Skip to main content
PMC home page
Journal of Cellular and Molecular Medicine logoLink to Journal of Cellular and Molecular Medicine
. 2007 May 1;10(2):353–363. doi: 10.1111/j.1582-4934.2006.tb00404.x

The Prohibitins: emerging roles in diverse functions

Suresh Mishra a, Leigh C Murphy b, Liam J Murphy a,c,*
PMCID: PMC3933126  PMID: 16796804

Abstract

The prohibitins, Phb1 and Phb2 are highly conserved proteins in eukaryotic cells that are present in multiple cellular compartments. Initial investigations focused on the role of Phb1 as an inhibitor of cell proliferation hence the original name prohibitin. However both proteins appear to have a diverse range of functions and recent evidence suggests that the prohibitins have very similar but as yet only partially understood functions. In addition to their role as chaperone proteins in the mitochondria, and their ability to target to lipid rafts, their is now compelling evidence that both prohibitins are localized in the nucleus and can modulate transcriptional activity by interacting with various transcription factors, including the steroid hormone receptors, either directly or indirectly. In addition Phb1 and Phb2 are present in the circulation and can be internalized when added to cultured cells suggesting that the circulating prohibitins may have some regulatory role. This review presents some of the recent developments in prohibitin research and focuses on the similarities in the structure and function of these interesting proteins.

Keywords: Prohibitins, repressor of estrogen receptor action, B-cell receptor associated protein, BAP32, BAP37, lipid rafts

References

  • 1.Lamers MC, Bacher S. Prohibitin and prohibitone, ubiquitous and abundant proteins that are reluctant to reveal their real identity. Int Arch Allergy Immunol. 1997;113:146–9. doi: 10.1159/000237530. [DOI] [PubMed] [Google Scholar]
  • 2.Terashima M, Kim KM, Adachi T, Nielsen PJ, Reth M, Kohler G, Lamers MC. The IgM antigen receptor of B lymphocytes is associated with prohibitin and a prohibitin-related protein. EMBO J. 1994;13:3782–92. doi: 10.1002/j.1460-2075.1994.tb06689.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Montano MM, Ekena K, Delage-Mourroux R, Chang W, Martini P, Katzenellenbogen BS. An estrogen receptor-selective coregulator that potentiates the effectiveness of antiestrogens and represses the activity of estrogens. Proc Natl Acad Sci USA. 1999;96:6947–52. doi: 10.1073/pnas.96.12.6947. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.McClung JK, Danner DB, Stewart DA, Smith JR, Schneider EL, Lumpkin CK, Dell'Orco RT, Nuell MJ. Isolation of a cDNA that hybrid selects antiproliferative mRNA from rat liver. Biochem. Biophys. Res. Commun. 1989;164:1316–22. doi: 10.1016/0006-291x(89)91813-5. [DOI] [PubMed] [Google Scholar]
  • 5.Manjeshwar S, Branam DE, Lerner MR, Brackett DJ, Jupe ER. Tumor suppression by the prohibitin gene 3'untranslated region RNA in human breast cancer. Cancer Res. 2003;63:5251–6. [PubMed] [Google Scholar]
  • 6.Wang S, Fusaro G, Padmanabhan J, Chellappan SP. Prohibitin co-localizes with Rb in the nucleus and recruits N-CoR and HDAC1 for transcriptional repression. Oncogene. 2002;21:8388–96. doi: 10.1038/sj.onc.1205944. [DOI] [PubMed] [Google Scholar]
  • 7.Thompson WE, Branch A, Whittaker JA, Lyn D, Zilberstein M, Mayo KE, Thomas K. Characterization of prohibitin in a newly established rat ovarian granulosa cell line. Endocrinology. 2001;142:4076–85. doi: 10.1210/endo.142.9.8354. [DOI] [PubMed] [Google Scholar]
  • 8.Fusaro G, Dasgupta P, Rastogi S, Joshi B, Chellappan S. Prohibitin induces the transcriptional activity of p53 and is exported from the nucleus upon apoptotic signaling. J Biol Chem. 2003;278:47853–61. doi: 10.1074/jbc.M305171200. [DOI] [PubMed] [Google Scholar]
  • 9.Nijtmans LG, Artal SM, Grivell LA, Coates PJ. The mitochondrial PHB complex: roles in mitochondrial respiratory complex assembly, aging and degenerative disease. CMLS, Cell Mol Life Sci. 2002;59:143–55. doi: 10.1007/s00018-002-8411-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Morrow IC, Parton RG. Flotillins and the PHB domain protein family: rafts, worms and anaesthetics. Traffic. 2005;6:725–40. doi: 10.1111/j.1600-0854.2005.00318.x. [DOI] [PubMed] [Google Scholar]
  • 11.Kolonin MG, Saha PK, Chan L, Pasqualini R, Arap W. Reversal of obesity by targeted ablation of adipose tissue. Nat Med. 2004;10:625–32. doi: 10.1038/nm1048. [DOI] [PubMed] [Google Scholar]
  • 12.Brasaemle DL, Dolios G, Shapiro L, Wang R. Proteomic analysis of proteins associated with lipid droplets of basal and lipolytically stimulated 3T3-L1 adipocytes. J Biol Chem. 2004;279:46835–42. doi: 10.1074/jbc.M409340200. [DOI] [PubMed] [Google Scholar]
  • 13.Garin J, Diez R, Kieffer S, Dermine JF, Duclus S, Gagnon E, Sadoul R, Rondeau C, Desjardins M. The phagosome proteome: insight into phagosome functions. J Cell Biol. 2001;152:165–80. doi: 10.1083/jcb.152.1.165. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Coates PJ, Jamieson DJ, Smart K, Prescott AR, Hall PA. The prohibitin family of mitochondrial proteins regulate replicative lifespan. Curr Biol. 1997;7:607–10. doi: 10.1016/s0960-9822(06)00261-2. [DOI] [PubMed] [Google Scholar]
  • 15.Nuell MJ, Stewart DA, Walker L, Friedman V, Wood CM, Owens GA, Smith JR, Schneider EL, Dell'Orco R, Lumpkin CK, et al. Prohibitin, an evolutionarily conserved intracellular protein that blocks DNA synthesis in normal fibroblasts and HeLa cells. Mol Cell Biol. 1991;11:1372–81. doi: 10.1128/mcb.11.3.1372. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Jupe ER, Liu XT, Kiehlbauch JL, McClung JK, Dell'Orco RT. The 3′ untranslated region of prohibitin and cellular immortalization. Exp Cell Res. 1996;224:128–35. doi: 10.1006/excr.1996.0120. [DOI] [PubMed] [Google Scholar]
  • 17.Choongkittaworn NM, Kim KH, Danner DB, Griswold MD. Expression of prohibitin in rat seminiferous epithelium. 1993;49:300–10. doi: 10.1095/biolreprod49.2.300. [DOI] [PubMed] [Google Scholar]
  • 18.Hussain-Hakimjee EA, Peng X, Mehta RR, Mehta RG. Growth inhibition of carcinogen-transformed MCF-12F breast epithelial cells and hormone-sensitive BT-474 breast cancer cells by 1alpha-hydroxyvitamin D5. 2006;27:551–9. doi: 10.1093/carcin/bgi231. [DOI] [PubMed] [Google Scholar]
  • 19.Miyamoto S, Qin J, Safer B. Detection of early gene expression changes during activation of human primary lymphocytes by in vitro synthesis of proteins from polysome-associated mRNAs. Protein Sci. 2001;10:423–33. doi: 10.1110/ps.21301. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Tanno S, Fukuda I, Saito Y, Ogawa K. Prohibitin expression is decreased in the regenerating liver but not in chemically induced hepatic tumors in rats. Jpn J Cancer Res. 1997;88:1155–64. doi: 10.1111/j.1349-7006.1997.tb00344.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Lumpkin CK, Jr, Moore TL, Tarpley MD, Taylor JM, Badger TM, McClung JK. Acute ethanol and selected growth suppressor transcripts in regenerating rat liver. Alcohol. 1995;12:357–62. doi: 10.1016/0741-8329(95)00018-m. [DOI] [PubMed] [Google Scholar]
  • 22.Jupe ER, Liu XT, Kiehlbauch JL, McClung JK, Dell'Orco RT. Prohibitin antiproliferative activity and lack of heterozygosity in immortalized cell lines. Exp Cell Res. 1995;218:577–80. doi: 10.1006/excr.1995.1194. [DOI] [PubMed] [Google Scholar]
  • 23.Altus MS, Wood CM, Stewart DA, Roskams AJ, Friedman V, Henderson T, Owens GA, Danner DB, Jupe ER, Dell'Orco RT, et al. Regions of evolutionary conservation between the rat and human prohibitin-encoding genes. Gene. 1995;158:291–4. doi: 10.1016/0378-1119(95)00164-2. [DOI] [PubMed] [Google Scholar]
  • 24. http://www.hprd.org/protein.
  • 25.Rastogi S, Joshi B, Fusaro G, Chellappan S. Camptothecin induces nuclear export of prohibitin prefer-entially in transformed cells through a CRM-1-dependent mechanism. J Biol Chem. 2006;281:2951–9. doi: 10.1074/jbc.M508669200. [DOI] [PubMed] [Google Scholar]
  • 26.Thompson WE, Sanbuissho A, Lee GY, Anderson E. Steroidogenic acute regulatory (StAR) protein (p25) and prohibitin (p28) from culture rat ovarian granulose cells. J Reprod Fertil. 1997;109:337–48. doi: 10.1530/jrf.0.1090337. [DOI] [PubMed] [Google Scholar]
  • 27.Thompson WE, Ramalho-Santos J, Sutovsky P. Ubiquitination of prohibitin in mammalian sperm mitochondria: possible roles in the regulation of mitochondrial inheritance and sperm quality control. Biol. Reprod. 2003;69:254–60. doi: 10.1095/biolreprod.102.010975. [DOI] [PubMed] [Google Scholar]
  • 28.Mengwasser J, Piau A, Schlag P, Sleeman JP. Differential immunization identifies PHB1/PHB2 as blood-borne tumor antigens. Oncogene. 2004;23:7430–5. doi: 10.1038/sj.onc.1207987. [DOI] [PubMed] [Google Scholar]
  • 29.Camps L, Reina M, Llobera M, Vilaro S, Olivecrona T. Lipoprotein lipase: cellular origin and functional distribution. Am J Physiol. 1990;258:C673–81. doi: 10.1152/ajpcell.1990.258.4.C673. [DOI] [PubMed] [Google Scholar]
  • 30.Nadimpalli R, Yalpani N, Johal GS, Simmons CR. Prohibitins, stomatins and plant desease response genes compose a superfamily that controls cell proliferation, ion channels regulation and death. J Biol Chem. 2000;275:29579–86. doi: 10.1074/jbc.M002339200. [DOI] [PubMed] [Google Scholar]
  • 31.Tavernarakis N, Driscoll M, Kyrpides NC. The SPFH domain: implicated in regulating targeted protein turnover in stomatins and other membrane-associated proteins. Trends Biochem Sci. 1999;24:425–7. doi: 10.1016/s0968-0004(99)01467-x. [DOI] [PubMed] [Google Scholar]
  • 32.Nijtmans LG, de Jong L, Artal Sanz M, Coates PJ, Berden JA, Back JW, Muijsers AO, van der Spek H, Grivell LA. Prohibitins act as a membrane-bound chaperone for the stabilization of mitochondrial proteins. EMBO J. 2000;19:2444–51. doi: 10.1093/emboj/19.11.2444. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Santamaria E, Avila MA, Latasa MU, Rubio A, Martin-Duce A, Lu SC, Mato JM, Corrales FJ. Functional proteomics of nonalcoholic steatohepatitis: mitochondrial proteins as targets of S-adenosylmethion-ine. Proc Natl Acad Sci USA. 2003;100:3065–70. doi: 10.1073/pnas.0536625100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Matsuyama S, Kubo K, Ohashi F, Takamori Y. Partial cloning of prohibitin cDNA from canine, feline, bovine, equine, and rabbit liver mRNA by RT-PCR. J Vet Med Sci. 1997;59:201–3. doi: 10.1292/jvms.59.201. [DOI] [PubMed] [Google Scholar]
  • 35.McClung JK, Jupe ER, Liu XT, Dell'Orco RT. Prohibitin: potential role in senescence, development, and tumor suppression. Exp Gerontol. 1995;30:99–124. doi: 10.1016/0531-5565(94)00069-7. [DOI] [PubMed] [Google Scholar]
  • 36.Tatsuta T, Model K, Langer T. Formation of membrane bound ring complexes by prohibitin in mitochondria. Mole. Biol. Cell. 2005;16:248–59. doi: 10.1091/mbc.E04-09-0807. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Gamble SC, Odontiadis M, Waxman J, Westbrook JA, Dunn MJ, Wait R, Lam EW, Bevan CL. Androgens target prohibitin to regulate proliferation of prostate cancer cells. Oncogene. 2004;23:2996–04. doi: 10.1038/sj.onc.1207444. [DOI] [PubMed] [Google Scholar]
  • 38.Kurtev V, Margueron R, Kroboth K, Ogris E, Cavailles V, Seiser C. Transcriptional regulation by the repressor of estrogen receptor activity via recruitment of histone deacetylases. J Biol Chem. 2004;279:24834–43. doi: 10.1074/jbc.M312300200. [DOI] [PubMed] [Google Scholar]
  • 39.Sun L, Liu L, Yang XJ, Wu Z. Akt binds prohibitin 2 and relieves its repression of MyoD and muscle differentiation. 2004;117:3021–9. doi: 10.1242/jcs.01142. [DOI] [PubMed] [Google Scholar]
  • 40.Berger KH, Yaffe MP. Prohibitin family members interact genetically with mitochondrial inheritance components in Saccharomyces cerevisiae. Mol Cell Biol. 1998;18:4043–52. doi: 10.1128/mcb.18.7.4043. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Back JW, Sanz MA, De Jong L, De Koning LJ, Nijtmans LG, De Koster CG, Grivell LA, Van Der Spek H, Muijsers AO. A structure for the yeast prohibitin complex: Structure prediction and evidence from chemical crosslinking and mass spectrometry. 2002;11:2471–8. doi: 10.1110/ps.0212602. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Park SE, Xu J, Frolova A, Liao L, O'Malley BW, Katzenellenbogen BS. Genetic deletion of the repressor of estrogen receptor activity (REA) enhances the response to estrogen in target tissues in vivo. Mol Cell Biol. 2005;25:1989–99. doi: 10.1128/MCB.25.5.1989-1999.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Birner R, Nebauer R, Schneiter R, Daum G. Synthetic lethal interaction of the mitochondrial phos-phatidylethanolamine biosynthetic machinery with the prohibitin complex of Saccharomyces cerevisiae. Mol Biol Cell. 2003;14:370–83. doi: 10.1091/mbc.E02-05-0263. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Vessal M, Mishra S, Moulik S, Murphy LJ. Prohibitin attenuates insulin-stimulated glucose and fatty acid oxidation in adipose tissue by inhibition of pyruvate carboxy-lase. FEBS J. 2006;273:568–76. doi: 10.1111/j.1742-4658.2005.05090.x. [DOI] [PubMed] [Google Scholar]
  • 45.Jitrapakdee S, Wallace JC. Structure, function and regulation of pyruvate carboxylase. Biochem J. 1999;340:1–16. doi: 10.1042/bj3400001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Liu XT, Stewart CA, King RL, Danner DA, Dell'Orco RT, McClung JK. Prohibitin expression during cellular senescence of human diploid fibroblasts. Biochem Biophys Res Commun. 1994;201:409–14. doi: 10.1006/bbrc.1994.1716. [DOI] [PubMed] [Google Scholar]
  • 47.Petersen KF, Befroy D, Dufour S, Dziura J, Ariyan C, Rothman DL, DiPietro L, Cline GW, Shulman GI. Mitochondrial dysfunction in the elderly: possible role in insulin resistance. Science. 2003;300:1140–2. doi: 10.1126/science.1082889. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.Wang S, Nath N, Adlam M, Chellappan S. Prohibitin, a potential tumor suppressor, interacts with RB and regulates E2F function. Oncogene. 1999;18:3501–10. doi: 10.1038/sj.onc.1202684. [DOI] [PubMed] [Google Scholar]
  • 49.Joshi B, Ko D, Ordonez-Ercan D, Chellappan SP. A putative coiled-coil domain of prohibitin is sufficient to repress E2F1-mediated transcription and induce apoptosis. Biochem Biophys Res Commun. 2003;312:459–66. doi: 10.1016/j.bbrc.2003.10.148. [DOI] [PubMed] [Google Scholar]
  • 50.Wang S, Zhang B, Faller DV. Rb and prohibitin target distinct regions of E2F1 for repression and respond to different upstream signals. Mol Cell Biol. 1999;19:7447–60. doi: 10.1128/mcb.19.11.7447. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51.Wang S, Zhang B, Faller DV. BRG1/BRM and prohibitin are required for growth suppression by estrogen antagonists. EMBO J. 2004;23:2293–303. doi: 10.1038/sj.emboj.7600231. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52.Liu K, Luo Y, Lin FT, Lin WC. TopBP1 recruits Brg1/Brm to repress E2F1-induced apoptosis, a novel pRb-independent and E2F1-specific control for cell survival. Genes Dev. 2004;18:673–86. doi: 10.1101/gad.1180204. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.DiRenzo J, Shang Y, Phelan M, Sif S, Myers M, Kingston R, Brown M. BRG-1 is recruited to estrogen-responsive promoters and cooperates with factors involved in histone acetylation. Mole Cell Biol. 2000;20:7541–9. doi: 10.1128/mcb.20.20.7541-7549.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54.Delage-Mourroux R, Martini PG, Choi I, Kraichely DM, Hoeksema J, Katzenellenbogen BS. Analysis of estrogen receptor interaction with a repressor of estrogen receptor activity(REA) and the regulation of estrogen receptor transcriptional activity by REA. J Biol Chem. 2000;275:35848–56. doi: 10.1074/jbc.M001327200. [DOI] [PubMed] [Google Scholar]
  • 55.Simon SL, Parkes A, Leygue E, Dotzlaw H, Snell L, Troup S, Adeyinka A, Watson PH, Murphy LC. Expression of a repressor of estrogen receptor activity in human breast tumors: relationship to some known prognostic markers. Cancer Res. 2000;60:2796–9. [PubMed] [Google Scholar]
  • 56.Liu J, Deyoung SM, Zhang M, Dold LH, Saltiel AR. The stomatin/prohibitin/flotillin/HflK/C domain of flotillin-1 contains distinct sequences that direct plasma membrane localization and protein interactions in 3T3-L1 adipocytes. 2005;280:16125–34. doi: 10.1074/jbc.M500940200. [DOI] [PubMed] [Google Scholar]
  • 57.Marchler-Bauer A, Bryant SH. CD-Search: protein domain annotations on the fly. Nucleic Acids Res. 2004;32:W327–31. doi: 10.1093/nar/gkh454. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Cellular and Molecular Medicine are provided here courtesy of Blackwell Publishing

RESOURCES