apoptosis, inhibition of angiogenesis, and genetic stability (2,(23)(24)(25). The data suggest that these genes could be mediators of p53 expression through transcriptional regulation.…”

Impact of Aging on Steroid Hormone Biosynthesis and Secretion

“…In addition, steroid producing tissues are thought to require AP-1 for the regulation of steroidogenesis [387,[385][386][387][388][389][390][391][392][393][394][395][396][397][398][399][400]. AP-1 transcription factors are homo-and hetero-dimers of Jun (c-Jun, JunB and JunD), Fos (c-Fos, FosB, FosB splice variants FosB2 and DeltaFosB2 and Fra-1 and Fra-2) Jun dimerization partner (JDP1 and JDP2) and the closely related activating transcription factor (ATFa, ATF2, LRF1/ATF3, B-ATF) family of proteins characterized by basic region and leucine-zipper domains [353,385,[389][390][391][392][393][394].…”

Cumulus cell gene expression following the LH surge in bovine preovulatory follicles: potential early markers of oocyte competence

“…2) is involved in the response to LH by the maturational events in mouse COC including cumulus expansion and oocyte meiosis resumption (GVBD; Su et al 2003). ERK1/2 is also suggested to phosphorylate several transcriptional factors implicated in the final maturation and the ovulation processes, including FOS, MYC, STAT3, and LH genomic effect on bovine cumulus cells AP1 (Sharma & Richards 2000, Roux & Blenis 2004, Russell & Robker 2007. AP1, for example (Fig.…”