Group I p21-activated kinases facilitate Tax-mediated transcriptional activation of the human T-cell leukemia virus type 1 long terminal repeats

Retrovirology

Dong-Yan Jin¹  Hei-Man Vincent Tang¹  Yick-Pang Ching²  Kin-Hang Kok¹  Yeung-Tung Siu¹  Ching-Ping Chan¹ 

[1] Department of Biochemistry, The University of Hong Kong, 3/F Laboratory Block, 21 Sassoon Road, Pokfulam, Hong Kong;Department of Anatomy and State Key Laboratory of Brain and Cognitive Science, The University of Hong Kong, 1/F Laboratory Block, 21 Sassoon Road, Pokfulam, Hong Kong

关键词: CREB-regulating transcriptional activators;    CREB;    p21-activated kinases;    Tax;    HTLV-1;   

Others  :  1209132
DOI  :  10.1186/1742-4690-10-47

 received in 2012-08-28, accepted in 2013-04-23,  发布年份 2013

【 摘 要 】

Background

Human T-cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia and tropical spastic paraparesis. HTLV-1 encodes transactivator protein Tax that interacts with various cellular factors to modulate transcription and other biological functions. Additional cellular mediators of Tax-mediated transcriptional activation of HTLV-1 long terminal repeats (LTR) remain to be identified and characterized.

Results

In this study, we investigated the regulatory role of group I p21-activated kinases (Paks) in Tax-induced LTR activation. Both wild-type and kinase-dead mutants of Pak3 were capable of potentiating the activity of Tax to activate LTR transcription. The effect of Paks on the LTR was attributed to the N-terminal regulatory domain and required the action of CREB, CREB-regulating transcriptional coactivators (CRTCs) and p300/CREB-binding protein. Paks physically associated with Tax and CRTCs. Paks were recruited to the LTR in the presence of Tax. siRNAs against either Pak1 or Pak3 prevented the interaction of Tax with CRTC1 and the recruitment of Tax to the LTR. These siRNAs also inhibited LTR-dependent transcription in HTLV-1-transformed MT4 cells and in cells transfected with an infectious clone of HTLV-1.

Conclusion

Group I Paks augment Tax-mediated transcriptional activation of HTLV-1 LTR in a kinase-independent manner.

【 授权许可】

   
2013 Chan et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Gonçalves DU, Proietti FA, Ribas JG, Araújo MG, Pinheiro SR, Guedes AC, Carneiro-Proietti AB: Epidemiology, treatment, and prevention of human T-cell leukemia virus type 1-associated diseases. Clin Microbiol Rev 2010, 23:577-589.
• [2]Iwanaga M, Watanabe T, Utsunomiya A, Okayama A, Uchimaru K, Koh KR, Ogata M, Kikuchi H, Sagara Y, Uozumi K, Mochizuki M, Tsukasaki K, Saburi Y, Yamamura M, Tanaka J, Moriuchi Y, Hino S, Kamihira S, Yamaguchi K: Human T-cell leukemia virus type I (HTLV-1) proviral load and disease progression in asymptomatic HTLV-1 carriers: a nationwide prospective study in Japan. Blood 2010, 116:1211-1219.
• [3]Tie F, Adya N, Greene WC, Giam CZ: Interaction of the human T-lymphotropic virus type 1 Tax dimer with CREB and the viral 21-base-pair repeat. J Virol 1996, 70:8368-8374.
• [4]Ching YP, Chun ACS, Chin KT, Zhang ZQ, Jeang KT, Jin DY: Specific TATAA and bZIP requirements suggest that HTLV-1 Tax has transcriptional activity subsequent to the assembly of an initiation complex. Retrovirology 2004, 1:18. BioMed Central Full Text
• [5]Kashanchi F, Brady JN: Transcriptional and post-transcriptional gene regulation of HTLV-1. Oncogene 2005, 24:5938-5951.
• [6]Kwok RP, Laurance ME, Lundblad JR, Goldman PS, Shih HM, Connor LM, Marriott SJ, Goodman RH: Control of cAMP-regulated enhancers by the viral transactivator Tax through CREB and the co-activator CBP. Nature 1996, 380:642-646.
• [7]Koga H, Ohshima T, Shimotohno K: Enhanced activation of Tax-dependent transcription of human T-cell leukemia virus type I (HTLV-I) long terminal repeat by TORC3. J Biol Chem 2004, 279:52978-52983.
• [8]Siu YT, Chin KT, Siu KL, Choy EYW, Jeang KT, Jin DY: TORC1 and TORC2 coactivators are required for Tax activation of the human T-cell leukemia virus type 1 long terminal repeats. J Virol 2006, 80:7052-7059.
• [9]Jiang S, Inada T, Tanaka M, Furuta RA, Shingu K, Fujisawa J: Involvement of TORC2, a CREB co-activator, in the in vivo-specific transcriptional control of HTLV-1. Retrovirology 2009, 6:73. BioMed Central Full Text
• [10]Kim YM, Geiger TR, Egan DI, Sharma N, Nyborg JK: The HTLV-1 Tax protein cooperates with phosphorylated CREB, TORC2 and p300 to activate CRE-dependent cyclin D1 transcription. Oncogene 2010, 29:2142-2152.
• [11]Bex F, Murphy K, Wattiez R, Burny A, Gaynor RB: Phosphorylation of the human T-cell leukemia virus type 1 transactivator Tax on adjacent serine residues is critical for Tax activation. J Virol 1999, 73:738-745.
• [12]Durkin SS, Ward MD, Fryrear KA, Semmes OJ: Site-specific phosphorylation differentiates active from inactive forms of the human T-cell leukemia virus type 1 Tax oncoprotein. J Biol Chem 2006, 281:31705-31712.
• [13]Geiger TR, Sharma N, Kim YM, Nyborg JK: The human T-cell leukemia virus type 1 Tax protein confers CBP/p300 recruitment and transcriptional activation properties to phosphorylated CREB. Mol Cell Biol 2008, 28:1383-1392.
• [14]Altarejos JY, Montminy M: CREB and the CRTC co-activators: sensors for hormonal and metabolic signals. Nat Rev Mol Cell Biol 2011, 12:141-151.
• [15]Matsuoka M, Jeang KT: Human T-cell leukemia virus type 1 (HTLV-1) and leukemic transformation: viral infectivity, Tax, HBZ and therapy. Oncogene 2011, 30:1379-1389.
• [16]Boxus M, Twizere JC, Legros S, Dewulf JF, Kettmann R, Willems L: The HTLV-1 Tax interactome. Retrovirology 2008, 5:76. BioMed Central Full Text
• [17]Simonis N, Rual JF, Lemmens I, Boxus M, Hirozane-Kishikawa T, Gatot JS, Dricot A, Hao T, Vertommen D, Legros S, Daakour S, Klitgord N, Martin M, Willaert JF, Dequiedt F, Navratil V, Cusick ME, Burny A, Van Lint C, Hill DE, Tavernier J, Kettmann R, Vidal M, Twizere JC: Host-pathogen interactome mapping for HTLV-1 and −2 retroviruses. Retrovirology 2012, 9:26. BioMed Central Full Text
• [18]Wu K, Bottazzi ME, de la Fuente C, Deng L, Gitlin SD, Maddukuri A, Dadgar S, Li H, Vertes A, Pumfery A, Kashanchi F: Protein profile of Tax-associated complexes. J Biol Chem 2004, 279:495-508.
• [19]Arias-Romero LE, Chernoff J: A tale of two Paks. Biol Cell 2008, 100:97-108.
• [20]Molli PR, Li DQ, Murray BW, Rayala SK, Kumar R: PAK signaling in oncogenesis. Oncogene 2009, 28:2545-2555.
• [21]Ching YP, Leong VYL, Lee MF, Xu HT, Jin DY, Ng IOL: p21-activated protein kinase is overexpressed in hepatocellular carcinoma and enhances cancer metastasis involving c-Jun NH2-terminal kinase activation and paxillin phosphorylation. Cancer Res 2007, 67:3601-3608.
• [22]Mak GWY, Chan MML, Leong VYL, Lee JMF, Yau TO, Ng IOL, Ching YP: Overexpression of a novel activator of PAK4, the CDK5 kinase-associated protein CDK5RAP3, promotes hepatocellular carcinoma metastasis. Cancer Res 2011, 71:2949-2958.
• [23]Van den Broeke C, Radu M, Chernoff J, Favoreel HW: An emerging role for p21-activated kinases (Paks) in viral infections. Trends Cell Biol 2010, 20:160-169.
• [24]Frost JA, Khokhlatchev A, Stippec S, White MA, Cobb MH: Differential effects of PAK1-activating mutations reveal activity-dependent and -independent effects on cytoskeletal regulation. J Biol Chem 1998, 273:28191-28198.
• [25]Vadlamudi RK, Li F, Adam L, Nguyen D, Ohta Y, Stossel TP, Kumar R: Filamin is essential in actin cytoskeletal assembly mediated by p21-activated kinase 1. Nat Cell Biol 2002, 4:681-690.
• [26]Thullberg M, Gad A, Beeser A, Chernoff J, Strömblad S: The kinase-inhibitory domain of p21-activated kinase 1 (PAK1) inhibits cell cycle progression independent of PAK1 kinase activity. Oncogene 2007, 26:1820-1828.
• [27]Higuchi M, Onishi K, Kikuchi C, Gotoh Y: Scaffolding function of PAK in the PDK1-Akt pathway. Nat Cell Biol 2008, 10:1356-1364.
• [28]Chan JK, Greene WC: Dynamic roles for NF-κB in HTLV-I and HIV-1 retroviral pathogenesis. Immunol Rev 2012, 246:286-310.
• [29]Wäldele K, Silbermann K, Schneider G, Ruckes T, Cullen BR, Grassmann R: Requirement of the human T-cell leukemia virus (HTLV-1) Tax-stimulated HIAP-1 gene for the survival of transformed lymphocytes. Blood 2006, 107:4491-4499.
• [30]Frost JA, Swantek JL, Stippec S, Yin MJ, Gaynor R, Cobb MH: Stimulation of NFκB activity by multiple signaling pathways requires PAK1. J Biol Chem 2000, 275:19693-19699.
• [31]Allen KM, Gleeson JG, Bagrodia S, Partington MW, MacMillan JC, Cerione RA, Mulley JC, Walsh CA: PAK3 mutation in nonsyndromic X-linked mental retardation. Nat Genet 1998, 20:25-30.
• [32]Thévenot E, Moreau AW, Rousseau V, Combeau G, Domenichini F, Jacquet C, Goupille O, Amar M, Kreis P, Fossier P, Barnier JV: p21-Activated kinase 3 (PAK3) protein regulates synaptic transmission through its interaction with the Nck2/Grb4 protein adaptor. J Biol Chem 2011, 286:40044-40059.
• [33]Semmes OJ, Jeang KT: Mutational analysis of human T-cell leukemia virus type I Tax: regions necessary for function determined with 47 mutant proteins. J Virol 1992, 66:7183-7192.
• [34]Semmes OJ, Jeang KT: Definition of a minimal activation domain in human T-cell leukemia virus type I Tax. J Virol 1995, 69:1827-1833.
• [35]Chun ACS, Zhou Y, Wong CM, Kung HF, Jeang KT, Jin DY: Coiled-coil motif as a structural basis for the interaction of HTLV type 1 Tax with cellular cofactors. AIDS Res Hum Retrov 2000, 16:1689-1694.
• [36]Ahn S, Olive M, Aggarwal S, Krylov D, Ginty D, Vinson C: A dominate-negative inhibitor of CREB reveals that it is a general mediator of stimulus-dependent transcription of c-fos. Mol Cell Biol 1998, 18:967-977.
• [37]Siu YT, Ching YP, Jin DY: Activation of TORC1 transcriptional coactivator through MEKK1-induced phosphorylation. Mol Biol Cell 2008, 19:4750-4761.
• [38]Madison DL, Yaciuk P, Kwok RP, Lundblad JR: Acetylation of the adenovirus-transforming protein E1A determines nuclear localization by disrupting association with importin-α. J Biol Chem 2002, 277:38755-38763.
• [39]Chin KT, Chun ACS, Ching YP, Jeang KT, Jin DY: Human T-cell leukemia virus oncoprotein Tax represses nuclear receptor-dependent transcription by targeting coactivator TAX1BP1. Cancer Res 2007, 67:1072-1081.
• [40]Singh RR, Song C, Yang Z, Kumar R: Nuclear localization and chromatin targets of p21-activated kinase 1. J Biol Chem 2005, 280:18130-18137.
• [41]Derse D, Mikovits J, Ruscetti F: X-I and X-II open reading frames of HTLV-I are not required for virus replication or for immortalization of primary T-cells in vitro. Virology 1997, 237:123-128.
• [42]Barnes CJ, Vadlamudi RK, Mishra SK, Jacobson RH, Li F, Kumar R: Functional inactivation of a transcriptional corepressor by a signalling kinase. Nat Struct Biol 2003, 10:622-628.
• [43]Meloni AR, Lai CH, Yao TP, Nevins JR: A mechanism of COOH-terminal binding protein-mediated repression. Mol Cancer Res 2005, 3:575-583.
• [44]Li F, Adam L, Vadlamudi RK, Zhou H, Sen S, Chernoff J, Mandal M, Kumar R: p21-activated kinase 1 interacts with and phosphorylates histone H3 in breast cancer cells. EMBO Rep 2002, 3:767-73.
• [45]Sawai ET, Khan IH, Montbriand PM, Peterlin BM, Cheng-Mayer C, Luciw PA: Activation of PAK by HIV and SIV Nef: importance for AIDS in rhesus macaques. Curr Biol 1996, 6:1519-1527.
• [46]Nguyen DG, Wolff KC, Yin H, Caldwell JS, Kuhen KL: "UnPAKing" human immunodeficiency virus (HIV) replication: using small interfering RNA screening to identify novel cofactors and elucidate the role of group I PAKs in HIV infection. J Virol 2006, 80:130-137.
• [47]Xu J, Liu H, Chen L, Wang S, Zhou L, Yun X, Sun L, Wen Y, Gu J: Hepatitis B virus X protein confers resistance of hepatoma cells to anoikis by up-regulating and activating p21-activated kinase 1. Gastroenterology 2012, 143:199-212.
• [48]Eswaran J, Li DQ, Shah A, Kumar R: Molecular pathways: targeting p21-activated kinase 1 signaling in cancer - opportunities, challenges, and limitations. Clin Cancer Res 2012, 18:3743-3749.
• [49]Grassmann R, Aboud M, Jeang KT: Molecular mechanisms of cellular transformation by HTLV-1 Tax. Oncogene 2005, 24:5976-5985.
• [50]Siu YT, Jin DY: CREB-a real culprit in oncogenesis. FEBS J 2007, 274:3224-3232.
• [51]Kok KH, Lui PY, Ng MHJ, Siu KL, Au SWN, Jin DY: The double-stranded RNA-binding protein PACT functions as a cellular activator of RIG-I to facilitate innate antiviral response. Cell Host Microbe 2011, 9:299-309.
• [52]Ng MHJ, Ho TH, Kok KH, Siu KL, Li J, Jin DY: MIP-T3 is a negative regulator of innate type I IFN response. J Immunol 2011, 187:6473-6482.
• [53]Johannessen CM, Boehm JS, Kim SY, Thomas SR, Wardwell L, Johnson LA, Emery CM, Stransky N, Cogdill AP, Barretina J, Caponigro G, Hieronymus H, Murray RR, Salehi-Ashtiani K, Hill DE, Vidal M, Zhao JJ, Yang X, Alkan O, Kim S, Harris JL, Wilson CJ, Myer VE, Finan PM, Root DE, Roberts TM, Golub T, Flaherty KT, Dummer R, Weber BL, Sellers WR, Schlegel R, Wargo JA, Hahn WC, Garraway LA: COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature 2010, 468:968-972.
• [54]Chun ACS, Kok KH, Jin DY: REV7 is required for anaphase promoting complex-dependent ubiquitination and degradation of translesion DNA polymerase REV1. Cell Cycle 2013, 12:365-378.
• [55]Chin KT, Zhou HJ, Wong CM, Lee JMF, Chan CP, Qiang BQ, Yuan JG, Ng IOL, Jin DY: The liver-enriched transcription factor CREB-H is a growth suppressor protein underexpressed in hepatocellular carcinoma. Nucleic Acids Res 2005, 33:1859-1873.
• [56]Tang HMV, Gao WW, Chan CP, Siu YT, Wong CM, Kok KH, Ching YP, Takemori H, Jin DY: LKB1 tumor suppressor and salt-inducible kinases negatively regulate human T-cell leukemia virus type 1 transcription. Retrovirology 2013, 10:40. BioMed Central Full Text