Gonadotropin-releasing hormone-regulated prohibitin mediates apoptosis of the gonadotrope cells

Dana Savulescu, Jiajun Feng, Yueh Shyang Ping, Oliver Mai, Ulrich Boehm, Bin He, Bert W. O'Malley, Philippa Melamed

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

GnRH regulates circulating levels of the gonadotropins but has also been implicated in establishing the gonadotrope cell population. Consistent with this, GnRH induces proliferation of partially differentiated gonadotropes, while reducing the numbers of fully differentiated cells. We have previously reported that the proapoptotic protein, prohibitin (PHB) is expressed more abundantly in gonadotrope-derived LβT2 cells than in partially differentiated βT3-1 gonadotrope precursor cells, suggesting a possible role for PHB in GnRH-induced apoptosis. We show here that PHB is required for GnRH-induced apoptosis in mature gonadotropes. PHB expression and activity are regulated by GnRH: its transcription is via c-Jun NH2-terminal kinase, whereas its nuclear export follows activation of ERK. Moreover, PHB levels are down-regulated by microRNA27, which is expressed at lower levels in mature gonadotropes, possibly explaining the switch to an apoptotic response with development. PHB is required for mitochondrial import of the proapoptotic BAX, whose expression is also induced by GnRH-activated c-Jun NH2-terminal kinase, as is expression of the BH3-only protein, HRK, and this too plays a role in GnRH-induced apoptosis. Finally, we show that gonadotrope-specific PHB-knockout mice display reproductive abnormalities, including a larger gonadotrope population, increased LH levels, reduced fertility, and altered gonad development. We thus demonstrate a role for PHB in GnRH-induced cell death in mature gonadotropes, which is crucial for the normal development and function of the reproductive axis.

Original languageEnglish (US)
Pages (from-to)1856-1870
Number of pages15
JournalMolecular Endocrinology
Volume27
Issue number11
DOIs
StatePublished - 2013

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

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