Prohibitin Explained

Prohibitin, also known as PHB, is a protein that in humans is encoded by the PHB gene.^[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]}

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.^[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.

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 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.^{[6] [7] [8] [9]}

Clinical significance

Human prohibitin 1 has some activity as a virus receptor protein, having been identified as a receptor for Chikungunya Virus (CHIKV)^[10] and Dengue Virus 2 (DENV-2).^[11] Little else is known about the activity of the prohibitins in viral pathogenesis.

Interactions

Prohibitin has been shown to interact with:

• ANXA2^[12]
• C-Raf,^[13]
• E2F1,^{[13] [14] [15]}
• HDAC1,^{[16] [17]}
• P53,^[14]
• RB1,^[13]
• RBL1,
• RBL2,^[18]
• SMARCA2,^[15] and
• SMARCA4.^[15]

Drugs that bind to prohibitin

• Aurilide^[19]
• Fluorizoline^{[20] [21]}
• Rocaglamide A^[22]

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).

Further reading

• McClung JK, Jupe ER, Liu XT, Dell'Orco RT . Prohibitin: potential role in senescence, development, and tumor suppression . Experimental Gerontology . 30 . 2 . 99–124 . 1996 . 8591812 . 10.1016/0531-5565(94)00069-7 . 9075146 .
• Dell'Orco RT, McClung JK, Jupe ER, Liu XT . Prohibitin and the senescent phenotype . Experimental Gerontology . 31 . 1–2 . 245–52 . 1996 . 8706794 . 10.1016/0531-5565(95)02009-8 . 22817314 .
• Mishra S, Murphy LC, Nyomba BL, Murphy LJ . Prohibitin: a potential target for new therapeutics . Trends in Molecular Medicine . 11 . 4 . 192–7 . Apr 2005 . 15823758 . 10.1016/j.molmed.2005.02.004 .
• Rajalingam K, Rudel T . Ras-Raf signaling needs prohibitin . Cell Cycle . 4 . 11 . 1503–5 . Nov 2005 . 16294014 . 10.4161/cc.4.11.2142 . free .
• Sato T, Saito H, Swensen J, Olifant A, Wood C, Danner D, Sakamoto T, Takita K, Kasumi F, Miki Y . The human prohibitin gene located on chromosome 17q21 is mutated in sporadic breast cancer . Cancer Research . 52 . 6 . 1643–6 . Mar 1992 . 1540973 .
• Dawson SJ, White LA . Treatment of Haemophilus aphrophilus endocarditis with ciprofloxacin . The Journal of Infection . 24 . 3 . 317–20 . May 1992 . 1602151 . 10.1016/S0163-4453(05)80037-4 .
• White JJ, Ledbetter DH, Eddy RL, Shows TB, Stewart DA, Nuell MJ, Friedman V, Wood CM, Owens GA, McClung JK . Assignment of the human prohibitin gene (PHB) to chromosome 17 and identification of a DNA polymorphism . Genomics . 11 . 1 . 228–30 . Sep 1991 . 1684951 . 10.1016/0888-7543(91)90126-Y .
• Altus MS, Wood CM, Stewart DA, Roskams AJ, Friedman V, Henderson T, Owens GA, Danner DB, Jupe ER, Dell'Orco RT . Regions of evolutionary conservation between the rat and human prohibitin-encoding genes . Gene . 158 . 2 . 291–4 . Jun 1995 . 7607556 . 10.1016/0378-1119(95)00164-2 .
• Ikonen E, Fiedler K, Parton RG, Simons K . Prohibitin, an antiproliferative protein, is localized to mitochondria . FEBS Letters . 358 . 3 . 273–7 . Jan 1995 . 7843414 . 10.1016/0014-5793(94)01444-6 . 31600675 . free .
• Maruyama K, Sugano S . Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides . Gene . 138 . 1–2 . 171–4 . Jan 1994 . 8125298 . 10.1016/0378-1119(94)90802-8 .
• Sato T, Sakamoto T, Takita K, Saito H, Okui K, Nakamura Y . The human prohibitin (PHB) gene family and its somatic mutations in human tumors . Genomics . 17 . 3 . 762–4 . Sep 1993 . 8244394 . 10.1006/geno.1993.1402 .
• Jupe ER, Liu XT, Kiehlbauch JL, McClung JK, Dell'Orco RT . The 3' untranslated region of prohibitin and cellular immortalization . Experimental Cell Research . 224 . 1 . 128–35 . Apr 1996 . 8612677 . 10.1006/excr.1996.0120 .
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S . Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library . Gene . 200 . 1–2 . 149–56 . Oct 1997 . 9373149 . 10.1016/S0378-1119(97)00411-3 .
• Rasmussen RK, Ji H, Eddes JS, Moritz RL, Reid GE, Simpson RJ, Dorow DS . Two-dimensional electrophoretic analysis of mixed lineage kinase 2 N-terminal domain binding proteins . Electrophoresis . 19 . 5 . 809–17 . May 1998 . 9629920 . 10.1002/elps.1150190535 . 21204230 .
• Wang S, Nath N, Adlam M, Chellappan S . Prohibitin, a potential tumor suppressor, interacts with RB and regulates E2F function . Oncogene . 18 . 23 . 3501–10 . Jun 1999 . 10376528 . 10.1038/sj.onc.1202684 . free .
• Wang S, Nath N, Fusaro G, Chellappan S . Rb and prohibitin target distinct regions of E2F1 for repression and respond to different upstream signals . Molecular and Cellular Biology . 19 . 11 . 7447–60 . Nov 1999 . 10523633 . 84738 . 10.1128/mcb.19.11.7447.
• Hartley JL, Temple GF, Brasch MA . DNA cloning using in vitro site-specific recombination . Genome Research . 10 . 11 . 1788–95 . Nov 2000 . 11076863 . 310948 . 10.1101/gr.143000 .
• 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 . 6 . Characterization and expression of prohibitin during the mexican bean weevil (Zabrotes subfasciatus, Boheman, 1833) larvae development . Comparative Biochemistry and Physiology. Part B, Biochemistry & Molecular Biology . 262 . 110770 . 2022 . 35644320 . 10.1016/j.cbpb.2022.110770 . 249145357 .
• Coates PJ, Nenutil R, McGregor A, Picksley SM, Crouch DH, Hall PA, Wright EG . Mammalian prohibitin proteins respond to mitochondrial stress and decrease during cellular senescence . Experimental Cell Research . 265 . 2 . 262–73 . May 2001 . 11302691 . 10.1006/excr.2001.5166 .
• 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 . Mitochondrial type-I prohibitins of Arabidopsis thaliana are required for supporting proficient meristem development . The Plant Journal . 52 . 5 . 850–64 . Dec 2007 . 17883375 . 10.1111/j.1365-313X.2007.03276.x . free .

Notes and References

1. Web site: Entrez Gene: PHB prohibitin.
2. 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 . Mitochondrial type-I prohibitins of Arabidopsis thaliana are required for supporting proficient meristem development . The Plant Journal . 52 . 5 . 850–64 . Dec 2007 . 17883375 . 10.1111/j.1365-313X.2007.03276.x . free .
3. Mishra S, Murphy LC, Murphy LJ . The Prohibitins: emerging roles in diverse functions . Journal of Cellular and Molecular Medicine . 10 . 2 . 353–63 . 2006 . 16796804 . 3933126 . 10.1111/j.1582-4934.2006.tb00404.x .
4. Dart DA, Spencer-Dene B, Gamble SC, Waxman J, Bevan CL . Manipulating prohibitin levels provides evidence for an in vivo role in androgen regulation of prostate tumours . Endocrine-Related Cancer . 16 . 4 . 1157–1169 . December 2009 . 19635783 . 2782800 . 10.1677/ERC-09-0028 .
5. Tatsuta T, Model K, Langer T . Formation of membrane-bound ring complexes by prohibitins in mitochondria . Molecular Biology of the Cell . 16 . 1 . 248–59 . Jan 2005 . 15525670 . 539169 . 10.1091/mbc.E04-09-0807 .
6. 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 . Proceedings of the National Academy of Sciences of the United States of America . 96 . 12 . 6947–52 . Jun 1999 . 10359819 . 22022 . 10.1073/pnas.96.12.6947 . 1999PNAS...96.6947M . free .
7. Gamble SC, Chotai D, Odontiadis M, Dart DA, Brooke GN, Powell SM, Reebye V, Varela-Carver A, Kawano Y, Waxman J, Bevan CL . Prohibitin, a protein downregulated by androgens, represses androgen receptor activity . Oncogene . 26 . 12 . 1757–68 . Mar 2007 . 16964284 . 10.1038/sj.onc.1209967 . 9592990 .
8. 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 . The Journal of Biological Chemistry . 279 . 23 . 24834–43 . Jun 2004 . 15140878 . 10.1074/jbc.M312300200 . free .
9. 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 . Molecular and Cellular Biology . 25 . 5 . 1989–99 . Mar 2005 . 15713652 . 549370 . 10.1128/MCB.25.5.1989-1999.2005 .
10. 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 . Identification of prohibitin as a Chikungunya virus receptor protein . Journal of Medical Virology . 84 . 11 . 1757–70 . Nov 2012 . 22997079 . 10.1002/jmv.23403 . 22172257 .
11. Kuadkitkan A, Wikan N, Fongsaran C, Smith DR . Identification and characterization of prohibitin as a receptor protein mediating DENV-2 entry into insect cells . Virology . 406 . 1 . 149–61 . Oct 2010 . 20674955 . 10.1016/j.virol.2010.07.015 . free .
12. Bacher S, Achatz G, Schmitz ML, Lamers MC . Prohibitin and prohibitone are contained in high-molecular weight complexes and interact with alpha-actinin and annexin A2 . Biochimie . 84 . 12 . 1207–20 . Dec 2002 . 12628297 . 10.1016/s0300-9084(02)00027-5 .
13. Wang S, Nath N, Fusaro G, Chellappan S . Rb and prohibitin target distinct regions of E2F1 for repression and respond to different upstream signals . Molecular and Cellular Biology . 19 . 11 . 7447–60 . Nov 1999 . 10523633 . 84738 . 10.1128/mcb.19.11.7447.
14. 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 . The Journal of Biological Chemistry . 278 . 48 . 47853–61 . Nov 2003 . 14500729 . 10.1074/jbc.M305171200 . free .
15. Wang S, Zhang B, Faller DV . Prohibitin requires Brg-1 and Brm for the repression of E2F and cell growth . The EMBO Journal . 21 . 12 . 3019–28 . Jun 2002 . 12065415 . 126057 . 10.1093/emboj/cdf302 .
16. 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 . Biochemical and Biophysical Research Communications . 312 . 2 . 459–66 . Dec 2003 . 14637159 . 10.1016/j.bbrc.2003.10.148 .
17. 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 . 21 . 55 . 8388–96 . Dec 2002 . 12466959 . 10.1038/sj.onc.1205944 . free .
18. Wang S, Nath N, Adlam M, Chellappan S . Prohibitin, a potential tumor suppressor, interacts with RB and regulates E2F function . Oncogene . 18 . 23 . 3501–10 . Jun 1999 . 10376528 . 10.1038/sj.onc.1202684 . free .
19. Sato S, Murata A, Orihara T, Shirakawa T, Suenaga K, Kigoshi H, Uesugi M . Marine natural product aurilide activates the OPA1-mediated apoptosis by binding to prohibitin . Chemistry & Biology . 18 . 1 . 131–9 . Jan 2011 . 21276946 . 10.1016/j.chembiol.2010.10.017 . free . 2433/137219 . free .
20. 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 . A trifluorinated thiazoline scaffold leading to pro-apoptotic agents targeting prohibitins . Angewandte Chemie . 53 . 38 . 10150–4 . Sep 2014 . 25196378 . 10.1002/anie.201405758 .
21. 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 . A novel prohibitin-binding compound induces the mitochondrial apoptotic pathway through NOXA and BIM upregulation . Oncotarget . 6 . 39 . 41750–65 . Dec 2015 . 26497683 . 10.18632/oncotarget.6154 . 4747186.
22. 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 . The natural anticancer compounds rocaglamides inhibit the Raf-MEK-ERK pathway by targeting prohibitin 1 and 2 . Chemistry & Biology . 19 . 9 . 1093–104 . Sep 2012 . 22999878 . 10.1016/j.chembiol.2012.07.012 . free .