Prohibitin co-localizes with Rb in the nucleus and recruits N-CoR and HDAC1 for transcriptional repression

Abstract

The potential tumor suppressor protein prohibitin can prevent cell proliferation and this required its binding to the Rb protein. Prohibitin could repress the transcriptional activity of E2F family members and this required a part of the marked box region of E2F. The sub-cellular localization of prohibitin has been variously attributed to the mitochondria as well as the inner cell membrane.Here we show that a subset of prohibitin molecules are present in the nucleus where it co-localizes with the Rb protein. Deletion of a putative amino-terminal membrane-docking domain of prohibitin had no effect on its ability to suppress cell proliferation or inhibit E2F activity. Our experiments show that a 53 amino-acid stretch of E2F1 is sufficient for being targeted by prohibitin; fusion of this region to GAL4 -VP16 construct could make it susceptible to prohibitinmediated, but not Rb-mediated repression. Prohibitin, like Rb, could repress transcription from SV40 and major late promoters when recruited directly to DNA. Prohibitin mediated transcriptional repression required histone-deacetylase activity, but unlike Rb, additional corepressors like N-CoR are also involved. Repression by prohibitin correlates with histone deacetylation on promoters and this was reversed by IgM stimulation of cells; IgM did not affect Rb-mediated repression or deacetylation of the promoters. Prohibitin thus appears to repress E2F-mediated transcription utilizing different molecular mediators and facilitate channeling of specific signaling pathways to the cell cycle machinery.

Prohibitin promotes androgen receptor activation in ER-positive breast cancer

“…PHB was also reported to physically interact with Rb family proteins in inhibiting E2F-mediated transcription to inhibit cell proliferation in breast cancer. 6,22 As shown in Fig. 2A, reduction of cell proliferation occurred in a time-dependent manner following overexpression of PHB in the both 2 ER-positive breast cancer cell lines.…”

“…[1][2][3][4] PHB has been reported to repress E2F via recruitment of the repressive proteins histone deacetylase 1 (HDAC1), nuclear receptor co-repressor (N-CoR) and the chromatin-condensing proteins brahma-related gene-1 (BRG1)/brahma (Brm). 5,6 PHB can also inhibit steroidactivated nuclear receptors, such as the androgen receptor (AR) and estrogen receptor (ER). 7,8 PHB was reported to act as a potent transcriptional co-repressor of ERa and associate with estrogen-regulated promoters in the absence of hormone, dissociating after hormone treatment in the breast cancer cells.…”

Androgens target prohibitin to regulate proliferation of prostate cancer cells

“…Prohibitin appears to have dual roles in the cell, being ubiquitously expressed in the mitochondria and also located in the nucleus of certain cell types (Thompson et al, 2001;Wang et al, 2002a). Prohibitin was initially suspected to be a tumour suppressor gene, due to the ability of the mRNA to inhibit DNA synthesis and cell cycle (McClung et al, 1989).…”

“…It has been demonstrated, using transfection assays, that prohibitin can reduce the amount of transcription mediated by E2F1 by interacting directly with E2F1 and also recruiting Rb, histone deacetylases and the corepressor NCoR (Wang et al, 2002b). This complex may form an alternative to the Rb-mediated repression of E2F, as Rb and prohibitin appear to bind E2F at different sites on the E2F protein and recruit different corepressors, prohibitin apparently linking E2F to HDACs via NCoR (Wang et al, 2002a). As the current literature suggests a cell-cycle role in other hormoneresponsive cells, possibly via the regulation of transcription and post-translational modification (Thompson et al, 2001), and we saw changes in prohibitin expression in prostate cancer cells simulated to grow by androgen, we have investigated its function further, with an aim of understanding its role in the cell cycle and growth responses to androgen stimulation in prostate cells.…”

Estudos transcriptômicos no contexto da conectividade perturbada em esquizofrenia

“…Alterations in prohibitin were hypothesized to be involved in disturbed synaptic plasticity 98 . It is known to control histone deacetylation 99 and can be localized in the inner membrane of mitochondria.…”