プロヒビチン

PHB1
PDBに登録されている構造
PDB	オルソログ検索: RCSB PDBe PDBj
PDBのIDコード一覧
	1LU7
識別子
記号	PHB1, prohibitin, HEL-S-54e, HEL-215, PHB, prohibitin 1
外部ID	OMIM: 176705 MGI: 97572 HomoloGene: 1980 GeneCards: PHB1
遺伝子の位置 (ヒト)
染色体	17番染色体 (ヒト)
終点	49,414,905 bp
遺伝子の位置 (マウス)
染色体	11番染色体 (マウス)
終点	95,571,599 bp
RNA発現パターン
	; ;
	さらなる参照発現データ
遺伝子オントロジー
分子機能	• ヒストンデアセチラーゼ結合; • complement component C3a binding; • protein C-terminus binding; • proteinase activated receptor binding; • complement component C3b binding; • 血漿タンパク結合; • 酵素結合; • DNA-binding transcription factor activity, RNA polymerase II-specific;
細胞の構成要素	• 細胞質; • 膜; • ミエリン鞘; • 細胞膜; • integral component of plasma membrane; • 核質; • cell surface; • early endosome; • ミトコンドリア; • ミトコンドリア内膜; • エキソソーム; • 細胞核; • シナプス後肥厚; • クリステ; • extrinsic component of mitochondrial outer membrane; • extrinsic component of presynaptic active zone membrane; • glutamatergic synapse; • GABA-ergic synapse;
生物学的プロセス	• regulation of apoptotic process; • negative regulation of glucocorticoid receptor signaling pathway; • DNA生合成プロセス; • regulation of transcription, DNA-templated; • cellular response to interleukin-6; • negative regulation of protein catabolic process; • negative regulation of transcription by competitive promoter binding; • タンパク質の安定化; • negative regulation of androgen receptor signaling pathway; • mitochondrion organization; • negative regulation of transcription by RNA polymerase II; • positive regulation of transcription, DNA-templated; • positive regulation of G protein-coupled receptor signaling pathway; • negative regulation of cell growth; • osteoblast differentiation; • positive regulation of ERK1 and ERK2 cascade; • positive regulation of complement activation; • negative regulation of ERK1 and ERK2 cascade; • progesterone receptor signaling pathway; • negative regulation of transcription, DNA-templated; • histone deacetylation; • シグナル伝達; • negative regulation of cell population proliferation; • positive regulation of gene expression; • positive regulation of cell death; • mitochondrial calcium ion transmembrane transport; • 卵胞発生; • ovarian follicle atresia; • animal organ regeneration; • response to cytokine; • response to immobilization stress; • negative regulation of apoptotic process; • response to peptide hormone; • response to ethanol;
	出典:Amigo / QuickGO
オルソログ
	5245
	18673
	ENSG00000167085
	ENSMUSG00000038845
	P35232,E7ESE2
	P67778
	NM_002634; NM_001281496; NM_001281497; NM_001281715
	NM_008831
	NP_001268425; NP_001268426; NP_001268644; NP_002625
	NP_032857
	ウィキデータ
閲覧/編集ヒト	閲覧/編集マウス

プロヒビチン（prohibitin）あるいはPHBは、ヒトにおいてPHB遺伝子によってコードされているタンパク質である^[5]。Phb遺伝子は、動物や真菌、植物、単細胞真核生物においても記載されている。プロヒビチン類は、酵母のPHB1およびPHB2に対する類似性に基づいて、それぞれType-IプロヒビチンとTyp2-IIプロヒビチンの2つのクラスに分類される。それぞれの生物は、それぞれのタイプのプロヒビチンを少なくとも1コピー有している^[6]^[7]。

発見[編集]

プロヒビチン類は、遍在的に発現している進化的に保存された遺伝子である。BRCA1染色体領域17q21に位置するヒトのプロヒビチン遺伝子は、元々は細胞増殖の負の制御因子でありがん抑制遺伝子であると考えられていた。この抗増殖活性は後に実際のタンパク質ではなくPHB遺伝子の3' UTRによるものであるとされた。ヒトPHBにおける変異は散発性乳がんと関連付けられている。プロヒビチンは3' 非翻訳領域の長さが異なる2つの転写産物として発現している。長い方の転写産物は増殖している組織や細胞において高いレベルで存在しており、このより長い3' 非翻訳領域がトランスに働く調節RNAとして機能することが示唆されている^[5]。

機能[編集]

プロヒビチン類は以下のような多面的機能を有している。

ミトコンドリアの機能および形態[編集]

プロヒビチン類は、ミトコンドリア内膜においてPhb1およびPhb2サブユニットが交互に16-20つながった環状構造をとる^[8]。PHB複合体の正確な分子機能は不明であるが、呼吸鎖タンパク質に対すシャペロンあるいは最適なミトコンドリア機能および形態に必要な一般構造骨格としての機能が推測されている。最近、プロヒビチン類は、植物ならびにマウスにおいて、細胞調節の負の調節因子ではなく正の調節因子であることが明らかにされた。

転写調節[編集]

ヒトのプロヒビチン類は、核に局在し核内受容体を含む様々な転写因子と直接的あるいは間接的に相互作用することによって転写活性を調節していることが示唆されている。しかしながら、プロヒビチン類の核ターゲッティングおよび転写因子との結合に関しての証拠は、その他の生物（酵母、植物、C. elegans等）においてほとんどなく、これがほ乳類細胞に特異的な機能であることを示している^[9]^[10]^[11]^[12]。

相互作用[編集]

プロヒビチンは、HDAC1^[13]^[14]、C-Raf^[15]、Retinoblastoma-like protein 2^[16]、Retinoblastoma-like protein 1^[16]、E2F1^[13]^[17]^[18]^[15]、SMARCA2^[18]、Rbタンパク質^[15]^[16]、P53^[17]、Annexin A2^[19]、SMARCA4^[18]と相互作用することが明らかにされている。

脚注[編集]

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000167085 - Ensembl, May 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000038845 - Ensembl, May 2017
^ Human PubMed Reference:
^ Mouse PubMed Reference:
^ ^a ^b “Entrez Gene: PHB prohibitin”. 2013年10月11日閲覧。
^ Van Aken O, Pecenkova T, van de Cotte B et al. (2007). “Mitochondrial type-I prohibitins of Arabidopsis thaliana are required for supporting proficient meristem development”. Plant J. 52 (5): 850–864. doi:10.1111/j.1365-313X.2007.03276.x. PMID 17883375.
^ Mishra S, Murphy LC, Murphy LJ (2006). “The Prohibitins: emerging roles in diverse functions”. J. Cell. Mol. Med. 10 (2): 353–63. doi:10.1111/j.1582-4934.2006.tb00404.x. PMID 16796804.
^ Tatsuta T, Model K, Langer T (January 2005). “Formation of Membrane-bound Ring Complexes by Prohibitins in Mitochondria”. Mol. Biol. Cell 16 (1): 248–59. doi:10.1091/mbc.E04-09-0807. PMC 539169. PMID 15525670.
^ Montano MM, Ekena K, Delage-Mourroux R, Chang W, Martini P, Katzenellenbogen BS (June 1999). “An estrogen receptor-selective coregulator that potentiates the effectiveness of antiestrogens and represses the activity of estrogens”. Proc. Natl. Acad. Sci. U.S.A. 96 (12): 6947–52. doi:10.1073/pnas.96.12.6947. PMC 22022. PMID 10359819.
^ Gamble SC, Chotai D, Odontiadis M, Dart DA, Brooke GN, Powell SM, Reebye V, Varela-Carver A, Kawano Y, Waxman J, Bevan C (March 2007). “Prohibitin, a protein downregulated by androgens, represses androgen receptor activity”. Oncogene 26 (12): 1757–68. doi:10.1038/sj.onc.1209967. PMID 16964284.
^ Kurtev V, Margueron R, Kroboth K, Ogris E, Cavailles V, Seiser C (June 2004). “Transcriptional regulation by the repressor of estrogen receptor activity via recruitment of histone deacetylases”. J. Biol. Chem. 279 (23): 24834–43. doi:10.1074/jbc.M312300200. PMID 15140878.
^ Park SE, Xu J, Frolova A, Liao L, O'Malley BW, Katzenellenbogen BS (March 2005). “Genetic Deletion of the Repressor of Estrogen Receptor Activity (REA) Enhances the Response to Estrogen in Target Tissues In Vivo”. Mol. Cell. Biol. 25 (5): 1989–99. doi:10.1128/MCB.25.5.1989-1999.2005. PMC 549370. PMID 15713652.
^ ^a ^b Joshi, Bharat; Ko Danette, Ordonez-Ercan Dalia, Chellappan Srikumar P (Dec. 2003). “A putative coiled-coil domain of prohibitin is sufficient to repress E2F1-mediated transcription and induce apoptosis”. Biochem. Biophys. Res. Commun. (United States) 312 (2): 459–66. doi:10.1016/j.bbrc.2003.10.148. ISSN 0006-291X. PMID 14637159.
^ Wang, Sheng; Fusaro Gina, Padmanabhan Jaya, Chellappan Srikumar P (Dec. 2002). “Prohibitin co-localizes with Rb in the nucleus and recruits N-CoR and HDAC1 for transcriptional repression”. Oncogene (England) 21 (55): 8388–96. doi:10.1038/sj.onc.1205944. ISSN 0950-9232. PMID 12466959.
^ ^a ^b ^c 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”. Mol. Cell. Biol. (UNITED STATES) 19 (11): 7447–60. ISSN 0270-7306. PMC 84738. PMID 10523633.
^ ^a ^b ^c Wang, S; Nath N, Adlam M, Chellappan S (Jun. 1999). “Prohibitin, a potential tumor suppressor, interacts with RB and regulates E2F function”. Oncogene (ENGLAND) 18 (23): 3501–10. doi:10.1038/sj.onc.1202684. ISSN 0950-9232. PMID 10376528.
^ ^a ^b Fusaro, Gina; Dasgupta Piyali, Rastogi Shipra, Joshi Bharat, Chellappan Srikumar (Nov. 2003). “Prohibitin induces the transcriptional activity of p53 and is exported from the nucleus upon apoptotic signaling”. J. Biol. Chem. (United States) 278 (48): 47853–61. doi:10.1074/jbc.M305171200. ISSN 0021-9258. PMID 14500729.
^ ^a ^b ^c Wang, Sheng; Zhang Baohua, Faller Douglas V (Jun. 2002). “Prohibitin requires Brg-1 and Brm for the repression of E2F and cell growth”. EMBO J. (England) 21 (12): 3019–28. doi:10.1093/emboj/cdf302. ISSN 0261-4189. PMC 126057. PMID 12065415.
^ Bacher, Susanne; Achatz Gernot, Schmitz M L, Lamers Marinus C (Dec. 2002). “Prohibitin and prohibitone are contained in high-molecular weight complexes and interact with alpha-actinin and annexin A2”. Biochimie (France) 84 (12): 1207–20. doi:10.1016/S0300-9084(02)00027-5. ISSN 0300-9084. PMID 12628297.

推薦文献[編集]

McClung JK, Jupe ER, Liu XT, Dell'Orco RT (1996). “Prohibitin: potential role in senescence, development, and tumor suppression”. Exp. Gerontol. 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”. Exp. Gerontol. 31 (1–2): 245–52. doi:10.1016/0531-5565(95)02009-8. PMID 8706794.
Mishra S, Murphy LC, Nyomba BL, Murphy LJ (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 (2007). “Ras-Raf signaling needs prohibitin”. Cell Cycle 4 (11): 1503–5. PMID 16294014.
Sato T, Saito H, Swensen J et al. (1992). “The human prohibitin gene located on chromosome 17q21 is mutated in sporadic breast cancer”. Cancer Res. 52 (6): 1643–6. PMID 1540973.
Dawson SJ, White LA (1992). “Treatment of Haemophilus aphrophilus endocarditis with ciprofloxacin”. J. Infect. 24 (3): 317–20. doi:10.1016/S0163-4453(05)80037-4. PMID 1602151.
White JJ, Ledbetter DH, Eddy RL et al. (1992). “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 et al. (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 (1995). “Prohibitin, an antiproliferative protein, is localized to mitochondria”. FEBS Lett. 358 (3): 273–7. doi:10.1016/0014-5793(94)01444-6. PMID 7843414.
Maruyama K, Sugano S (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 et al. (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 et al. (1996). “The 3' untranslated region of prohibitin and cellular immortalization”. Exp. Cell Res. 224 (1): 128–35. doi:10.1006/excr.1996.0120. PMID 8612677.
Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K et al. (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 et al. (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 (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 (1999). “Rb and Prohibitin Target Distinct Regions of E2F1 for Repression and Respond to Different Upstream Signals”. Mol. Cell. Biol. 19 (11): 7447–60. PMC 84738. PMID 10523633.
Hartley JL, Temple GF, Brasch MA (2001). “DNA Cloning Using In Vitro Site-Specific Recombination”. Genome Res. 10 (11): 1788–95. doi:10.1101/gr.143000. PMC 310948. PMID 11076863.
Coates PJ, Nenutil R, McGregor A et al. (2001). “Mammalian prohibitin proteins respond to mitochondrial stress and decrease during cellular senescence”. Exp. Cell Res. 265 (2): 262–73. doi:10.1006/excr.2001.5166. PMID 11302691.
Van Aken O, Pecenkova T, van de Cotte B et al. (2007). “Mitochondrial type-I prohibitins of Arabidopsis thaliana are required for supporting proficient meristem development”. Plant J. 52 (5): 850–864. doi:10.1111/j.1365-313X.2007.03276.x. PMID 17883375.

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000167085 - Ensembl, May 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000038845 - Ensembl, May 2017

[3] Human PubMed Reference:

[4] Mouse PubMed Reference:

[entrez-5] “Entrez Gene: PHB prohibitin”. 2013年10月11日閲覧。

[6] Van Aken O, Pecenkova T, van de Cotte B et al. (2007). “Mitochondrial type-I prohibitins of Arabidopsis thaliana are required for supporting proficient meristem development”. Plant J. 52 (5): 850–864. doi:10.1111/j.1365-313X.2007.03276.x. PMID 17883375.

[pmid16796804-7] Mishra S, Murphy LC, Murphy LJ (2006). “The Prohibitins: emerging roles in diverse functions”. J. Cell. Mol. Med. 10 (2): 353–63. doi:10.1111/j.1582-4934.2006.tb00404.x. PMID 16796804.

[pmid15525670-8] Tatsuta T, Model K, Langer T (January 2005). “Formation of Membrane-bound Ring Complexes by Prohibitins in Mitochondria”. Mol. Biol. Cell 16 (1): 248–59. doi:10.1091/mbc.E04-09-0807. PMC 539169. PMID 15525670.

[pmid10359819-9] Montano MM, Ekena K, Delage-Mourroux R, Chang W, Martini P, Katzenellenbogen BS (June 1999). “An estrogen receptor-selective coregulator that potentiates the effectiveness of antiestrogens and represses the activity of estrogens”. Proc. Natl. Acad. Sci. U.S.A. 96 (12): 6947–52. doi:10.1073/pnas.96.12.6947. PMC 22022. PMID 10359819.

[pmid16964284-10] Gamble SC, Chotai D, Odontiadis M, Dart DA, Brooke GN, Powell SM, Reebye V, Varela-Carver A, Kawano Y, Waxman J, Bevan C (March 2007). “Prohibitin, a protein downregulated by androgens, represses androgen receptor activity”. Oncogene 26 (12): 1757–68. doi:10.1038/sj.onc.1209967. PMID 16964284.

[pmid15140878-11] Kurtev V, Margueron R, Kroboth K, Ogris E, Cavailles V, Seiser C (June 2004). “Transcriptional regulation by the repressor of estrogen receptor activity via recruitment of histone deacetylases”. J. Biol. Chem. 279 (23): 24834–43. doi:10.1074/jbc.M312300200. PMID 15140878.

[pmid15713652-12] Park SE, Xu J, Frolova A, Liao L, O'Malley BW, Katzenellenbogen BS (March 2005). “Genetic Deletion of the Repressor of Estrogen Receptor Activity (REA) Enhances the Response to Estrogen in Target Tissues In Vivo”. Mol. Cell. Biol. 25 (5): 1989–99. doi:10.1128/MCB.25.5.1989-1999.2005. PMC 549370. PMID 15713652.

[pmid14637159-13] Joshi, Bharat; Ko Danette, Ordonez-Ercan Dalia, Chellappan Srikumar P (Dec. 2003). “A putative coiled-coil domain of prohibitin is sufficient to repress E2F1-mediated transcription and induce apoptosis”. Biochem. Biophys. Res. Commun. (United States) 312 (2): 459–66. doi:10.1016/j.bbrc.2003.10.148. ISSN 0006-291X. PMID 14637159.

[pmid12466959-14] Wang, Sheng; Fusaro Gina, Padmanabhan Jaya, Chellappan Srikumar P (Dec. 2002). “Prohibitin co-localizes with Rb in the nucleus and recruits N-CoR and HDAC1 for transcriptional repression”. Oncogene (England) 21 (55): 8388–96. doi:10.1038/sj.onc.1205944. ISSN 0950-9232. PMID 12466959.

[pmid10523633-15] 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”. Mol. Cell. Biol. (UNITED STATES) 19 (11): 7447–60. ISSN 0270-7306. PMC 84738. PMID 10523633.

[pmid10376528-16] Wang, S; Nath N, Adlam M, Chellappan S (Jun. 1999). “Prohibitin, a potential tumor suppressor, interacts with RB and regulates E2F function”. Oncogene (ENGLAND) 18 (23): 3501–10. doi:10.1038/sj.onc.1202684. ISSN 0950-9232. PMID 10376528.

[pmid14500729-17] Fusaro, Gina; Dasgupta Piyali, Rastogi Shipra, Joshi Bharat, Chellappan Srikumar (Nov. 2003). “Prohibitin induces the transcriptional activity of p53 and is exported from the nucleus upon apoptotic signaling”. J. Biol. Chem. (United States) 278 (48): 47853–61. doi:10.1074/jbc.M305171200. ISSN 0021-9258. PMID 14500729.

[pmid12065415-18] Wang, Sheng; Zhang Baohua, Faller Douglas V (Jun. 2002). “Prohibitin requires Brg-1 and Brm for the repression of E2F and cell growth”. EMBO J. (England) 21 (12): 3019–28. doi:10.1093/emboj/cdf302. ISSN 0261-4189. PMC 126057. PMID 12065415.

[pmid12628297-19] Bacher, Susanne; Achatz Gernot, Schmitz M L, Lamers Marinus C (Dec. 2002). “Prohibitin and prohibitone are contained in high-molecular weight complexes and interact with alpha-actinin and annexin A2”. Biochimie (France) 84 (12): 1207–20. doi:10.1016/S0300-9084(02)00027-5. ISSN 0300-9084. PMID 12628297.

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