Abstract
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 anti-proliferative and tumor suppressive properties.
Highlights
Polycomb proteins as well as chromatin-remodeling complexes like Brg and Brm (8 –12) to mediate transcriptional repression
We demonstrate that prohibitin undergoes nuclear export upon camptothecin treatment mainly in cancer cells; normal cell lines appear to be resistant to this effect of camptothecin
A double immunofluorescence experiment was conducted to examine whether this event was specific to camptothecin, or the translocation occurred when the cells were treated with other apoptotic agents as well
Summary
Polycomb proteins as well as chromatin-remodeling complexes like Brg and Brm (8 –12) to mediate transcriptional repression. Prohibitin and a related protein, prohibitin 2 ( known as REA and BAP37), have been shown to regulate the transcription of other factors like the estrogen receptor [18, 19] and myoD [20] These studies clearly demonstrate a nuclear function for prohibitin. An additional insight into the modulation of apoptosis by prohibitin was provided by the finding that it could physically interact with the p53 tumor suppressor protein and enhance its transcriptional activity [26] This transcriptional induction was mediated by enhanced recruitment of p53 to its target DNA binding sites, as seen by chromatin immunoprecipitation assays [26]. Inhibition of the binding of prohibitin to CRM-1 by a peptide prevented the export of prohibitin and negatively impacted apoptosis These results suggest that the nuclear export of prohibitin contributes to its multiple cellular functions
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