Regulation of Prohibitin Expression During Follicular Development and Atresia in the Mammalian Ovary1

Thompson, Winston E.; Asselin, Éric; Branch, Alicia; Stiles, Jonathan K.; Šutovský, Peter; Lai, Liangxue; Im, Gi‐Sun; Prather, Randall S.; Isom, S. Clay; Rucker, Edmund B.; Tsang, Benjamin K.

doi:10.1095/biolreprod.103.024125

Cited by 44 publications

(52 citation statements)

References 40 publications

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“…In contrast, studies from many laboratories, including ours have attributed a predominantly nuclear function for prohibitin (13-16, 24, 26, 53-55). It has been shown recently that prohibitin is localized to the nucleus and cytoplasm of LnCAP cells (55); similarly, studies on prohibitin in rat ovary showed that prohibitin translocated from the cytoplasm to the nucleus in atretic follicles (54). A protein very similar to prohibitin (prohibitin 2, REA, and BAP37) has been described to repress the transcriptional activity of the estrogen receptor (18,19) as well as myoD (20).…”

Section: Discussionmentioning

confidence: 91%

Camptothecin Induces Nuclear Export of Prohibitin Preferentially in Transformed Cells through a CRM-1-dependent Mechanism

Rastogi

Joshi²,

Fusaro³

et al. 2006

Journal of Biological Chemistry

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Prohibitin is a growth-suppressive protein that has multiple functions in the nucleus and the mitochondria. Our earlier studies had shown that prohibitin represses the activity of E2F transcription factors while enhancing p53-mediated transcription. At the same time, prohibitin has been implicated in mediating the proper folding of mitochondrial proteins. We had found that treatment of cells with camptothecin, a topoisomerase 1 inhibitor, led to the export of prohibitin and p53 from the nucleus to the mitochondria. Here we show that the camptothecin-induced export of prohibitin occurs preferentially in transformed cell lines, but not in untransformed or primary cells. Cells that did not display the translocation of prohibitin were refractive to the apoptotic effects of camptothecin. The translocation was mediated by a putative nuclear export signal at the C-terminal region of prohibitin; fusion of the nuclear export signal (NES) of prohibitin to green fluorescence protein led to its export from the nucleus. Leptomycin B could inhibit the nuclear export of prohibitin showing that it was a CRM-1-dependent event driven by Ran GTPase. Confirming this, prohibitin was found to physically interact with CRM-1, and this interaction was significantly higher in transformed cells. Delivery of a peptide corresponding to the NES of prohibitin prevented the export of prohibitin to cytoplasm and protected cells from apoptosis. These results suggest that the regulated translocation of prohibitin from the nucleus to the mitochondria facilitates its pleiotropic functions and might contribute to its antiproliferative and tumor suppressive properties.Mammalian cells are exposed to a variety of extracellular signals that induce proliferation, differentiation, and apoptosis (1-3). The E2F transcription factors play a major role in regulating the above processes in a signal-dependent fashion (4) and are known to regulate the expression of a wide variety of genes involved in cell-cycle progression as well as apoptosis. The transcriptional activity of E2F1 is mainly regulated by the retinoblastoma tumor suppressor protein, Rb (5-7), which recruits a variety of transcriptional co-repressors, including HDAC1, 4 DNMT, polycomb proteins as well as chromatin-remodeling complexes like Brg and Brm (8 -12) to mediate transcriptional repression. In addition, our laboratory found that prohibitin, a potential tumor suppressor protein, could bind to and repress the activity of E2F transcription factors (13,14). The inhibition of E2F1 activity by prohibitin was reversed by specific extracellular signals like IgM stimulation and involved the recruitment of HDACs, N-CoR as well as chromatin-remodeling proteins like Brg and Brm (15,16). Prohibitin was found to bind to E2F1 through a putative coiled-coil domain spanning residues 185-215 and this region alone could repress the transcriptional activity of E2F1 (17). Interestingly, the growth-suppressive properties of prohibitin strongly correlated with its ability to repress E2F-mediated transcription. Pro...

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Section: Discussionmentioning

confidence: 91%

Camptothecin Induces Nuclear Export of Prohibitin Preferentially in Transformed Cells through a CRM-1-dependent Mechanism

Rastogi

Joshi²,

Fusaro³

et al. 2006

Journal of Biological Chemistry

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“…Besides, a different role of prohibitin in cancer cells as a crucial prerequisite for cell proliferation and survival was reported, which seemed to be associated with adhesion or migration signaling, and most likely as chaperones and scaffolding proteins as in mitochondria [23]. However, it is unknown if prohibitin plays any role in ovarian epithelial cells, particularly in the process of OET development, although prohibitin does have biological function in folliculogenesis [24]. In contrast to those in normal ovarian epithelium, a higher prohibitin expression level was observed in ovarian papillary serous and endometrioid carcinomas, which was inversely associated with cellular Ki-67 expression, a marker of cell proliferation and positively correlated with the cell survival marker X-linked inhibitor of apoptosis protein (XIAP).…”

Section: Discussionmentioning

confidence: 99%

Prohibitin as a novel target protein of luteinizing hormone in ovarian epithelial carcinogenesis

Ji¹,

Yi²,

Zhang³

et al. 2011

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The exact role of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in ovarian epithelial carcinoma (OEC) development has not been yet characterized. This prompted us to identify particular proteins to better understand the underlying mechanism. Total proteins from ovarian epithelial tumor (OET) cells treated with gonadotropins were analyzed by proteomics. Western blot and immunohistochemistry were used to validate the target protein (prohibitin) and to detect its expression in human ovarian tissue of serous tumors. As the results, prohibitin was found to be significantly up-regulated by LH, with a maximum of 2.5-fold increase at the concentration of 200 mIU/mL. The expression of prohibitin was steadily decreased from benign serous cystadenomas to borderline tumors and serous carcinomas (P < 0.0001). The difference between any two groups was significant (P < 0.001). Collectively, data from this study indicate that prohibitin is one LH-associated protein and it may be protective of ovarian cancer development and progression, supporting that LH may play an inhibitory role in ovarian tumorigenesis.

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“…Earlier work considered prohibitin as a potential tumor suppressor gene because microinjection of prohibitin transcripts resulted in growth arrest in HeLa cells (11). Prohibitin has also been reported to be localized to the nuclei of breast cancer cells (12) and to mediate hormone response in prostate cancer and ovary granulosa cells (13,14). There is evidence for the interaction of prohibitin with the cell cycle checkpoint molecules, including E2F (15), p53 (12), and pRB (16,17), and the overexpression of prohibitin can modulate transcription of multiple genes in the transfection experiments.…”

Section: Introductionmentioning

confidence: 99%

Prohibitin Is a Novel Target Gene of Vitamin D Involved in Its Antiproliferative Action in Breast Cancer Cells

et al. 2006

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Previously, we showed that N-methyl-N-nitrosourea-transformed MCF12F breast epithelial cells exhibited differential expression of several genes, including up-regulation of prohibitin and elevated sensitivity to a relatively noncalcemic vitamin D analogue, 1A-hydroxyvitamin D5 [1A(OH)D 5 ]. In this report, we evaluated the functional significance of prohibitin in relation to the cellular response to vitamin D. The in silico screening for putative transcription factor binding sites identified two vitamin D receptor (VDR)/retinoid X receptor binding sites in the 1-kb promoter region of prohibitin. Prohibitin up-regulation by 1A(OH)D 5 treatment at both transcriptional and translational levels was confirmed by real-time reverse transcription-PCR and Western blot analysis in breast cancer cells, identifying prohibitin as a vitamin D target gene. Confocal microscopic analysis showed that prohibitin was localized in the nuclei of MCF-7 cells and a portion of prohibitin was colocalized with VDR, but direct physical interaction between VDR and prohibitin in cell lysates was not detectable. In MCF-7 cells expressing tetracycline-inducible prohibitin (Tet-On model), the overexpression of prohibitin inhibited cell proliferation and enhanced vitamin D-induced antiproliferative activity. Knockdown of prohibitin was accompanied by increased number of cells incorporating bromodeoxyuridine in the whole population and increased cell distribution in the S phase of cell cycle. In addition, prohibitin level had no significant effect on the vitamin D-induced transactivation of CYP24, a VDR target gene. This is the first report to suggest that prohibitin serves as a novel vitamin D target gene, which is involved in the antiproliferative action of vitamin D without affecting CYP24 transactivation in breast cancer cells.

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Regulation of Prohibitin Expression During Follicular Development and Atresia in the Mammalian Ovary1

Cited by 44 publications

References 40 publications

Camptothecin Induces Nuclear Export of Prohibitin Preferentially in Transformed Cells through a CRM-1-dependent Mechanism

Camptothecin Induces Nuclear Export of Prohibitin Preferentially in Transformed Cells through a CRM-1-dependent Mechanism

Prohibitin as a novel target protein of luteinizing hormone in ovarian epithelial carcinogenesis

Prohibitin Is a Novel Target Gene of Vitamin D Involved in Its Antiproliferative Action in Breast Cancer Cells

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