Prohibitin, also known as PHB, is a protein that in humans is encoded by the PHBgene.[1]
The Phb gene has also been described in animals, fungi, plants, and unicellular eukaryotes. Prohibitins are divided in two classes, termed Type-I and Type-II prohibitins, based on their similarity to yeast PHB1 and PHB2, respectively. Each organism has at least one copy of each type of prohibitin gene.[2][3]
Prohibitins are evolutionarily conserved genes that are ubiquitously expressed. The human prohibitin gene, located on the BRCA1 chromosome region 17q21, was originally thought to be a negative regulator of cell proliferation and a tumor suppressor. This anti-proliferative activity was later attributed to the 3' UTR of the PHB gene, and not to the actual protein. Mutations in human PHB have been linked to sporadic breast cancer. However, over-expression of PHB has been associated with a reduction in the androgen receptor activity and a reduction in PSA gene expression resulting in a decrease of androgen-dependent growth of cancerous prostate cells.[4]
Prohibitin is expressed as two transcripts with varying lengths of 3' untranslated region. The longer transcript is present at higher levels in proliferating tissues and cells, suggesting that this longer 3' untranslated region may function as a trans-acting regulatory RNA.[1]
Function
Prohibitins may have multiple functions including:
Mitochondrial function and morphology
Prohibitins are assembled into a ring-like structure with 16–20 alternating Phb1 and Phb2 subunits in the inner mitochondrial membrane.[5] The precise molecular function of the PHB complex is not clear, but a role as chaperone for respiration chain proteins or as a general structuring scaffold required for optimal mitochondrial morphology and function are suspected. Recently, prohibitins have been demonstrated to be positive, rather than negative, regulators of cell proliferation in both plants and mice.
Transcriptional modulation
Both human prohibitins have also been suggested to be localized in the nucleus and modulate transcriptional activity by interacting with various transcription factors, including nuclear receptors, either directly or indirectly. However, little evidence for nuclear targeting and transcription factor-binding of prohibitins has been found in other organism (yeast, plants, C. elegans, etc.), indicating that this may be a specific function in mammalian cells.[6][7][8][9]
↑Van Aken O, Pecenková T, van de Cotte B, De Rycke R, Eeckhout D, Fromm H, De Jaeger G, Witters E, Beemster GT, Inzé D, Van Breusegem F (Dec 2007). "Mitochondrial type-I prohibitins of Arabidopsis thaliana are required for supporting proficient meristem development". The Plant Journal. 52 (5): 850–64. doi:10.1111/j.1365-313X.2007.03276.x. PMID17883375.
↑Mishra S, Murphy LC, Murphy LJ (2006). "The Prohibitins: emerging roles in diverse functions". Journal of Cellular and Molecular Medicine. 10 (2): 353–63. doi:10.1111/j.1582-4934.2006.tb00404.x. PMID16796804.
↑Dart, D Alwyn. "Manipulating prohibitin levels provides evidence for an in vivo role in androgen regulation of prostate tumours". Endocr Relat Cancer. PMC2782800. Missing or empty |url= (help)
↑Gamble SC, Chotai D, Odontiadis M, Dart DA, Brooke GN, Powell SM, Reebye V, Varela-Carver A, Kawano Y, Waxman J, Bevan CL (Mar 2007). "Prohibitin, a protein downregulated by androgens, represses androgen receptor activity". Oncogene. 26 (12): 1757–68. doi:10.1038/sj.onc.1209967. PMID16964284.
↑Kurtev V, Margueron R, Kroboth K, Ogris E, Cavailles V, Seiser C (Jun 2004). "Transcriptional regulation by the repressor of estrogen receptor activity via recruitment of histone deacetylases". The Journal of Biological Chemistry. 279 (23): 24834–43. doi:10.1074/jbc.M312300200. PMID15140878.
↑Wintachai P, Wikan N, Kuadkitkan A, Jaimipuk T, Ubol S, Pulmanausahakul R, Auewarakul P, Kasinrerk W, Weng WY, Panyasrivanit M, Paemanee A, Kittisenachai S, Roytrakul S, Smith DR (Nov 2012). "Identification of prohibitin as a Chikungunya virus receptor protein". Journal of Medical Virology. 84 (11): 1757–70. doi:10.1002/jmv.23403. PMID22997079.
↑Kuadkitkan A, Wikan N, Fongsaran C, Smith DR (Oct 2010). "Identification and characterization of prohibitin as a receptor protein mediating DENV-2 entry into insect cells". Virology. 406 (1): 149–61. doi:10.1016/j.virol.2010.07.015. PMID20674955.
↑Bacher S, Achatz G, Schmitz ML, Lamers MC (Dec 2002). "Prohibitin and prohibitone are contained in high-molecular weight complexes and interact with alpha-actinin and annexin A2". Biochimie. 84 (12): 1207–20. doi:10.1016/s0300-9084(02)00027-5. PMID12628297.
↑ 14.014.1Joshi B, Ko D, Ordonez-Ercan D, Chellappan SP (Dec 2003). "A putative coiled-coil domain of prohibitin is sufficient to repress E2F1-mediated transcription and induce apoptosis". Biochemical and Biophysical Research Communications. 312 (2): 459–66. doi:10.1016/j.bbrc.2003.10.148. PMID14637159.
↑ 15.015.1Fusaro G, Dasgupta P, Rastogi S, Joshi B, Chellappan S (Nov 2003). "Prohibitin induces the transcriptional activity of p53 and is exported from the nucleus upon apoptotic signaling". The Journal of Biological Chemistry. 278 (48): 47853–61. doi:10.1074/jbc.M305171200. PMID14500729.
↑Wang S, Fusaro G, Padmanabhan J, Chellappan SP (Dec 2002). "Prohibitin co-localizes with Rb in the nucleus and recruits N-CoR and HDAC1 for transcriptional repression". Oncogene. 21 (55): 8388–96. doi:10.1038/sj.onc.1205944. PMID12466959.
↑ 18.018.118.2Wang S, Nath N, Adlam M, Chellappan S (Jun 1999). "Prohibitin, a potential tumor suppressor, interacts with RB and regulates E2F function". Oncogene. 18 (23): 3501–10. doi:10.1038/sj.onc.1202684. PMID10376528.
↑Sato S, Murata A, Orihara T, Shirakawa T, Suenaga K, Kigoshi H, Uesugi M (Jan 2011). "Marine natural product aurilide activates the OPA1-mediated apoptosis by binding to prohibitin". Chemistry & Biology. 18 (1): 131–9. doi:10.1016/j.chembiol.2010.10.017. PMID21276946.
↑Pérez-Perarnau A, Preciado S, Palmeri CM, Moncunill-Massaguer C, Iglesias-Serret D, González-Gironès DM, Miguel M, Karasawa S, Sakamoto S, Cosialls AM, Rubio-Patiño C, Saura-Esteller J, Ramón R, Caja L, Fabregat I, Pons G, Handa H, Albericio F, Gil J, Lavilla R (Sep 2014). "A trifluorinated thiazoline scaffold leading to pro-apoptotic agents targeting prohibitins". Angewandte Chemie. 53 (38): 10150–4. doi:10.1002/anie.201405758. PMID25196378.
↑Polier G, Neumann J, Thuaud F, Ribeiro N, Gelhaus C, Schmidt H, Giaisi M, Köhler R, Müller WW, Proksch P, Leippe M, Janssen O, Désaubry L, Krammer PH, Li-Weber M (Sep 2012). "The natural anticancer compounds rocaglamides inhibit the Raf-MEK-ERK pathway by targeting prohibitin 1 and 2". Chemistry & Biology. 19 (9): 1093–104. doi:10.1016/j.chembiol.2012.07.012. PMID22999878.
Further reading
McClung JK, Jupe ER, Liu XT, Dell'Orco RT (1996). "Prohibitin: potential role in senescence, development, and tumor suppression". Experimental Gerontology. 30 (2): 99–124. doi:10.1016/0531-5565(94)00069-7. PMID8591812.
Dell'Orco RT, McClung JK, Jupe ER, Liu XT (1996). "Prohibitin and the senescent phenotype". Experimental Gerontology. 31 (1–2): 245–52. doi:10.1016/0531-5565(95)02009-8. PMID8706794.
Mishra S, Murphy LC, Nyomba BL, Murphy LJ (Apr 2005). "Prohibitin: a potential target for new therapeutics". Trends in Molecular Medicine. 11 (4): 192–7. doi:10.1016/j.molmed.2005.02.004. PMID15823758.
Sato T, Saito H, Swensen J, Olifant A, Wood C, Danner D, Sakamoto T, Takita K, Kasumi F, Miki Y (Mar 1992). "The human prohibitin gene located on chromosome 17q21 is mutated in sporadic breast cancer". Cancer Research. 52 (6): 1643–6. PMID1540973.
Dawson SJ, White LA (May 1992). "Treatment of Haemophilus aphrophilus endocarditis with ciprofloxacin". The Journal of Infection. 24 (3): 317–20. doi:10.1016/S0163-4453(05)80037-4. PMID1602151.
White JJ, Ledbetter DH, Eddy RL, Shows TB, Stewart DA, Nuell MJ, Friedman V, Wood CM, Owens GA, McClung JK (Sep 1991). "Assignment of the human prohibitin gene (PHB) to chromosome 17 and identification of a DNA polymorphism". Genomics. 11 (1): 228–30. doi:10.1016/0888-7543(91)90126-Y. PMID1684951.
Altus MS, Wood CM, Stewart DA, Roskams AJ, Friedman V, Henderson T, Owens GA, Danner DB, Jupe ER, Dell'Orco RT (Jun 1995). "Regions of evolutionary conservation between the rat and human prohibitin-encoding genes". Gene. 158 (2): 291–4. doi:10.1016/0378-1119(95)00164-2. PMID7607556.
Ikonen E, Fiedler K, Parton RG, Simons K (Jan 1995). "Prohibitin, an antiproliferative protein, is localized to mitochondria". FEBS Letters. 358 (3): 273–7. doi:10.1016/0014-5793(94)01444-6. PMID7843414.
Maruyama K, Sugano S (Jan 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID8125298.
Sato T, Sakamoto T, Takita K, Saito H, Okui K, Nakamura Y (Sep 1993). "The human prohibitin (PHB) gene family and its somatic mutations in human tumors". Genomics. 17 (3): 762–4. doi:10.1006/geno.1993.1402. PMID8244394.
Jupe ER, Liu XT, Kiehlbauch JL, McClung JK, Dell'Orco RT (Apr 1996). "The 3' untranslated region of prohibitin and cellular immortalization". Experimental Cell Research. 224 (1): 128–35. doi:10.1006/excr.1996.0120. PMID8612677.
Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (Oct 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID9373149.
Wang S, Nath N, Adlam M, Chellappan S (Jun 1999). "Prohibitin, a potential tumor suppressor, interacts with RB and regulates E2F function". Oncogene. 18 (23): 3501–10. doi:10.1038/sj.onc.1202684. PMID10376528.
Coates PJ, Nenutil R, McGregor A, Picksley SM, Crouch DH, Hall PA, Wright EG (May 2001). "Mammalian prohibitin proteins respond to mitochondrial stress and decrease during cellular senescence". Experimental Cell Research. 265 (2): 262–73. doi:10.1006/excr.2001.5166. PMID11302691.
Van Aken O, Pecenková T, van de Cotte B, De Rycke R, Eeckhout D, Fromm H, De Jaeger G, Witters E, Beemster GT, Inzé D, Van Breusegem F (Dec 2007). "Mitochondrial type-I prohibitins of Arabidopsis thaliana are required for supporting proficient meristem development". The Plant Journal. 52 (5): 850–64. doi:10.1111/j.1365-313X.2007.03276.x. PMID17883375.