Abstract
BackgroundFollicular growth and atresia are tightly regulated processes, which involve the participation of endocrine, autocrine and paracrine factors at the cellular level. Prohibitin (PHB) is a multifunctional intracellular protein playing an important role in the regulation of proliferation, apoptosis and differentiation. Here we examined the expression of PHB and its regulation by FSH in vitro and studied the role of PHB in the regulation of apoptosis and steroidogenesis in response to the apoptosis inducer staurosporine (STS) and to FSH, respectively.MethodsUndifferentiated and differentiated granulosa cells were collected from diethylstilbestrol (DES)- and equine chronic gonadotropin (eCG)-primed immature rats, respectively and then cultured with various treatments (FSH, adenovirus infection, STS) according to experimental design. The apoptosis rate, the production of estradiol and progesterone, and the expression of distinct proteins (PHB, caspase-3, phospho- and total Akt) were assessed.ResultsPHB is anti-apoptotic and its action is dependent on the differentiated state of the granulosa cells. Data from gain- and loss-of-function experiments demonstrate that PHB inhibited STS-induced caspase-3 cleavage and apoptosis in undifferentiated granulosa cells, but was ineffective in differentiated cells. In contrast, PHB suppresses FSH-induced steroidogenesis and this response is evident irrespective of the differentiated state of granulosa cells.ConclusionThese findings suggest that PHB regulates granulosa cell apoptosis and steroidogenesis in a follicular stage-dependent manner and that the dysregulation of PHB expression and action may be relevant to ovarian dysfunction.
Highlights
Follicular growth and atresia are tightly regulated processes, which involve the participation of endocrine, autocrine and paracrine factors at the cellular level
PHB is differentially expressed in granulosa cells from different follicular stages To examine whether PHB is expressed in vivo in a follicular stage-dependent manner, differentiated and undifferentiated granulosa cells were collected and the gene expression of PHB was analyzed by traditional PCR
FSH upregulates PHB content in differentiated but not undifferentiated granulosa cells To explore whether FSH regulates PHB expression in vitro, undifferentiated and differentiated granulosa cells were cultured with FSH (100 ng/ml) for designated time (0–24 h) and the contents of PHB in two types of cells were examined
Summary
Follicular growth and atresia are tightly regulated processes, which involve the participation of endocrine, autocrine and paracrine factors at the cellular level. The destiny of the growing follicles (ovulation or atresia) is dependent on the fate of the cells within them (proliferation, differentiation or apoptosis) and is tightly regulated by endocrine, autocrine and paracrine factors [1]. Prohibitin (PHB) is a multifunctional protein highly conserved in various species, with identical amino acid sequences in mouse and rat and only one residue differing from that in human [5]. It is present in multiple cellular compartments, including nucleus, mitochondria, plasma membrane and lipid droplets, as well as in the circulation [6,7,8,9,10]. Nuclear PHB has been implicated in the regulation of gene expression by interacting with various transcriptional factors, such as E2F, p53 and estrogen receptor α (ERα) [7,17,18]
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