Regulation of steroidogenesis by p53 in macaque granulosa cells and H295R human adrenocortical cells

Mary Cherian-Shaw, Rituparna Das, Catherine A. Vandevoort, Charles L. Chaffin

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Ovulation and formation of a functional corpus luteum in primates involve cascades of events, including increased progesterone synthesis and changes in granulosa cell proliferation. However, critical gaps remain in our understanding of how an ovulatory gonadotropin surge initiates these processes. To more fully elucidate changes in the cell cycle during luteal formation, the actions of the tumor suppressor p53 were examined. Rhesus macaque granulosa cells were isolated during controlled ovarian stimulation protocols before (nonluteinized) or after (luteinized) an ovulatory gonadotropin stimulus. Phosphorylated p53 protein was detected in the cytoplasm of granulosa cells before and after human chorionic gonadotropin (hCG) treatment, whereas granulosa cells from hormonally controlled rats did not express p53 before or after hCG. Treatment of nonluteinized macaque granulosa cells with hCG and the p53 inhibitor pifithrin-α (PFT) in vitro did not alter markers of the cell cycle, including proliferating cell nuclear antigen, p21, and human double minute (HDM)-2 expression compared with hCG alone. Levels of pregnenolone and progesterone increased 2- and 4-fold, respectively, within 6 h of hCG treatment, whereas PFT completely blocked this hCG-induced effect. Estradiol was increased transiently (> 10-fold) by hCG plus PFT relative to levels after hCG alone. PFT also inhibited hCG-induced increases in steroidogenic acute regulatory protein and 3β-hydroxysteroid dehydrogenase mRNAs. Similar results were obtained using the human adrenocortical cell line H295R, suggesting that p53 may have a general function in primate steroidogenesis. These data indicate that p53 plays a key role in luteinization of the primate ovarian follicle though the regulation of steroidogenic enzymes leading to progesterone synthesis.

Original languageEnglish (US)
Pages (from-to)5734-5744
Number of pages11
JournalEndocrinology
Volume145
Issue number12
DOIs
StatePublished - Dec 2004

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

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