Prohibitin: a potential target for new therapeutics Suresh Mishra 1 , Leigh C. Murphy 2 , B.L. Gregoire Nyomba 1,3 and Liam J. Murphy 1,3 1 Department of Physiology, University of Manitoba, Winnipeg, Manitoba R3E 3P4, Canada 2 Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba R3E 3P4, Canada 3 Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba R3E 3P4, Canada Prohibitin (PHB) is localized to the mitochondria where it might have a role in the maintenance of mitochondrial function and protection against senescence. There is considerable controversy concerning the function of nuclear-localized PHB. PHB has potential roles as a tumor suppressor, an anti-proliferative protein, a reg- ulator of cell-cycle progression and in apoptosis. PHB might also function as a cell-surface receptor for an as- yet0unidentified ligand. Cell-associated PHB in the gastrointestinal tract has been implicated in protection against infection and inflammation and the induction of apoptosis in other tissues. The diverse array of functions of PHB, together with the emerging evidence that its function can be modulated specifically in certain tissues, suggest that targeting PHB would be a useful thera- peutic approach for the treatment of variety of disease states, including inflammation, obesity and cancer. Introduction Prohibitin (PHB) has a molecular mass of w30–32 kDa, whereas the closely related protein prohibitone, some- times referred to as B-cell-receptor-associated protein 37 (BAP 37) or prohibitin 2 (PHB2), has a mass of w37 kDa. The prohibitins (PHB and PHB2) together can form a high molecular weight complex. These complexes have been identified in both the mitochondria [1] and the plasma membrane [2]. PHB is a highly conserved protein. The deduced amino acid sequences of the proteins from mouse and rat are identical, and these differ from the human protein sequence by a single amino acid. PHB orthologues have also been identified in other mammals, Drosophila, yeast and plants [3]. The Drosophila gene Cc appears to be the orthologue of PHB and is vital for normal development [4]. As implied by the name, PHB was originally thought to have a central role in the inhibition of cell-cycle progression. Although there is evidence for the interaction of PHB with E2F, p53 and pRb, and the transfection of PHB can modulate transcription in cell-transfection experiments, this putative role of PHB as a regulator of cell-cycle progression has recently been challenged [5]. The best-characterized function of the prohibitins is as chaperones involved in the stabilization of mitochondrial proteins [1]. PHB is also localized to the plasma membrane in certain cell types and two recent reports suggest that it might function as a surface-binding site [2,6]. Furthermore, these reports provide ‘proof of prin- ciple’ that membrane-associated PHB can be targeted to modulate disease states [2,6]. In this review, the potential functions of prohibitin and the opportunities to target PHB will be discussed in relationship to its subcellular localization. Mitochondrial prohibitin The least controversial and best-described function of the prohibitins is as chaperone proteins in the mitochondria. This has been extensively reviewed elsewhere [3,5,7]. The prohibitins (PHB and PHB2) form a high molecular weight complex in the mitochondrial inner membrane, and this complex has been shown to have a role in the stabilization of newly synthesized subunits of mitochon- drial respiratory enzymes [1]. PHB is essential for normal mitochondrial development, and PHB deficiency in Caenorhabditis elegans is associated with deficient mito- chondrial biogenesis [7]. The expression of the prohibitins changes with senescence, both in mammalian fibroblasts [2,8] and yeast [9], a finding that suggests that the decline in prohibitins might be associated with the accumulation of damage from mitochondrial oxygen radicals. Furthermore, the loss of prohibitin function in yeast is associated with a reduced replicative lifespan [3,9]. These observations led to considerable interest in PHB among investigators involved in aging research, and the potential exists to modify the expression and functional activity of mitochondrial PHB to attenuate cellular senescence and aging (Table 1). Nuclear prohibitin The nuclear localization of PHB has been reported in a variety of cell lines. Confocal microscopy of androgen- stimulated LNCaP prostate-cancer cells has shown the localization of PHB in the nucleus and mitochondria [10]. Similarly, Fusaro et al. [11] have reported that PHB is predominantly nuclear in two breast cancer cell lines, in which it colocalizes with E2F1 and p53. Prohibitin, cell proliferation and apoptosis The suggestion that PHB has cell-cycle regulatory activity came from the observation that the microinjection of PHB mRNA blocks human fibroblasts from entering the S-phase, whereas antisense oligonucleotides stimulate Corresponding author: Murphy, L.J. (ljmurph@cc.umanitoba.ca). Available online 9 March 2005 Review TRENDS in Molecular Medicine Vol.11 No.4 April 2005 www.sciencedirect.com 1471-4914/$ - see front matter Q 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.molmed.2005.02.004