Biology:Prohibitin
 Generic protein structure example |
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]
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
- ↑ 1.0 1.1 "Entrez Gene: PHB prohibitin". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5245.
- ↑ "Mitochondrial type-I prohibitins of Arabidopsis thaliana are required for supporting proficient meristem development". The Plant Journal 52 (5): 850–64. Dec 2007. doi:10.1111/j.1365-313X.2007.03276.x. PMID 17883375.
- ↑ "The Prohibitins: emerging roles in diverse functions". Journal of Cellular and Molecular Medicine 10 (2): 353–63. 2006. doi:10.1111/j.1582-4934.2006.tb00404.x. PMID 16796804.
- ↑ "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. doi:10.1677/ERC-09-0028. PMID 19635783.
- ↑ "Formation of membrane-bound ring complexes by prohibitins in mitochondria". Molecular Biology of the Cell 16 (1): 248–59. Jan 2005. doi:10.1091/mbc.E04-09-0807. PMID 15525670.
- ↑ "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. doi:10.1073/pnas.96.12.6947. PMID 10359819. Bibcode: 1999PNAS...96.6947M.
- ↑ "Prohibitin, a protein downregulated by androgens, represses androgen receptor activity". Oncogene 26 (12): 1757–68. Mar 2007. doi:10.1038/sj.onc.1209967. PMID 16964284.
- ↑ "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. doi:10.1074/jbc.M312300200. PMID 15140878.
- ↑ "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. doi:10.1128/MCB.25.5.1989-1999.2005. PMID 15713652.
- ↑ "Identification of prohibitin as a Chikungunya virus receptor protein". Journal of Medical Virology 84 (11): 1757–70. Nov 2012. doi:10.1002/jmv.23403. PMID 22997079.
- ↑ "Identification and characterization of prohibitin as a receptor protein mediating DENV-2 entry into insect cells". Virology 406 (1): 149–61. Oct 2010. doi:10.1016/j.virol.2010.07.015. PMID 20674955.
- ↑ "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. doi:10.1016/s0300-9084(02)00027-5. PMID 12628297.
- ↑ 13.0 13.1 13.2 "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. doi:10.1128/mcb.19.11.7447. PMID 10523633.
- ↑ 14.0 14.1 "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. doi:10.1016/j.bbrc.2003.10.148. PMID 14637159.
- ↑ 15.0 15.1 "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. doi:10.1074/jbc.M305171200. PMID 14500729.
- ↑ 16.0 16.1 16.2 "Prohibitin requires Brg-1 and Brm for the repression of E2F and cell growth". The EMBO Journal 21 (12): 3019–28. Jun 2002. doi:10.1093/emboj/cdf302. PMID 12065415.
- ↑ "Prohibitin co-localizes with Rb in the nucleus and recruits N-CoR and HDAC1 for transcriptional repression". Oncogene 21 (55): 8388–96. Dec 2002. doi:10.1038/sj.onc.1205944. PMID 12466959.
- ↑ 18.0 18.1 18.2 "Prohibitin, a potential tumor suppressor, interacts with RB and regulates E2F function". Oncogene 18 (23): 3501–10. Jun 1999. doi:10.1038/sj.onc.1202684. PMID 10376528.
- ↑ "Marine natural product aurilide activates the OPA1-mediated apoptosis by binding to prohibitin". Chemistry & Biology 18 (1): 131–9. Jan 2011. doi:10.1016/j.chembiol.2010.10.017. PMID 21276946.
- ↑ "A trifluorinated thiazoline scaffold leading to pro-apoptotic agents targeting prohibitins". Angewandte Chemie 53 (38): 10150–4. Sep 2014. doi:10.1002/anie.201405758. PMID 25196378.
- ↑ "A novel prohibitin-binding compound induces the mitochondrial apoptotic pathway through NOXA and BIM upregulation". Oncotarget 6 (39): 41750–65. Dec 2015. doi:10.18632/oncotarget.6154. PMID 26497683.
- ↑ "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. doi:10.1016/j.chembiol.2012.07.012. PMID 22999878.
Further reading
- "Prohibitin: potential role in senescence, development, and tumor suppression". Experimental Gerontology 30 (2): 99–124. 1996. doi:10.1016/0531-5565(94)00069-7. PMID 8591812.
- "Prohibitin and the senescent phenotype". Experimental Gerontology 31 (1–2): 245–52. 1996. doi:10.1016/0531-5565(95)02009-8. PMID 8706794.
- "Prohibitin: a potential target for new therapeutics". Trends in Molecular Medicine 11 (4): 192–7. Apr 2005. doi:10.1016/j.molmed.2005.02.004. PMID 15823758.
- "Ras-Raf signaling needs prohibitin". Cell Cycle 4 (11): 1503–5. Nov 2005. doi:10.4161/cc.4.11.2142. PMID 16294014.
- "The human prohibitin gene located on chromosome 17q21 is mutated in sporadic breast cancer". Cancer Research 52 (6): 1643–6. Mar 1992. PMID 1540973.
- "Treatment of Haemophilus aphrophilus endocarditis with ciprofloxacin". The Journal of Infection 24 (3): 317–20. May 1992. doi:10.1016/S0163-4453(05)80037-4. PMID 1602151.
- "Assignment of the human prohibitin gene (PHB) to chromosome 17 and identification of a DNA polymorphism". Genomics 11 (1): 228–30. Sep 1991. doi:10.1016/0888-7543(91)90126-Y. PMID 1684951.
- "Regions of evolutionary conservation between the rat and human prohibitin-encoding genes". Gene 158 (2): 291–4. Jun 1995. doi:10.1016/0378-1119(95)00164-2. PMID 7607556.
- "Prohibitin, an antiproliferative protein, is localized to mitochondria". FEBS Letters 358 (3): 273–7. Jan 1995. doi:10.1016/0014-5793(94)01444-6. PMID 7843414.
- "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene 138 (1–2): 171–4. Jan 1994. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
- "The human prohibitin (PHB) gene family and its somatic mutations in human tumors". Genomics 17 (3): 762–4. Sep 1993. doi:10.1006/geno.1993.1402. PMID 8244394.
- "The 3' untranslated region of prohibitin and cellular immortalization". Experimental Cell Research 224 (1): 128–35. Apr 1996. doi:10.1006/excr.1996.0120. PMID 8612677.
- "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene 200 (1–2): 149–56. Oct 1997. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
- "Two-dimensional electrophoretic analysis of mixed lineage kinase 2 N-terminal domain binding proteins". Electrophoresis 19 (5): 809–17. May 1998. doi:10.1002/elps.1150190535. PMID 9629920.
- "Prohibitin, a potential tumor suppressor, interacts with RB and regulates E2F function". Oncogene 18 (23): 3501–10. Jun 1999. doi:10.1038/sj.onc.1202684. PMID 10376528.
- "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. doi:10.1128/mcb.19.11.7447. PMID 10523633.
- "DNA cloning using in vitro site-specific recombination". Genome Research 10 (11): 1788–95. Nov 2000. doi:10.1101/gr.143000. PMID 11076863.
- "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. doi:10.1016/j.cbpb.2022.110770. PMID 35644320.
- "Mammalian prohibitin proteins respond to mitochondrial stress and decrease during cellular senescence". Experimental Cell Research 265 (2): 262–73. May 2001. doi:10.1006/excr.2001.5166. PMID 11302691.
- "Mitochondrial type-I prohibitins of Arabidopsis thaliana are required for supporting proficient meristem development". The Plant Journal 52 (5): 850–64. Dec 2007. doi:10.1111/j.1365-313X.2007.03276.x. PMID 17883375.
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