{{cs1 config|name-list-style=vanc}} {{Short description|Mammalian protein found in Homo sapiens}} {{Infobox_gene}} '''Prohibitin''', also known as '''PHB''', is a protein that in humans is encoded by the ''PHB'' gene.<ref name="entrez">{{cite web | title = Entrez Gene: PHB prohibitin| url = https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=5245}}</ref> 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.<ref>{{cite journal | vauthors = 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 | title = Mitochondrial type-I prohibitins of Arabidopsis thaliana are required for supporting proficient meristem development | journal = The Plant Journal | volume = 52 | issue = 5 | pages = 850–64 | date = Dec 2007 | pmid = 17883375 | doi = 10.1111/j.1365-313X.2007.03276.x | doi-access = free }}</ref><ref name="pmid16796804">{{cite journal | vauthors = Mishra S, Murphy LC, Murphy LJ | title = The Prohibitins: emerging roles in diverse functions | journal = Journal of Cellular and Molecular Medicine | volume = 10 | issue = 2 | pages = 353–63 | year = 2006 | pmid = 16796804 | pmc = 3933126 | doi = 10.1111/j.1582-4934.2006.tb00404.x }}</ref>
== Discovery == 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' untranslated region 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 androgen receptor activity and a reduction in PSA gene expression resulting in a decrease of androgen-dependent growth of prostate cancer cells.<ref>{{cite journal | vauthors = Dart DA, Spencer-Dene B, Gamble SC, Waxman J, Bevan CL | title = Manipulating prohibitin levels provides evidence for an in vivo role in androgen regulation of prostate tumours | journal = Endocrine-Related Cancer | volume = 16 | issue = 4 | pages = 1157–1169 | date = December 2009 | pmid = 19635783 | pmc = 2782800 | doi = 10.1677/ERC-09-0028 }}</ref> 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.<ref name="entrez" />
== 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.<ref name="pmid15525670">{{cite journal | vauthors = Tatsuta T, Model K, Langer T | title = Formation of membrane-bound ring complexes by prohibitins in mitochondria | journal = Molecular Biology of the Cell | volume = 16 | issue = 1 | pages = 248–59 | date = Jan 2005 | pmid = 15525670 | pmc = 539169 | doi = 10.1091/mbc.E04-09-0807 }}</ref> The precise molecular function of the PHB complex is not clear, but a role as chaperone for respiratory 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 cell 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.<ref name="pmid10359819">{{cite journal | vauthors = Montano MM, Ekena K, Delage-Mourroux R, Chang W, Martini P, Katzenellenbogen BS | title = An estrogen receptor-selective coregulator that potentiates the effectiveness of antiestrogens and represses the activity of estrogens | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 96 | issue = 12 | pages = 6947–52 | date = Jun 1999 | pmid = 10359819 | pmc = 22022 | doi = 10.1073/pnas.96.12.6947 | bibcode = 1999PNAS...96.6947M | doi-access = free }}</ref><ref name="pmid16964284">{{cite journal | vauthors = Gamble SC, Chotai D, Odontiadis M, Dart DA, Brooke GN, Powell SM, Reebye V, Varela-Carver A, Kawano Y, Waxman J, Bevan CL | title = Prohibitin, a protein downregulated by androgens, represses androgen receptor activity | journal = Oncogene | volume = 26 | issue = 12 | pages = 1757–68 | date = Mar 2007 | pmid = 16964284 | doi = 10.1038/sj.onc.1209967 | s2cid = 9592990 }}</ref><ref name="pmid15140878">{{cite journal | vauthors = Kurtev V, Margueron R, Kroboth K, Ogris E, Cavailles V, Seiser C | title = Transcriptional regulation by the repressor of estrogen receptor activity via recruitment of histone deacetylases | journal = The Journal of Biological Chemistry | volume = 279 | issue = 23 | pages = 24834–43 | date = Jun 2004 | pmid = 15140878 | doi = 10.1074/jbc.M312300200 | doi-access = free }}</ref><ref name="pmid15713652">{{cite journal | vauthors = Park SE, Xu J, Frolova A, Liao L, O'Malley BW, Katzenellenbogen BS | title = Genetic deletion of the repressor of estrogen receptor activity (REA) enhances the response to estrogen in target tissues in vivo | journal = Molecular and Cellular Biology | volume = 25 | issue = 5 | pages = 1989–99 | date = Mar 2005 | pmid = 15713652 | pmc = 549370 | doi = 10.1128/MCB.25.5.1989-1999.2005 }}</ref>
== Clinical significance ==
Human prohibitin 1 has some activity as a virus receptor protein, having been identified as a receptor for Chikungunya Virus (CHIKV)<ref name="pmid22997079">{{cite journal | vauthors = 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 | title = Identification of prohibitin as a Chikungunya virus receptor protein | journal = Journal of Medical Virology | volume = 84 | issue = 11 | pages = 1757–70 | date = Nov 2012 | pmid = 22997079 | doi = 10.1002/jmv.23403 | s2cid = 22172257 }}</ref> and Dengue Virus 2 (DENV-2).<ref name="pmid20674955">{{cite journal | vauthors = Kuadkitkan A, Wikan N, Fongsaran C, Smith DR | title = Identification and characterization of prohibitin as a receptor protein mediating DENV-2 entry into insect cells | journal = Virology | volume = 406 | issue = 1 | pages = 149–61 | date = Oct 2010 | pmid = 20674955 | doi = 10.1016/j.virol.2010.07.015 | doi-access = free }}</ref> Little else is known about the activity of the prohibitins in viral pathogenesis.
== Interactions ==
Prohibitin has been shown to interact with: {{div col|colwidth=20em}} * ANXA2<ref name = pmid12628297>{{cite journal | vauthors = Bacher S, Achatz G, Schmitz ML, Lamers MC | title = Prohibitin and prohibitone are contained in high-molecular weight complexes and interact with alpha-actinin and annexin A2 | journal = Biochimie | volume = 84 | issue = 12 | pages = 1207–20 | date = Dec 2002 | pmid = 12628297 | doi = 10.1016/s0300-9084(02)00027-5 }}</ref> * C-Raf,<ref name = pmid10523633>{{cite journal | vauthors = Wang S, Nath N, Fusaro G, Chellappan S | title = Rb and prohibitin target distinct regions of E2F1 for repression and respond to different upstream signals | journal = Molecular and Cellular Biology | volume = 19 | issue = 11 | pages = 7447–60 | date = Nov 1999 | pmid = 10523633 | pmc = 84738 | doi = 10.1128/mcb.19.11.7447}}</ref> * E2F1,<ref name = pmid10523633/><ref name = pmid14637159/><ref name = pmid14500729>{{cite journal | vauthors = Fusaro G, Dasgupta P, Rastogi S, Joshi B, Chellappan S | title = Prohibitin induces the transcriptional activity of p53 and is exported from the nucleus upon apoptotic signaling | journal = The Journal of Biological Chemistry | volume = 278 | issue = 48 | pages = 47853–61 | date = Nov 2003 | pmid = 14500729 | doi = 10.1074/jbc.M305171200 | doi-access = free }}</ref><ref name = pmid12065415>{{cite journal | vauthors = Wang S, Zhang B, Faller DV | title = Prohibitin requires Brg-1 and Brm for the repression of E2F and cell growth | journal = The EMBO Journal | volume = 21 | issue = 12 | pages = 3019–28 | date = Jun 2002 | pmid = 12065415 | pmc = 126057 | doi = 10.1093/emboj/cdf302 }}</ref> * HDAC1,<ref name = pmid14637159>{{cite journal | vauthors = Joshi B, Ko D, Ordonez-Ercan D, Chellappan SP | title = A putative coiled-coil domain of prohibitin is sufficient to repress E2F1-mediated transcription and induce apoptosis | journal = Biochemical and Biophysical Research Communications | volume = 312 | issue = 2 | pages = 459–66 | date = Dec 2003 | pmid = 14637159 | doi = 10.1016/j.bbrc.2003.10.148 }}</ref><ref name = pmid12466959>{{cite journal | vauthors = Wang S, Fusaro G, Padmanabhan J, Chellappan SP | title = Prohibitin co-localizes with Rb in the nucleus and recruits N-CoR and HDAC1 for transcriptional repression | journal = Oncogene | volume = 21 | issue = 55 | pages = 8388–96 | date = Dec 2002 | pmid = 12466959 | doi = 10.1038/sj.onc.1205944 | doi-access = free }}</ref> * P53,<ref name = pmid14500729/> * RB1,<ref name = pmid10523633/><ref name = pmid10376528/> * RBL1,<ref name = pmid10376528/> * RBL2,<ref name = pmid10376528>{{cite journal | vauthors = Wang S, Nath N, Adlam M, Chellappan S | title = Prohibitin, a potential tumor suppressor, interacts with RB and regulates E2F function | journal = Oncogene | volume = 18 | issue = 23 | pages = 3501–10 | date = Jun 1999 | pmid = 10376528 | doi = 10.1038/sj.onc.1202684 | doi-access = free }}</ref> * SMARCA2,<ref name = pmid12065415/> and * SMARCA4.<ref name = pmid12065415/> {{Div col end}}
==Drugs that bind to prohibitin== * Aurilide<ref>{{cite journal | vauthors = Sato S, Murata A, Orihara T, Shirakawa T, Suenaga K, Kigoshi H, Uesugi M | title = Marine natural product aurilide activates the OPA1-mediated apoptosis by binding to prohibitin | journal = Chemistry & Biology | volume = 18 | issue = 1 | pages = 131–9 | date = Jan 2011 | pmid = 21276946 | doi = 10.1016/j.chembiol.2010.10.017 | doi-access = free | hdl = 2433/137219 | hdl-access = free }}</ref> * Fluorizoline<ref>{{cite journal | vauthors = 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 | title = A trifluorinated thiazoline scaffold leading to pro-apoptotic agents targeting prohibitins | journal = Angewandte Chemie | volume = 53 | issue = 38 | pages = 10150–4 | date = Sep 2014 | pmid = 25196378 | doi = 10.1002/anie.201405758 }}</ref><ref>{{cite journal | vauthors = Moncunill-Massaguer C, Saura-Esteller J, Pérez-Perarnau A, Palmeri CM, Núñez-Vázquez S, Cosialls AM, González-Gironès DM, Pomares H, Korwitz A, Preciado S, Albericio F, Lavilla R, Pons G, Langer T, Iglesias-Serret D, Gil J | title = A novel prohibitin-binding compound induces the mitochondrial apoptotic pathway through NOXA and BIM upregulation | journal = Oncotarget | volume = 6 | issue = 39 | pages = 41750–65 | date = Dec 2015 | pmid = 26497683 | doi = 10.18632/oncotarget.6154 | pmc=4747186}}</ref> * Rocaglamide A<ref>{{cite journal | vauthors = 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 | title = The natural anticancer compounds rocaglamides inhibit the Raf-MEK-ERK pathway by targeting prohibitin 1 and 2 | journal = Chemistry & Biology | volume = 19 | issue = 9 | pages = 1093–104 | date = Sep 2012 | pmid = 22999878 | doi = 10.1016/j.chembiol.2012.07.012 | doi-access = free }}</ref> Prohibitinn in insect Prohibitin (PHB) is a highly conserved eukaryotic protein complex involved in multiple cellular processes. In insects, PHB has been identified as a potential target protein to insecticidal molecules acting as a receptor of PF2 insecticidal lectin in the midgut of Zabrotes subfasciatus larvae (bean pest) and Cry protein of Bacillus thuringiensis in Leptinotarsa decemlineata (Colorado potato beetle). == References == {{Reflist|33em}}
== Further reading == {{refbegin|33em}} * {{cite journal | vauthors = McClung JK, Jupe ER, Liu XT, Dell'Orco RT | title = Prohibitin: potential role in senescence, development, and tumor suppression | journal = Experimental Gerontology | volume = 30 | issue = 2 | pages = 99–124 | year = 1996 | pmid = 8591812 | doi = 10.1016/0531-5565(94)00069-7 | s2cid = 9075146 }} * {{cite journal | vauthors = Dell'Orco RT, McClung JK, Jupe ER, Liu XT | title = Prohibitin and the senescent phenotype | journal = Experimental Gerontology | volume = 31 | issue = 1–2 | pages = 245–52 | year = 1996 | pmid = 8706794 | doi = 10.1016/0531-5565(95)02009-8 | s2cid = 22817314 }} * {{cite journal | vauthors = Mishra S, Murphy LC, Nyomba BL, Murphy LJ | title = Prohibitin: a potential target for new therapeutics | journal = Trends in Molecular Medicine | volume = 11 | issue = 4 | pages = 192–7 | date = Apr 2005 | pmid = 15823758 | doi = 10.1016/j.molmed.2005.02.004 }} * {{cite journal | vauthors = Rajalingam K, Rudel T | title = Ras-Raf signaling needs prohibitin | journal = Cell Cycle | volume = 4 | issue = 11 | pages = 1503–5 | date = Nov 2005 | pmid = 16294014 | doi = 10.4161/cc.4.11.2142 | doi-access = free }} * {{cite journal | vauthors = Sato T, Saito H, Swensen J, Olifant A, Wood C, Danner D, Sakamoto T, Takita K, Kasumi F, Miki Y | title = The human prohibitin gene located on chromosome 17q21 is mutated in sporadic breast cancer | journal = Cancer Research | volume = 52 | issue = 6 | pages = 1643–6 | date = Mar 1992 | pmid = 1540973 }} * {{cite journal | vauthors = Dawson SJ, White LA | title = Treatment of Haemophilus aphrophilus endocarditis with ciprofloxacin | journal = The Journal of Infection | volume = 24 | issue = 3 | pages = 317–20 | date = May 1992 | pmid = 1602151 | doi = 10.1016/S0163-4453(05)80037-4 }} * {{cite journal | vauthors = White JJ, Ledbetter DH, Eddy RL, Shows TB, Stewart DA, Nuell MJ, Friedman V, Wood CM, Owens GA, McClung JK | title = Assignment of the human prohibitin gene (PHB) to chromosome 17 and identification of a DNA polymorphism | journal = Genomics | volume = 11 | issue = 1 | pages = 228–30 | date = Sep 1991 | pmid = 1684951 | doi = 10.1016/0888-7543(91)90126-Y }} * {{cite journal | vauthors = Altus MS, Wood CM, Stewart DA, Roskams AJ, Friedman V, Henderson T, Owens GA, Danner DB, Jupe ER, Dell'Orco RT | title = Regions of evolutionary conservation between the rat and human prohibitin-encoding genes | journal = Gene | volume = 158 | issue = 2 | pages = 291–4 | date = Jun 1995 | pmid = 7607556 | doi = 10.1016/0378-1119(95)00164-2 }} * {{cite journal | vauthors = Ikonen E, Fiedler K, Parton RG, Simons K | title = Prohibitin, an antiproliferative protein, is localized to mitochondria | journal = FEBS Letters | volume = 358 | issue = 3 | pages = 273–7 | date = Jan 1995 | pmid = 7843414 | doi = 10.1016/0014-5793(94)01444-6 | s2cid = 31600675 | doi-access = free }} * {{cite journal | vauthors = Maruyama K, Sugano S | title = Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides | journal = Gene | volume = 138 | issue = 1–2 | pages = 171–4 | date = Jan 1994 | pmid = 8125298 | doi = 10.1016/0378-1119(94)90802-8 }} * {{cite journal | vauthors = Sato T, Sakamoto T, Takita K, Saito H, Okui K, Nakamura Y | title = The human prohibitin (PHB) gene family and its somatic mutations in human tumors | journal = Genomics | volume = 17 | issue = 3 | pages = 762–4 | date = Sep 1993 | pmid = 8244394 | doi = 10.1006/geno.1993.1402 }} * {{cite journal | vauthors = Jupe ER, Liu XT, Kiehlbauch JL, McClung JK, Dell'Orco RT | title = The 3' untranslated region of prohibitin and cellular immortalization | journal = Experimental Cell Research | volume = 224 | issue = 1 | pages = 128–35 | date = Apr 1996 | pmid = 8612677 | doi = 10.1006/excr.1996.0120 }} * {{cite journal | vauthors = Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S | title = Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library | journal = Gene | volume = 200 | issue = 1–2 | pages = 149–56 | date = Oct 1997 | pmid = 9373149 | doi = 10.1016/S0378-1119(97)00411-3 }} * {{cite journal | vauthors = Rasmussen RK, Ji H, Eddes JS, Moritz RL, Reid GE, Simpson RJ, Dorow DS | title = Two-dimensional electrophoretic analysis of mixed lineage kinase 2 N-terminal domain binding proteins | journal = Electrophoresis | volume = 19 | issue = 5 | pages = 809–17 | date = May 1998 | pmid = 9629920 | doi = 10.1002/elps.1150190535 | s2cid = 21204230 }} * {{cite journal | vauthors = Wang S, Nath N, Adlam M, Chellappan S | title = Prohibitin, a potential tumor suppressor, interacts with RB and regulates E2F function | journal = Oncogene | volume = 18 | issue = 23 | pages = 3501–10 | date = Jun 1999 | pmid = 10376528 | doi = 10.1038/sj.onc.1202684 | doi-access = free }} * {{cite journal | vauthors = Wang S, Nath N, Fusaro G, Chellappan S | title = Rb and prohibitin target distinct regions of E2F1 for repression and respond to different upstream signals | journal = Molecular and Cellular Biology | volume = 19 | issue = 11 | pages = 7447–60 | date = Nov 1999 | pmid = 10523633 | pmc = 84738 | doi = 10.1128/mcb.19.11.7447}} * {{cite journal | vauthors = Hartley JL, Temple GF, Brasch MA | title = DNA cloning using in vitro site-specific recombination | journal = Genome Research | volume = 10 | issue = 11 | pages = 1788–95 | date = Nov 2000 | pmid = 11076863 | pmc = 310948 | doi = 10.1101/gr.143000 }} * {{cite journal | vauthors = Villegas-Coronado D, Guzman-Partida AM, Aispuro-Hernandez E, Vazquez-Moreno L, Huerta-Ocampo JÁ, Sarabia-Sainz JA, Teran-Saavedra NG, Minjarez-Osorio C, Castro-Longoria R, Maldonado A, Lagarda-Diaz I | display-authors = 6 | title = Characterization and expression of prohibitin during the mexican bean weevil (Zabrotes subfasciatus, Boheman, 1833) larvae development | journal = Comparative Biochemistry and Physiology. Part B, Biochemistry & Molecular Biology | volume = 262 | issue = | article-number = 110770 | date = 2022 | pmid = 35644320 | doi = 10.1016/j.cbpb.2022.110770 | s2cid = 249145357 }} * {{cite journal | vauthors = Coates PJ, Nenutil R, McGregor A, Picksley SM, Crouch DH, Hall PA, Wright EG | title = Mammalian prohibitin proteins respond to mitochondrial stress and decrease during cellular senescence | journal = Experimental Cell Research | volume = 265 | issue = 2 | pages = 262–73 | date = May 2001 | pmid = 11302691 | doi = 10.1006/excr.2001.5166 }} * {{cite journal | vauthors = 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 | title = Mitochondrial type-I prohibitins of Arabidopsis thaliana are required for supporting proficient meristem development | journal = The Plant Journal | volume = 52 | issue = 5 | pages = 850–64 | date = Dec 2007 | pmid = 17883375 | doi = 10.1111/j.1365-313X.2007.03276.x | doi-access = free }} {{refend}}
Category:Genes on human chromosome 17