Prohibitin

Prohibitin
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1LU7​
Identifiers
Symbols	PHB ; HEL-215; HEL-S-54e; PHB1
External IDs	OMIM: 176705 MGI: 97572 HomoloGene: 1980 GeneCards: PHB Gene
Gene ontology Molecular function • RNA polymerase II transcription factor activity, sequence-specific DNA binding • complement component C3a binding • complement component C3b binding • protein binding • protein C-terminus binding • enzyme binding • proteinase activated receptor binding • histone deacetylase binding • transcription regulatory region DNA binding Cellular component • nucleus • nucleoplasm • cytoplasm • mitochondrion • mitochondrial inner membrane • early endosome • plasma membrane • integral component of plasma membrane • cell surface • membrane • myelin sheath • extracellular exosome Biological process • negative regulation of transcription from RNA polymerase II promoter • osteoblast differentiation • regulation of transcription, DNA-templated • transcription from RNA polymerase II promoter • mitochondrion organization • signal transduction • negative regulation of cell proliferation • negative regulation of transcription by competitive promoter binding • histone deacetylation • negative regulation of cell growth • negative regulation of protein catabolic process • regulation of apoptotic process • positive regulation of G-protein coupled receptor protein signaling pathway • negative regulation of transcription, DNA-templated • positive regulation of transcription, DNA-templated • positive regulation of complement activation • protein stabilization • progesterone receptor signaling pathway • negative regulation of androgen receptor signaling pathway • negative regulation of ERK1 and ERK2 cascade • positive regulation of ERK1 and ERK2 cascade • cellular response to interleukin-6 • DNA biosynthetic process • negative regulation of glucocorticoid receptor signaling pathway Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	5245	18673
Ensembl	ENSG00000167085	ENSMUSG00000038845
UniProt	P35232	P67778
RefSeq (mRNA)	NM_001281496	NM_008831
RefSeq (protein)	NP_001268425	NP_032857
Location (UCSC)	Chr 17: 49.4 – 49.41 Mb	Chr 11: 95.67 – 95.68 Mb
PubMed search

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' 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]

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][16]}
• HDAC1,^[14][17]
• P53,^[15]
• RB1,^[13][18]
• RBL1,^[18]
• RBL2,^[18]
• SMARCA2,^[16] and
• SMARCA4.^[16]

Drugs that bind to prohibitin

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

References

1. "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 (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. PMID 17883375.
3. 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. PMID 16796804.
4. Dart, D Alwyn. "Manipulating prohibitin levels provides evidence for an in vivo role in androgen regulation of prostate tumours". Endocr Relat Cancer. Retrieved 20 April 2016.
5. Tatsuta T, Model K, Langer T (Jan 2005). "Formation of membrane-bound ring complexes by prohibitins in mitochondria". Molecular Biology of the Cell 16 (1): 248–59. doi:10.1091/mbc.E04-09-0807. PMC: 539169. PMID 15525670.
6. Montano MM, Ekena K, Delage-Mourroux R, Chang W, Martini P, Katzenellenbogen BS (Jun 1999). "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. doi:10.1073/pnas.96.12.6947. PMC: 22022. PMID 10359819.
7. 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. PMID 16964284.
8. 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. PMID 15140878.
9. Park SE, Xu J, Frolova A, Liao L, O'Malley BW, Katzenellenbogen BS (Mar 2005). "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. doi:10.1128/MCB.25.5.1989-1999.2005. PMC: 549370. PMID 15713652.
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 (Nov 2012). "Identification of prohibitin as a Chikungunya virus receptor protein". Journal of Medical Virology 84 (11): 1757–70. doi:10.1002/jmv.23403. PMID 22997079.
11. 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. PMID 20674955.
12. 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. PMID 12628297.
13. Wang S, Nath N, Fusaro G, Chellappan S (Nov 1999). "Rb and prohibitin target distinct regions of E2F1 for repression and respond to different upstream signals". Molecular and Cellular Biology 19 (11): 7447–60. PMC: 84738. PMID 10523633.
14. Joshi 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. PMID 14637159.
15. Fusaro 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. PMID 14500729.
16. Wang S, Zhang B, Faller DV (Jun 2002). "Prohibitin requires Brg-1 and Brm for the repression of E2F and cell growth". The EMBO Journal 21 (12): 3019–28. doi:10.1093/emboj/cdf302. PMC: 126057. PMID 12065415.
17. 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. PMID 12466959.
18. 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. PMID 10376528.
19. 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. PMID 21276946.
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 (Sep 2014). "A trifluorinated thiazoline scaffold leading to pro-apoptotic agents targeting prohibitins". Angewandte Chemie 53 (38): 10150–4. doi:10.1002/anie.201405758. PMID 25196378.
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 (Dec 2015). "A novel prohibitin-binding compound induces the mitochondrial apoptotic pathway through NOXA and BIM upregulation". Oncotarget 6 (39): 41750–65. doi:10.18632/oncotarget.6154. PMID 26497683.
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 (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. PMID 22999878.

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. PMID 8591812.
• 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. PMID 8706794.
• 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. PMID 15823758.
• Rajalingam K, Rudel T (Nov 2005). "Ras-Raf signaling needs prohibitin". Cell Cycle 4 (11): 1503–5. doi:10.4161/cc.4.11.2142. PMID 16294014.
• 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. PMID 1540973.
• 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. PMID 1602151.
• 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. PMID 1684951.
• 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. PMID 7607556.
• 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. PMID 7843414.
• 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. PMID 8125298.
• 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. PMID 8244394.
• 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. PMID 8612677.
• 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. PMID 9373149.
• Rasmussen RK, Ji H, Eddes JS, Moritz RL, Reid GE, Simpson RJ, Dorow DS (May 1998). "Two-dimensional electrophoretic analysis of mixed lineage kinase 2 N-terminal domain binding proteins". Electrophoresis 19 (5): 809–17. doi:10.1002/elps.1150190535. PMID 9629920.
• 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. PMID 10376528.
• Wang S, Nath N, Fusaro G, Chellappan S (Nov 1999). "Rb and prohibitin target distinct regions of E2F1 for repression and respond to different upstream signals". Molecular and Cellular Biology 19 (11): 7447–60. PMC: 84738. PMID 10523633.
• Hartley JL, Temple GF, Brasch MA (Nov 2000). "DNA cloning using in vitro site-specific recombination". Genome Research 10 (11): 1788–95. doi:10.1101/gr.143000. PMC: 310948. PMID 11076863.
• 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. PMID 11302691.
• 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. PMID 17883375.