41
Views
14
CrossRef citations to date
0
Altmetric
Article

NFAT2 Isoforms Differentially Regulate Gene Expression, Cell Death, and Transformation through Alternative N-Terminal Domains

, , , , , & ORCID Icon show all
Pages 119-131 | Received 13 May 2015, Accepted 08 Oct 2015, Published online: 18 Mar 2023

REFERENCES

  • Shaw JP, Utz PJ, Durand DB, Toole JJ, Emmel EA, Crabtree GR. 1988. Identification of a putative regulator of early T cell activation genes. Science 241:202–205. http://dx.doi.org/10.1126/science.3260404.
  • McCaffrey PG, Perrino BA, Soderling TR, Rao A. 1993. NF-ATp, a T lymphocyte DNA-binding protein that is a target for calcineurin and immunosuppressive drugs. J Biol Chem 268:3747–3752.
  • Northrop JP, Ho SN, Chen L, Thomas DJ, Timmerman LA, Nolan GP, Admon A, Crabtree GR. 1994. NF-AT components define a family of transcription factors targeted in T-cell activation. Nature 369:497–502. http://dx.doi.org/10.1038/369497a0.
  • Hoey T, Sun YL, Williamson K, Xu X. 1995. Isolation of two new members of the NF-AT gene family and functional characterization of the NF-AT proteins. Immunity 2:461–472. http://dx.doi.org/10.1016/1074-7613(95)90027-6.
  • Masuda ES, Naito Y, Tokumitsu H, Campbell D, Saito F, Hannum C, Arai K, Arai N. 1995. NFATx, a novel member of the nuclear factor of activated T cells family that is expressed predominantly in the thymus. Mol Cell Biol 15:2697–2706. http://dx.doi.org/10.1128/MCB.15.5.2697.
  • Rao A, Luo C, Hogan PG. 1997. Transcription factors of the NFAT family: regulation and function. Annu Rev Immunol 15:707–747. http://dx.doi.org/10.1146/annurev.immunol.15.1.707.
  • Vihma H, Pruunsild P, Timmusk T. 2008. Alternative splicing and expression of human and mouse NFAT genes. Genomics 92:279–291. http://dx.doi.org/10.1016/j.ygeno.2008.06.011.
  • Macian F. 2005. NFAT proteins: key regulators of T-cell development and function. Nat Rev Immunol 5:472–484. http://dx.doi.org/10.1038/nri1632.
  • Robbs BK, Cruz AL, Werneck MB, Mognol GP, Viola JP. 2008. Dual roles for NFAT transcription factor genes as oncogenes and tumor suppressors. Mol Cell Biol 28:7168–7181. http://dx.doi.org/10.1128/MCB.00256-08.
  • Viola JP, Carvalho LD, Fonseca BP, Teixeira LK. 2005. NFAT transcription factors: from cell cycle to tumor development. Braz J Med Biol Res 38:335–344. http://dx.doi.org/10.1590/S0100-879X2005000300003.
  • Buchholz M, Schatz A, Wagner M, Michl P, Linhart T, Adler G, Gress TM, Ellenrieder V. 2006. Overexpression of c-myc in pancreatic cancer caused by ectopic activation of NFATc1 and the Ca2+/calcineurin signaling pathway. EMBO J 25:3714–3724. http://dx.doi.org/10.1038/sj.emboj.7601246.
  • Mognol GP, de Araujo-Souza PS, Robbs BK, Teixeira LK, Viola JP. 2012. Transcriptional regulation of the c-Myc promoter by NFAT1 involves negative and positive NFAT-responsive elements. Cell Cycle 11:1014–1028. http://dx.doi.org/10.4161/cc.11.5.19518.
  • Carvalho LD, Teixeira LK, Carrossini N, Caldeira AT, Ansel KM, Rao A, Viola JP. 2007. The NFAT1 transcription factor is a repressor of cyclin A2 gene expression. Cell Cycle 6:1789–1795. http://dx.doi.org/10.4161/cc.6.14.4473.
  • Pedrosa AM, Weinlich R, Mognol GP, Robbs BK, Viola JP, Campa A, Amarante-Mendes GP. 2010. Melatonin protects CD4+ T cells from activation-induced cell death by blocking NFAT-mediated CD95 ligand upregulation. J Immunol 184:3487–3494. http://dx.doi.org/10.4049/jimmunol.0902961.
  • Youn HD, Chatila TA, Liu JO. 2000. Integration of calcineurin and MEF2 signals by the coactivator p300 during T-cell apoptosis. EMBO J 19:4323–4331. http://dx.doi.org/10.1093/emboj/19.16.4323.
  • Zaichuk TA, Shroff EH, Emmanuel R, Filleur S, Nelius T, Volpert OV. 2004. Nuclear factor of activated T cells balances angiogenesis activation and inhibition. J Exp Med 199:1513–1522. http://dx.doi.org/10.1084/jem.20040474.
  • Robbs BK, Lucena PI, Viola JP. 2013. The transcription factor NFAT1 induces apoptosis through cooperation with Ras/Raf/MEK/ERK pathway and upregulation of TNF-alpha expression. Biochim Biophys Acta 1833:2016–2028. http://dx.doi.org/10.1016/j.bbamcr.2013.04.003.
  • Medyouf H, Ghysdael J. 2008. The calcineurin/NFAT signaling pathway: a novel therapeutic target in leukemia and solid tumors. Cell Cycle 7:297–303. http://dx.doi.org/10.4161/cc.7.3.5357.
  • Qin JJ, Nag S, Wang W, Zhou J, Zhang WD, Wang H, Zhang R. 2014. NFAT as cancer target: mission possible? Biochim Biophys Acta 1846:297–311. http://dx.doi.org/10.1016/j.bbcan.2014.07.009.
  • Levin-Gromiko U, Koshelev V, Kushnir P, Fedida-Metula S, Voronov E, Fishman D. 2014. Amplified lipid rafts of malignant cells constitute a target for inhibition of aberrantly active NFAT and melanoma tumor growth by the aminobisphosphonate zoledronic acid. Carcinogenesis 35:2555–2566. http://dx.doi.org/10.1093/carcin/bgu178.
  • Tripathi MK, Deane NG, Zhu J, An H, Mima S, Wang X, Padmanabhan S, Shi Z, Prodduturi N, Ciombor KK, Chen X, Washington MK, Zhang B, Beauchamp RD. 2014. Nuclear factor of activated T-cell activity is associated with metastatic capacity in colon cancer. Cancer Res 74:6947–6957. http://dx.doi.org/10.1158/0008-5472.CAN-14-1592.
  • Marafioti T, Pozzobon M, Hansmann ML, Ventura R, Pileri SA, Roberton H, Gesk S, Gaulard P, Barth TF, Du MQ, Leoncini L, Moller P, Natkunam Y, Siebert R, Mason DY. 2005. The NFATc1 transcription factor is widely expressed in white cells and translocates from the cytoplasm to the nucleus in a subset of human lymphomas. Br J Haematol 128:333–342. http://dx.doi.org/10.1111/j.1365-2141.2004.05313.x.
  • Le Roy C, Deglesne PA, Chevallier N, Beitar T, Eclache V, Quettier M, Boubaya M, Letestu R, Levy V, Ajchenbaum-Cymbalista F, Varin-Blank N. 2012. The degree of BCR and NFAT activation predicts clinical outcomes in chronic lymphocytic leukemia. Blood 120:356–365. http://dx.doi.org/10.1182/blood-2011-12-397158.
  • Chuvpilo S, Jankevics E, Tyrsin D, Akimzhanov A, Moroz D, Jha MK, Schulze-Luehrmann J, Santner-Nanan B, Feoktistova E, Konig T, Avots A, Schmitt E, Berberich-Siebelt F, Schimpl A, Serfling E. 2002. Autoregulation of NFATc1/A expression facilitates effector T cells to escape from rapid apoptosis. Immunity 16:881–895. http://dx.doi.org/10.1016/S1074-7613(02)00329-1.
  • Sherman MA, Powell DR, Weiss DL, Brown MA. 1999. NF-ATc isoforms are differentially expressed and regulated in murine T and mast cells. J Immunol 162:2820–2828.
  • Bhattacharyya S, Deb J, Patra AK, Thuy Pham DA, Chen W, Vaeth M, Berberich-Siebelt F, Klein-Hessling S, Lamperti ED, Reifenberg K, Jellusova J, Schweizer A, Nitschke L, Leich E, Rosenwald A, Brunner C, Engelmann S, Bommhardt U, Avots A, Muller MR, Kondo E, Serfling E. 2011. NFATc1 affects mouse splenic B cell function by controlling the calcineurin-NFAT signaling network. J Exp Med 208:823–839. http://dx.doi.org/10.1084/jem.20100945.
  • Hock M, Vaeth M, Rudolf R, Patra AK, Pham DA, Muhammad K, Pusch T, Bopp T, Schmitt E, Rost R, Berberich-Siebelt F, Tyrsin D, Chuvpilo S, Avots A, Serfling E, Klein-Hessling S. 2013. NFATc1 induction in peripheral T and B lymphocytes. J Immunol 190:2345–2353. http://dx.doi.org/10.4049/jimmunol.1201591.
  • Hock MB, Brown MA. 2003. Nuclear factor of activated T cells 2 transactivation in mast cells: a novel isoform-specific transactivation domain confers unique FcepsilonRI responsiveness. J Biol Chem 278:26695–26703. http://dx.doi.org/10.1074/jbc.M301007200.
  • Martinez GJ, Pereira RM, Aijo T, Kim EY, Marangoni F, Pipkin ME, Togher S, Heissmeyer V, Zhang YC, Crotty S, Lamperti ED, Ansel KM, Mempel TR, Lahdesmaki H, Hogan PG, Rao A. 2015. The transcription factor NFAT promotes exhaustion of activated CD8(+) T cells. Immunity 42:265–278. http://dx.doi.org/10.1016/j.immuni.2015.01.006.
  • Teixeira LK, Fonseca BP, Vieira-de-Abreu A, Barboza BA, Robbs BK, Bozza PT, Viola JP. 2005. IFN-gamma production by CD8+ T cells depends on NFAT1 transcription factor and regulates Th differentiation. J Immunol 175:5931–5939. http://dx.doi.org/10.4049/jimmunol.175.9.5931.
  • Monticelli S, Rao A. 2002. NFAT1 and NFAT2 are positive regulators of IL-4 gene transcription. Eur J Immunol 32:2971–2978. http://dx.doi.org/10.1002/1521-4141(2002010)32:10<2971::AID-IMMU2971>3.0.CO;2-G.
  • Tsai EY, Jain J, Pesavento PA, Rao A, Goldfeld AE. 1996. Tumor necrosis factor alpha gene regulation in activated T cells involves ATF-2/Jun and NFATp. Mol Cell Biol 16:459–467. http://dx.doi.org/10.1128/MCB.16.2.459.
  • Triezenberg SJ. 1995. Structure and function of transcriptional activation domains. Curr Opin Genet Dev 5:190–196. http://dx.doi.org/10.1016/0959-437X(95)80007-7.
  • Giniger E, Ptashne M. 1987. Transcription in yeast activated by a putative amphipathic alpha helix linked to a DNA binding unit. Nature 330:670–672. http://dx.doi.org/10.1038/330670a0.
  • Falvo JV, Tsytsykova AV, Goldfeld AE. 2010. Transcriptional control of the TNF gene. Curr Dir Autoimmun 11:27–60. http://dx.doi.org/10.1159/000289196.
  • Vaeth M, Schliesser U, Muller G, Reissig S, Satoh K, Tuettenberg A, Jonuleit H, Waisman A, Muller MR, Serfling E, Sawitzki BS, Berberich-Siebelt F. 2012. Dependence on nuclear factor of activated T-cells (NFAT) levels discriminates conventional T cells from Foxp3+ regulatory T cells. Proc Natl Acad Sci U S A 109:16258–16263. http://dx.doi.org/10.1073/pnas.1203870109.
  • Chuvpilo S, Avots A, Berberich-Siebelt F, Glockner J, Fischer C, Kerstan A, Escher C, Inashkina I, Hlubek F, Jankevics E, Brabletz T, Serfling E. 1999. Multiple NF-ATc isoforms with individual transcriptional properties are synthesized in T lymphocytes. J Immunol 162:7294–7301.
  • Chuvpilo S, Zimmer M, Kerstan A, Glockner J, Avots A, Escher C, Fischer C, Inashkina I, Jankevics E, Berberich-Siebelt F, Schmitt E, Serfling E. 1999. Alternative polyadenylation events contribute to the induction of NF-ATc in effector T cells. Immunity 10:261–269. http://dx.doi.org/10.1016/S1074-7613(00)80026-6.
  • Zhou B, Cron RQ, Wu B, Genin A, Wang Z, Liu S, Robson P, Baldwin HS. 2002. Regulation of the murine Nfatc1 gene by NFATc2. J Biol Chem 277:10704–10711. http://dx.doi.org/10.1074/jbc.M107068200.
  • Luo C, Burgeon E, Rao A. 1996. Mechanisms of transactivation by nuclear factor of activated T cells-1. J Exp Med 184:141–147. http://dx.doi.org/10.1084/jem.184.1.141.
  • Yang T, Davis RJ, Chow CW. 2001. Requirement of two NFATc4 transactivation domains for CBP potentiation. J Biol Chem 276:39569–39576. http://dx.doi.org/10.1074/jbc.M102961200.
  • Oum JH, Han J, Myung H, Hleb M, Sharma S, Park J. 2002. Molecular mechanism of NFAT family proteins for differential regulation of the IL-2 and TNF-alpha promoters. Mol Cells 13:77–84.
  • Kaminuma O, Kitamura F, Kitamura N, Hiroi T, Miyoshi H, Miyawaki A, Miyatake S. 2008. Differential contribution of NFATc2 and NFATc1 to TNF-alpha gene expression in T cells. J Immunol 180:319–326. http://dx.doi.org/10.4049/jimmunol.180.1.319.
  • Luo C, Burgeon E, Carew JA, McCaffrey PG, Badalian TM, Lane WS, Hogan PG, Rao A. 1996. Recombinant NFAT1 (NFATp) is regulated by calcineurin in T cells and mediates transcription of several cytokine genes. Mol Cell Biol 16:3955–3966. http://dx.doi.org/10.1128/MCB.16.7.3955.
  • Faget DV, Lucena PI, Robbs BK, Viola JP. 2012. NFAT1 C-terminal domains are necessary but not sufficient for inducing cell death. PLoS One 7:e47868. http://dx.doi.org/10.1371/journal.pone.0047868.
  • Green DR, Droin N, Pinkoski M. 2003. Activation-induced cell death in T cells. Immunol Rev 193:70–81. http://dx.doi.org/10.1034/j.1600-065X.2003.00051.x.
  • Arron JR, Winslow MM, Polleri A, Chang CP, Wu H, Gao X, Neilson JR, Chen L, Heit JJ, Kim SK, Yamasaki N, Miyakawa T, Francke U, Graef IA, Crabtree GR. 2006. NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21. Nature 441:595–600. http://dx.doi.org/10.1038/nature04678.
  • Yao K, Cho YY, Bergen HR, III, Madden BJ, Choi BY, Ma WY, Bode AM, Dong Z. 2007. Nuclear factor of activated T3 is a negative regulator of Ras-JNK1/2-AP-1 induced cell transformation. Cancer Res 67:8725–8735. http://dx.doi.org/10.1158/0008-5472.CAN-06-4788.
  • Neal JW, Clipstone NA. 2003. A constitutively active NFATc1 mutant induces a transformed phenotype in 3T3-L1 fibroblasts. J Biol Chem 278:17246–17254. http://dx.doi.org/10.1074/jbc.M300528200.
  • Medyouf H, Alcalde H, Berthier C, Guillemin MC, dos Santos NR, Janin A, Decaudin D, de The H, Ghysdael J. 2007. Targeting calcineurin activation as a therapeutic strategy for T-cell acute lymphoblastic leukemia. Nat Med 13:736–741. http://dx.doi.org/10.1038/nm1588.
  • Pham LV, Tamayo AT, Li C, Bueso-Ramos C, Ford RJ. 2010. An epigenetic chromatin remodeling role for NFATc1 in transcriptional regulation of growth and survival genes in diffuse large B-cell lymphomas. Blood 116:3899–3906. http://dx.doi.org/10.1182/blood-2009-12-257378.
  • Fu L, Lin-Lee YC, Pham LV, Tamayo A, Yoshimura L, Ford RJ. 2006. Constitutive NF-kappaB and NFAT activation leads to stimulation of the BLyS survival pathway in aggressive B-cell lymphomas. Blood 107:4540–4548. http://dx.doi.org/10.1182/blood-2005-10-4042.
  • Duque J, Fresno M, Iniguez MA. 2005. Expression and function of the nuclear factor of activated T cells in colon carcinoma cells: involvement in the regulation of cyclooxygenase-2. J Biol Chem 280:8686–8693. http://dx.doi.org/10.1074/jbc.M413076200.
  • Hogan PG, Chen L, Nardone J, Rao A. 2003. Transcriptional regulation by calcium, calcineurin, and NFAT. Genes Dev 17:2205–2232. http://dx.doi.org/10.1101/gad.1102703.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.