抗增殖蛋白2:一种线粒体和细胞核之间的重要媒介
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摘要
抗增殖蛋白2(prohibitin2,PHB2)是抗增殖蛋白(prohibitin,PHB)家族中的重要成员,是主要定位于线粒体内膜的多功能蛋白质,对维持线粒体形态和功能的稳定具有重要作用,同时也是细胞内稳态和细胞分化的重要调节因子。随着对PHB2的深入研究,已发现PHB2是一种线粒体和细胞核之间重要的媒介。PHB2是细胞中必不可少的,它直接参与多种细胞进程并发挥重要作用,如调节转录因子的转录活性、调节细胞的分化与凋亡、维持线粒体形态和功能的稳定、调节姐妹染色单体的结合、神经细胞的修复和再生、轴突的发育形成和增强细胞氧化应激耐受性。近年来,PHB2在病理生理学中的作用及其在疾病治疗中的药靶地位受到高度重视。本文对PHB2研究的最新进展进行综述。
Prohibitin2(PHB2) is an important member of the prohibitin protein(PHB) family. It is a multifunctional protein mainly located in the inner mitochondrial membrane and plays an important role in maintaining the stability of mitochondrial morphology and function. It is also an important regulator of intracellular homeostasis and cell differentiation. Intensive studies about PHB2 have revealed that PHB2 is an important shuttle protein between the mitochondria and nuclei. PHB2 is directly involved in a variety of cellular processes and plays important roles in the regulation of various transcription factors,cell differentiation and apoptosis,sister chromatid cohesion,neuronal cell repair and regeneration,axonal development and enhances cellular tolerance of oxidative stress,etc. In recent years,the role of PHB2 in pathophysiology and its role as a drug target in disease treatment have been highly evaluated. This paper reviews the latest advances in PHB2 research.
Prohibitin2(PHB2) is an important member of the prohibitin protein(PHB) family. It is a multifunctional protein mainly located in the inner mitochondrial membrane and plays an important role in maintaining the stability of mitochondrial morphology and function. It is also an important regulator of intracellular homeostasis and cell differentiation. Intensive studies about PHB2 have revealed that PHB2 is an important shuttle protein between the mitochondria and nuclei. PHB2 is directly involved in a variety of cellular processes and plays important roles in the regulation of various transcription factors,cell differentiation and apoptosis,sister chromatid cohesion,neuronal cell repair and regeneration,axonal development and enhances cellular tolerance of oxidative stress,etc. In recent years,the role of PHB2 in pathophysiology and its role as a drug target in disease treatment have been highly evaluated. This paper reviews the latest advances in PHB2 research.
引文
[1]Mc Clung JK,Danner DB,Stewart DA,et al.Isolation of a c DNA that hybrid selects antiproliferative mRNA from rat liver[J].Biochem Biophys Res Commun,1989,164(3):1316-1322
[2]李铁松,高杨,王颖,等.抗增殖蛋白与氧化应激[J].生物技术通报(Li TS,Gao Y,Wang Y,et al.Prohibitin and oxidative stress[J].Biotechnol Bull),2013,10:35-39
[3]Nijtmans LG,Artal SM,Grivell LA,et al.The mitochondrial PHB complex:roles in mitochondrial respiratory complex assembly,ageing and degenerative disease[J].Cell Mol Life Sci,2002,59(1):143-155
[4]Merkwirth C,Langer T.Prohibitin function within mitochondria:essential roles for cell proliferation and cristae morphogenesis[J].Biochim Biophys Acta,2009,1793(1):27-32
[5]Osman C,Merkwirth C,Langer T.Prohibitins and the functional compartmentalization of mitochondrial membranes[J].J Cell Sci,2009,122(Pt 21):3823-3830
[6]Steglich G,Neupert W,Langer T.Prohibitins regulate membrane protein degradation by the m-AAA protease in mitochondria[J].Mol Cell Biol,1999,19(5):3435-3442
[7]Sun L,Liu L,Yang XJ,et al.Akt binds prohibitin 2 and relieves its repression of Myo D and muscle differentiation[J].J Cell Sci,2004,117(Pt 14):3021-3029
[8]Choi D,Lee SJ,Hong S,et al.Prohibitin interacts with RNF2and regulates E2F1 function via dual pathways[J].Oncogene,2008,27(12):1716-1725
[9]Fusaro G,Dasgupta P,Rastogi S,et al.Prohibitin induces the transcriptional activity of p53 and is exported from the nucleus upon apoptotic signaling[J].J Biol Chem,2003,278(48):47853-47861
[10]Ande SR,Mishra S.Palmitoylation of prohibitin at cysteine 69facilitates its membrane translocation and interaction with Eps 15homology domain protein 2(EHD2)[J].Biochem Cell Biol,2010,88(3):553-558
[11]Terashima M,Kim K M,Adachi T,et al.The Ig M antigen receptor of B lymphocytes is associated with prohibitin and a prohibitin-related protein[J].EMBO J,1994,13(16):3782-3792
[12]Kasashima K,Ohta E,Kagawa Y,et al.Mitochondrial functions and estrogen receptor-dependent nuclear translocation of pleiotropic human prohibitin 2[J].J Biol Chem,2006,281(47):36401-36410
[13]Thuaud F,Ribeiro N,Nebigil CG,et al.Prohibitin ligands in cell death and survival:mode of action and therapeutic potential[J].Chem Biol,2013,20(3):316-331
[14]Montano MM,Ekena K,Delage-Mourroux R,et al.An estrogen receptor-selective coregulator that potentiates the effectiveness of antiestrogens and represses the activity of estrogens[J].Proc Natl Acad Sci U S A,1999,96(12):6947-6952
[15]Park SE,Xu J,Frolova A,et al.Genetic deletion of the repressor of estrogen receptor activity(REA)enhances the response to estrogen in target tissues in vivo[J].Mol Cell Biol,2005,25(5):1989-1999
[16]Yoshimaru T,Komatsu M,Miyoshi Y,et al.Therapeutic advances in BIG3-PHB2 inhibition targeting the crosstalk between estrogen and growth factors in breast cancer[J].Cancer Sci,2015,106(5):550-558
[17]Delage-Mourroux R,Martini PG,Choi I,et al.Analysis of estrogen receptor interaction with a repressor of estrogen receptor activity(REA)and the regulation of estrogen receptor transcriptional activity by REA[J].J Biol Chem,2000,275(46):35848-35856
[18]Kim JW,Akiyama M,Park JH,et al.Activation of an estrogen/estrogen receptor signaling by BIG3 through its inhibitory effect on nuclear transport of PHB2/REA in breast cancer[J].Cancer Sci,2009,100(8):1468-1478
[19]Yoshimaru T,Komatsu M,Matsuo T,et al.Targeting BIG3-PHB2 interaction to overcome tamoxifen resistance in breast cancer cells[J].Nat Commun,2013,4:2443
[20]Kowno M,Watanabe-Susaki K,Ishimine H,et al.Prohibitin 2regulates the proliferation and lineage-specific differentiation of mouse embryonic stem cells in mitochondria[J].PLo S One,2014,9(4):e81552
[21]Santhanam SK,Dutta D,Parween F,et al.The virulence polysaccharide Vi released by Salmonella Typhi targets membrane prohibitin to inhibit T-cell activation[J].J Infect Dis,2014,210(1):79-88
[22]Joshi B,Ko D,Ordonez-Ercan D,et al.A putative coiled-coil domain of prohibitin is sufficient to repress E2F1-mediated transcription and induce apoptosis[J].Biochem Biophys Res Commun,2003,312(2):459-466
[23]Merkwirth C,Dargazanli S,Tatsuta T,et al.Prohibitins control cell proliferation and apoptosis by regulating OPA1-dependent cristae morphogenesis in mitochondria[J].Genes Dev,2008,22(4):476-488
[24]Merkwirth C,Martinelli P,Korwitz A,et al.Loss of prohibitin membrane scaffolds impairs mitochondrial architecture and leads to tau hyperphosphorylation and neurodegeneration[J].PLo S Genet,2012,8(11):e1003021
[25]M9pert K,Hajek P,Frank S,et al.Loss of Drp1 function alters OPA1 processing and changes mitochondrial membrane organization[J].Exp Cell Res,2009,315(13):2165-2180
[26]Wei Y,Chiang WC,Sumpter R Jr,et al.Prohibitin 2 is an inner mitochondrial membrane mitophagy receptor[J].Cell,2017,168(1-2):224-238
[27]Wang X,Yang Y,Dai W.Differential subcellular localizations of two human Sgo1 isoforms:implications in regulation of sister chromatid cohesion and microtubule dynamics[J].Cell Cycle,2006,5(6):635-640
[28]Takata H,Matsunaga S,Morimoto A,et al.PHB2 protects sister-chromatid cohesion in mitosis[J].Curr Biol,2007,17(15):1356-1361
[29]Mc Clung JK,Jupe ER,Liu XT,et al.Prohibitin:Potential role in senescence,development,and tumor suppression[J].Exp Gerontol,1995,30(2):99-124
[30]Long L,Huang Y,Wu H,et al.Dynamic change of Prohibitin2expression in rat sciatic nerve after crush[J].Cell Mol Neurobiol,2013,33(5):689-698
[31]Neumann C A,Krause D S,Carman C V,et al.Essential role for the peroxiredoxin Prdx1 in erythrocyte antioxidant defence and tumour suppression[J].Nature,2003,424(6948):561-565
[32]Lachén-Montes M,González-Morales A,Zelaya MV,et al.Olfactory bulb neuroproteomics reveals a chronological perturbation of survival routes and a disruption of prohibitin complex during Alzheimer’s disease progression[J].Sci Rep,2017,7(1):9115
[33]Li T,Wang Y,Gao Y,et al.Identification and characterisation of the anti-oxidative stress properties of the lamprey prohibitin 2gene[J].Fish Shellfish Immunol,2015,42(2):447-456
[34]Zhou P,Qian L,D’Aurelio M,et al.Prohibitin reduces mitochondrial free radical production and protects brain cells from different injury modalities[J].J Neurosci,2012,32(2):583-592
[35]Kuadkitkan A,Wikan N,Fongsaran C,et al.Identification and characterization of prohibitin as a receptor protein mediating DENV-2 entry into insect cells[J].Virology,2010,406(1):149-161
[36]Koushyar S,Economides G,Zaat S,et al.The prohibitinrepressive interaction with E2F1 is rapidly inhibited by androgen signalling in prostate cancer cells[J].Oncogenesis,2017,6(5):e333
[37]Wang S,Zhang B,Faller DV.Prohibitin requires Brg-1 and Brm for the repression of E2F and cell growth[J].EMBO J,2002,21(12):3019-3028
[38]Kim NH,Yoshimaru T,Chen YA,et al.BIG3 inhibits the estrogen-dependent nuclear translocation of PHB2 via multiple karyopherin-alpha proteins in breast cancer cells[J].PLo S One,2015,10(6):e0127707
[39]Yoshimaru T,Komatsu M,Miyoshi Y,et al.Therapeutic advances in BIG3-PHB2 inhibition targeting the crosstalk between estrogen and growth factors in breast cancer[J].Cancer Sci,2015,106(5):550-558
[40]Harasta AE,Ittner LM.Alzheimer’s disease:insights from genetic mouse models and current advances in human IPSCderived neurons[J].Adv Neurobiol,2017,15:3-29
[41]Santangelo R,Cecchetti G,Bernasconi MP,et al.Cerebrospinal fluid amyloid-β42,total tau,and phosphorylated tau are low in patients with normal pressure hydrocephalus:analogies and differences with Alzheimer’s disease[J].J Alzheimers Dis,2017,60(1):183-200
[42]Emerson V,Holtkotte D,Pfeiffer T,et al.Identification of the cellular prohibitin 1/prohibitin 2 heterodimer as an interaction partner of the C-terminal cytoplasmic domain of the HIV-1glycoprotein[J].J Virol,2010,84(3):1355-1365
[43]Liu S,Wang W,Brown LE,et al.A novel class of small molecule compounds that inhibit hepatitis C virus infection by targeting the prohibitin-CRaf pathway[J].EBio Medicine,2015,2(11):1600-1606
[2]李铁松,高杨,王颖,等.抗增殖蛋白与氧化应激[J].生物技术通报(Li TS,Gao Y,Wang Y,et al.Prohibitin and oxidative stress[J].Biotechnol Bull),2013,10:35-39
[3]Nijtmans LG,Artal SM,Grivell LA,et al.The mitochondrial PHB complex:roles in mitochondrial respiratory complex assembly,ageing and degenerative disease[J].Cell Mol Life Sci,2002,59(1):143-155
[4]Merkwirth C,Langer T.Prohibitin function within mitochondria:essential roles for cell proliferation and cristae morphogenesis[J].Biochim Biophys Acta,2009,1793(1):27-32
[5]Osman C,Merkwirth C,Langer T.Prohibitins and the functional compartmentalization of mitochondrial membranes[J].J Cell Sci,2009,122(Pt 21):3823-3830
[6]Steglich G,Neupert W,Langer T.Prohibitins regulate membrane protein degradation by the m-AAA protease in mitochondria[J].Mol Cell Biol,1999,19(5):3435-3442
[7]Sun L,Liu L,Yang XJ,et al.Akt binds prohibitin 2 and relieves its repression of Myo D and muscle differentiation[J].J Cell Sci,2004,117(Pt 14):3021-3029
[8]Choi D,Lee SJ,Hong S,et al.Prohibitin interacts with RNF2and regulates E2F1 function via dual pathways[J].Oncogene,2008,27(12):1716-1725
[9]Fusaro G,Dasgupta P,Rastogi S,et al.Prohibitin induces the transcriptional activity of p53 and is exported from the nucleus upon apoptotic signaling[J].J Biol Chem,2003,278(48):47853-47861
[10]Ande SR,Mishra S.Palmitoylation of prohibitin at cysteine 69facilitates its membrane translocation and interaction with Eps 15homology domain protein 2(EHD2)[J].Biochem Cell Biol,2010,88(3):553-558
[11]Terashima M,Kim K M,Adachi T,et al.The Ig M antigen receptor of B lymphocytes is associated with prohibitin and a prohibitin-related protein[J].EMBO J,1994,13(16):3782-3792
[12]Kasashima K,Ohta E,Kagawa Y,et al.Mitochondrial functions and estrogen receptor-dependent nuclear translocation of pleiotropic human prohibitin 2[J].J Biol Chem,2006,281(47):36401-36410
[13]Thuaud F,Ribeiro N,Nebigil CG,et al.Prohibitin ligands in cell death and survival:mode of action and therapeutic potential[J].Chem Biol,2013,20(3):316-331
[14]Montano MM,Ekena K,Delage-Mourroux R,et al.An estrogen receptor-selective coregulator that potentiates the effectiveness of antiestrogens and represses the activity of estrogens[J].Proc Natl Acad Sci U S A,1999,96(12):6947-6952
[15]Park SE,Xu J,Frolova A,et al.Genetic deletion of the repressor of estrogen receptor activity(REA)enhances the response to estrogen in target tissues in vivo[J].Mol Cell Biol,2005,25(5):1989-1999
[16]Yoshimaru T,Komatsu M,Miyoshi Y,et al.Therapeutic advances in BIG3-PHB2 inhibition targeting the crosstalk between estrogen and growth factors in breast cancer[J].Cancer Sci,2015,106(5):550-558
[17]Delage-Mourroux R,Martini PG,Choi I,et al.Analysis of estrogen receptor interaction with a repressor of estrogen receptor activity(REA)and the regulation of estrogen receptor transcriptional activity by REA[J].J Biol Chem,2000,275(46):35848-35856
[18]Kim JW,Akiyama M,Park JH,et al.Activation of an estrogen/estrogen receptor signaling by BIG3 through its inhibitory effect on nuclear transport of PHB2/REA in breast cancer[J].Cancer Sci,2009,100(8):1468-1478
[19]Yoshimaru T,Komatsu M,Matsuo T,et al.Targeting BIG3-PHB2 interaction to overcome tamoxifen resistance in breast cancer cells[J].Nat Commun,2013,4:2443
[20]Kowno M,Watanabe-Susaki K,Ishimine H,et al.Prohibitin 2regulates the proliferation and lineage-specific differentiation of mouse embryonic stem cells in mitochondria[J].PLo S One,2014,9(4):e81552
[21]Santhanam SK,Dutta D,Parween F,et al.The virulence polysaccharide Vi released by Salmonella Typhi targets membrane prohibitin to inhibit T-cell activation[J].J Infect Dis,2014,210(1):79-88
[22]Joshi B,Ko D,Ordonez-Ercan D,et al.A putative coiled-coil domain of prohibitin is sufficient to repress E2F1-mediated transcription and induce apoptosis[J].Biochem Biophys Res Commun,2003,312(2):459-466
[23]Merkwirth C,Dargazanli S,Tatsuta T,et al.Prohibitins control cell proliferation and apoptosis by regulating OPA1-dependent cristae morphogenesis in mitochondria[J].Genes Dev,2008,22(4):476-488
[24]Merkwirth C,Martinelli P,Korwitz A,et al.Loss of prohibitin membrane scaffolds impairs mitochondrial architecture and leads to tau hyperphosphorylation and neurodegeneration[J].PLo S Genet,2012,8(11):e1003021
[25]M9pert K,Hajek P,Frank S,et al.Loss of Drp1 function alters OPA1 processing and changes mitochondrial membrane organization[J].Exp Cell Res,2009,315(13):2165-2180
[26]Wei Y,Chiang WC,Sumpter R Jr,et al.Prohibitin 2 is an inner mitochondrial membrane mitophagy receptor[J].Cell,2017,168(1-2):224-238
[27]Wang X,Yang Y,Dai W.Differential subcellular localizations of two human Sgo1 isoforms:implications in regulation of sister chromatid cohesion and microtubule dynamics[J].Cell Cycle,2006,5(6):635-640
[28]Takata H,Matsunaga S,Morimoto A,et al.PHB2 protects sister-chromatid cohesion in mitosis[J].Curr Biol,2007,17(15):1356-1361
[29]Mc Clung JK,Jupe ER,Liu XT,et al.Prohibitin:Potential role in senescence,development,and tumor suppression[J].Exp Gerontol,1995,30(2):99-124
[30]Long L,Huang Y,Wu H,et al.Dynamic change of Prohibitin2expression in rat sciatic nerve after crush[J].Cell Mol Neurobiol,2013,33(5):689-698
[31]Neumann C A,Krause D S,Carman C V,et al.Essential role for the peroxiredoxin Prdx1 in erythrocyte antioxidant defence and tumour suppression[J].Nature,2003,424(6948):561-565
[32]Lachén-Montes M,González-Morales A,Zelaya MV,et al.Olfactory bulb neuroproteomics reveals a chronological perturbation of survival routes and a disruption of prohibitin complex during Alzheimer’s disease progression[J].Sci Rep,2017,7(1):9115
[33]Li T,Wang Y,Gao Y,et al.Identification and characterisation of the anti-oxidative stress properties of the lamprey prohibitin 2gene[J].Fish Shellfish Immunol,2015,42(2):447-456
[34]Zhou P,Qian L,D’Aurelio M,et al.Prohibitin reduces mitochondrial free radical production and protects brain cells from different injury modalities[J].J Neurosci,2012,32(2):583-592
[35]Kuadkitkan A,Wikan N,Fongsaran C,et al.Identification and characterization of prohibitin as a receptor protein mediating DENV-2 entry into insect cells[J].Virology,2010,406(1):149-161
[36]Koushyar S,Economides G,Zaat S,et al.The prohibitinrepressive interaction with E2F1 is rapidly inhibited by androgen signalling in prostate cancer cells[J].Oncogenesis,2017,6(5):e333
[37]Wang S,Zhang B,Faller DV.Prohibitin requires Brg-1 and Brm for the repression of E2F and cell growth[J].EMBO J,2002,21(12):3019-3028
[38]Kim NH,Yoshimaru T,Chen YA,et al.BIG3 inhibits the estrogen-dependent nuclear translocation of PHB2 via multiple karyopherin-alpha proteins in breast cancer cells[J].PLo S One,2015,10(6):e0127707
[39]Yoshimaru T,Komatsu M,Miyoshi Y,et al.Therapeutic advances in BIG3-PHB2 inhibition targeting the crosstalk between estrogen and growth factors in breast cancer[J].Cancer Sci,2015,106(5):550-558
[40]Harasta AE,Ittner LM.Alzheimer’s disease:insights from genetic mouse models and current advances in human IPSCderived neurons[J].Adv Neurobiol,2017,15:3-29
[41]Santangelo R,Cecchetti G,Bernasconi MP,et al.Cerebrospinal fluid amyloid-β42,total tau,and phosphorylated tau are low in patients with normal pressure hydrocephalus:analogies and differences with Alzheimer’s disease[J].J Alzheimers Dis,2017,60(1):183-200
[42]Emerson V,Holtkotte D,Pfeiffer T,et al.Identification of the cellular prohibitin 1/prohibitin 2 heterodimer as an interaction partner of the C-terminal cytoplasmic domain of the HIV-1glycoprotein[J].J Virol,2010,84(3):1355-1365
[43]Liu S,Wang W,Brown LE,et al.A novel class of small molecule compounds that inhibit hepatitis C virus infection by targeting the prohibitin-CRaf pathway[J].EBio Medicine,2015,2(11):1600-1606