NFAT gene family in inflammation and cancer

Current Molecular Medicine

Volumn 13, Issue 4, 2013, Pages 543-554

  Pan, M G ^a   Xiong, Y ^b   Chen, F ^c  

^a KAISER PERMANENTE MEDICAL CENTER   (United States)

^b STANFORD UNIVERSITY SCHOOL OF MEDICINE   (United States)

^c WASHINGTON UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Calcineurin; Cancer; Inflammation; NFAT; Nuclear export; Nuclear import

Indexed keywords

CALCINEURIN; CALCIUM RELEASE ACTIVATED CALCIUM CHANNEL; CALMODULIN; CASEIN KINASE I; DIACYLGLYCEROL; PHOSPHOLIPASE C; PROTEIN KINASE C; TRANSCRIPTION FACTOR NFAT; TRANSCRIPTION FACTOR NFAT3;

ANGIOGENESIS; CANCER INHIBITION; ENTERITIS; GENE EXPRESSION; GLOMERULOSCLEROSIS; HUMAN; IMMUNOREGULATION; INFLAMMATION; METASTASIS; MULTIGENE FAMILY; NEOPLASM; NONHUMAN; NUCLEAR EXPORT SIGNAL; NUCLEAR IMPORT; NUCLEAR LOCALIZATION SIGNAL; REVIEW; RHEUMATOID ARTHRITIS; SYSTEMIC LUPUS ERYTHEMATOSUS;

HUMANS; INFLAMMATION; MULTIGENE FAMILY; NEOPLASMS; NFATC TRANSCRIPTION FACTORS; SIGNAL TRANSDUCTION;

VERTEBRATA;

EID: 84876737068     PISSN: 15665240     EISSN: 18755666     Source Type: Journal    
DOI: 10.2174/1566524011313040007     Document Type: Review

References (122)

1. Shaw JP, Utz PJ, Durand DB, Toole JJ, Emmel EA, Crabtree, GR. Identification of a putative regulator of early T cell activation genes. Science 1988; 241: 202-205.
2. Durand DB, Shaw JP, Bush MR, Replogle RE, Belagaje R, Crabtree GR. Characterization of antigen receptor response elements within the interleukin-2 enhancer. Mol Cell Biol 1988; 8: 1715-1724.
3. Wu H, Peisley A, Graef IA, Crabtree, GR. NFAT signaling and the invention of vertebrates. Trends in Cell Biol 2007; 17: 251-260.
4. Crabtree GR, Olsen EN. NFAT signaling: choreographing the social lives of cells. Cell 2002; 109: S67-S79.
5. Hogan PG, Chen L, Nardone J, Rao A. Transcription regulation by calcium, calcineurin, and NFAT. Genes Dev 2003; 17: 2205-2232.
6. Graef IA, Chen F, Crabtree GR. NFAT signaling in vertebrate development. Curr Opinion Genet Dev 2001; 11: 505-512.
7. 2+ Influx. Curr Biol 2005; 15: 1235-1241.
8. 2+ store to the plasma membranes. Nature 2005; 437: 902-905.
9. Stathopulos PB, Zheng L, Ikura M. Stromal Interaction Molecule (STIM) 1 and STIM2 calcium sensing regions exhibit distinct unfolding and oligomerization kinetics. J Biol Chem 2009; 284: 728-732.
10. Luik RM, Wang B, Prakriya M, Wu MM, Lewis RS. Oligomerization of STIM1 couples ER calcium depletion to CRAC channel activation. Nature 2008; 454: 538-542.
11. Wang Y, Deng X, Mancarella S, et al. The Calcium Store Sensor, STIM1, Reciprocally Controls Orai and CaV1.2 Channels. Science 2010; 330: 105-109.
12. Prakriya M, Feske S, Gwack Y, Srikanth S, Rao, A, Hogan P. Orai1 is an essential pore subunit of the CRAC channel. Nature 2006; 443: 230-233.
13. Park CY, Shcheglovitov A, Dolmetsch R. The CRAC channel activator binds and inhibits L-type voltage-gated calcium channels. Science 2010; 330: 101-105.
14. Liu J, Farmer JD Jr, Lane WS, Friedman J, Weissman I, Schreiber SL. Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell 1991; 66: 807-815.
15. Okamura H, Aramburu J, García-Rodríguez C, et al. Concerted dephosphorylation of the transcription factor NFAT1 induces a conformational switch that regulates transcriptional activity. Mol Cell 2000; 6: 539-550.
16. Beals CR, Clipstone NA, Ho SN, Crabtree GR. Nuclear localization of NF-ATc by a calcineurin-dependent, cyclosporin-sensitive intramolecular interaction. Genes Dev 1997; 11: 824-834.
17. Lin X, Sikkink RA, Rusnak F, Barber, DL. Inhibition of calcineurin phosphatase activity by a calcineurin B homologous protein. J Biol Chem 1999; 274: 36125-36131.
18. Fuentes JJ, Genescà L, Kingsbury TJ, et al. DSCR1, overexpressed in Down syndrome, is an inhibitor of calcineurin-mediated signaling pathways. Hum Mol Genet 2000; 9: 1681-1690.
19. Mulero MC, Aubareda A, Schlüter A, Pérez-Riba M. RCAN3, a novel calcineurin inhibitor that down-regulates NFAT-dependent cytokine gene expression. Biochim Biophys Acta 2007; 1773: 330-341.
20. Arron JR, Winslow MM, Polleri A, et al. NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21. Nature 2006; 441: 595-600.
21. Jurado S, Biou V, Malenka RC. A calcineurin/AKAP complex is required for NMDA receptor-dependent long-term depression. Nat Neurosci 2010; 13: 1053-55.
22. Lai MM, Burnett PE, Wolosker H, Blackshaw S, Snyder SH. Cain, a novel physiologic protein inhibitor of calcineurin. J Biol Chem 1998; 273: 18325-31.
23. Sheridan CM, Heist EK, Beals CR, Crabtree GR, Gardner P. Protein kinase A negatively modulates the nuclear accumulation of NF-ATc1 by priming for subsequent phosphorylation by glycogen synthase kinase-3. J Biol Chem 2002; 277: 48664-76.
24. Beals CR, Sheridan CM, Turck CW, Gardner P, Crabtree GR. Nuclear export of NF-ATc enhanced by glycogen synthase kinase-3. Science 1997; 275: 1930-34.
25. Chow CW, Davis RJ. Integraiton of calcium and cyclic AMP signaling pathways by 14-3-3. Mol Cell Biol 2000; 20: 702-12.
26. Gwack Y, Sharma S, Nardone J, et al. A genome-wide Drosophila RNAi screen identifies DYRK-family kinases as regulators of NFAT. Nature 2006; 441: 646-50.
27. Okamura H, Garcia-Rodriguez C, Martinson H, Qin J, Virshup DM, Rao A. A conserved docking motif for CK1 binding controls the nuclear localization of NFAT1. Mol Cell Biol 2004; 24: 4184-95.
28. Zhu J, Shibasaki F, Price R, et al. Intramolecular masksing of nuclear import signal on NFAT4 by casein kinase I and MEKK1. Cell 1998; 93: 851-61.
29. Chow CW, Rincón M, Cavanagh J, Dickens M, Davis RJ. Nuclear accumulation of NFAT4 opposed by the JNK signal transduction pathway. Science 1997; 278: 1638-41.
30. Chow CW, Chen D, Flavell RA, Davis RJ. (2000) c-Jun NH2-terminal kinase inhibits targeting of the protein phosphotase calcineurin to NFATc1. Mol Cell Biol 2000; 20: 5227-34.
31. Yang TC, Xiong Q, Enslen H, Davis RJ, Chow CW. Phosphorylation of NFATc4 by p38 mitogen-activated protein kinase. Mol Cell Biol 2002; 22: 3892-904.
32. Gómez del Arco P, Martínez-Martínez S, Maldonado JL, Ortega-Pérez I, Redondo JM. A role for the p38 MAP kinase pathway in the nuclear shuttling of NFATp. J Biol Chem 2000; 275: 13872-78.
33. Terui Y, Saad N, Jia S, McKeon F, Yuan J. Dual role of sumoylation in the nuclear localization and transcriptional activation of NFAT1. J Biol Chem 2004; 279: 28257-65.
34. Nayak A, Glöckner-Pagel J, Vaeth M, et al. Sumoylation of the transcription factor NFATc1 leads to its subnuclear relocalization and interleukin-2 repression by histone deacetylase. J Biol Chem 2009; 284: 10935-46.
35. Sharma S, Findlay GM, Bandukwala HS, et al. Dephosphorylation of the nuclear factor of activated T cells (NFAT) transcription factor is regulated by an RNA-protein scaffold complex. Proc Natl Acad Sci USA 2001; 108: 11381-86.
36. Colombel JF, Sandborn WJ, Reinisch W, et al. Infliximab, azathioprine, or combination for Crohn's disease. N Engl J Med 2010; 362: 1383-95.
37. Liu Z, Lee J, Krummey S, Lu W, Cai H, Lenardo MJ. The kinase LRRK2 is a regulator of the transcription factor NFAT that modulates the severity of inflammatory bowel disease. Nat Immunol 2011; 12: 1063-70.
38. Weigmann B, Lehr HA, Yancopoulos G, et al. The transcription factor NFATc2 controls IL-6-dependent T cell activation in experimental colitis. J Exp Med 2008; 209: 2099-110.
39. John G, Hegary JP, Yu W, et al. NKX2-3 variant rs11190140 is associated with IBD and alters binding of NFAT. Mol Genet Metab 2011; 104: 174-9.
40. Yu W, Hegarty JP, Berg A, et al. NKX2-3 transcriptional regulation of endothelin-1 and VEGF signaling in human intestinal microvascular endothelial cells. PLoS One 2011; 6: e20454.
41. Shih TC, Hsieh SY, Hsieh YY, et al. Aberrant activation of nuclear factor of activated T cell 2 in lamina propria mononuclear cells in ulcerative colitis. World J Gastroenterol 2008; 14: 1759-67.
42. Wang Q, Zhou Y, Weiss HL, Chow CW, Evers BM. NFATc1 regulation of TRAIL expression in human intestinal cells. PLoS One 2011; 6: e19882.
43. Wang Q, Zhou Y, Jackson LN, Johnson SM, Chow CW, Evers BM. Nuclear factor of activated T cells (NFAT) signaling regulates PTEN expression and intestinal cell differentiation. Mol Biol Cell 2011; 22: 412-20.
44. Deng L. Zhou JF, Sellers RS, et al. A novel mouse model of inflammatory bowel disease links mammalian target of rapamycin-dependent hyperproliferation of colonic epithelium to inflammation-associated tumorigenesis. Am J Pathol 2010; 176: 952-67.
45. Zhou Y, Wang Q, Guo Z, Weiss HL, Evers BM. Nuclear factor of activated T-cell c3 inhibition of mammalian target of rapamycin signaling through induction of regulated in development and DNA damage response 1 in human intestinal cells. Mol Biol Cell 2012; 23: 2963-72.
46. Peng SL, Gerth AJ, Ranger AM, Glimcher LH. NFATc1 and NFATc2 together control both T and B cell activation and differentiation. Immunity 2001; 14: 13-20.
47. Xanthoudakis S, Viola JP, Shaw KT, et al. An enhanced immune response in mice lacking the transcription factor NFAT1. Science 1996; 272: 892-5.
48. Ranger AM, Oukka M, Rengarajan J, Glimcher LH. Inhibitory function of two NFAT family members in lymphoid homeostasis and Th2 development. Immunity 1998; 9: 627-35.
49. Oukka M, Ho IC, de la Brousse FC, Hoey T, Grusby MJ, Glimcher LH. The transcription factor NFAT4 is involved in the generation and survival of T cells. Immunity 1998; 9: 295-304.
50. Pan M, Winslow M, Chen L, Kuo A, Felsher D, Crabtree GR. Enhanced NFATc1 nuclear occupancy causes T cell activation independent of CD28 costimulation. J Immunol 2007; 178: 4315-21.
51. Yarilina A, Xu K, Chen J, Ivashkiv LB. TNF activates calcium-nuclear factor of activated T cells NFATc1 signaling pathways in human macrophages. Proc Natl Acad Sci USA 2011; 108: 1573-8.
52. Cho ML, Kim WU, Min SY, et al. Cyclosporine differentially regulates interleukin-10, interleukin-15, and tumor necrosis factor a production by rheumatoid synoviocytes. Arthritis Rheum 2002; 46: 42-51.
53. Yoo SA, Park BH, Park GS, et al. Calcineurin is expressed and plays a critical role in inflammatory arthritis. J Immunol 2006; 177: 2681-90.
54. van Rijthoven AW, Dijkmans BA, Goei The, HS, et al. Cyclosporin treatment for rheumatoid arthritis: a placebo controlled, double blind, and multicentre study. Ann Rheum Dis 1986; 45: 726-31.
55. Lai NS, Yu CL, Yin WY, et al. Combination of nifedipine and subtherapeutic dose of cyclosporin additively suppresses mononuclear cells activation of patients with rheumatoid arthritis and normal individuals via Ca(2+) -calcineurin-nuclear factor of activated T cells pathway. Clin Exp Immunol 2012; 168: 78-86.
56. Zavada J, Pesickova S, Rysava R, et al. Cyclosporine A or intravenous cyclophosphomide for lupus nephritis: the Cyclofa-Lune study. Lupus 2010; 19: 1281-9.
57. Ogawa H, Kameda H, Amano K, Takeuchi T. Efficacy and safety of cyclosporine A in patients with refractory systemic lupus erythematosus in a daily clinical practice. Lupus 2010; 19: 162-9.
58. Austin III, HA, Illei GG, Braun M, Balow JE. Randomized, Controlled Trial of Prednisone, Cyclophosphamide, and Cyclosporine in Lupus Membranous Nephropathy. J Am Soc Nephrol 2009; 20: 901-11.
59. Szeto CC, Kwan C-H, Lai FM, et al. Tacrolimus for the treatment of systemic lupus erythematosus with pure class V nephritis. Rheumatol 2008; 68: 1678-81.
60. Vasileios CK, Zhang Z, Kampagiannni Q, Tsokos GC. Calcium signaling in systemic lupus erytematosus T cells. Arthritis Rheum 2011; 63: 2058-66.
61. Tsokos GC, Moulton VR. Abnormalities of T cell signaling in systemic lupus erythematosus. Arthr Res Ther 2011; 13: 207-15.
62. Mehta J, Genin A, Brunner M, et al. Prolonged CD154 expression on pediatric Lupus CD4 T Cells Correlates with increased CD154 Transcription, increased NFAT activity, and glomerulonephritis. Arthritis Rheum 2010; 62: 2499-509.
63. Kyttaris VC, Wang Y, Juang YT, Weinstein A, Tsokos GC. Increased levels of NF-ATc2 differentially regulate CD154 and IL-2 genes in T cells from patients with systemic lupus erythematosus. J Immunol 2007; 178: 1960-6.
64. Fujii Y, Fujii K, Iwata S, et al. Abnormal intracellular distribution of NFAT1 in T lymphocytes from patients with systemic lupus erythematosus and characteristic clinical features. Clin Immunol 2006; 119: 297-306.
65. Lagagione T, Gulko PS. mTOR regulates the invasive properties of synovial fibroblasts in rheumatoid arthritiss. Mol Med 2010; 16: 352-358.
66. Singh K, Deshpande P, Pryshchep S, et al. ERK-dependent T cell receptor threshold calibration in rheumatoid arthritis. J Immunol 2009; 183: 8258-67.
67. Strehlau J, Schachter AD, Pavlakis M, Singh, A, Tejani A, Strom TB. Activated intrarenal transcription of CTL-effectors and TGF-1 in children with focal segmental glomerulosclerosis. Kidney Int 2002; 61: 90-5.
68. Bantis C, Heering PJ, Aker S, Klein-Vehne, N, Grabensee B, Ivens K. Association of interleukin-10 gene G-1082A polymorphism with the progression of primary glomerulonephritis. Kidney Int 2004; 66: 288-94.
69. Raafat RH, Kalia A, Travis LB, Diven SC. High-dose oral cyclosporin therapy for recurrent focal segmental glomerulosclerosis in children. Am J Kidney Dis 2004; 44: 50-6.
70. Winn MP, Conlon PJ, Lynn KL, et al. A mutation in the TRPC6 cation channel causes familial focal segmental glomerulosclerosis. Science 2005; 308: 1801-4.
71. Reiser J, Polu KR, Möller CC, et al. TRPC6 is a glomerular slit diaphragm-associated channel required for normal renal function. Nat Genet 2005; 37: 739-44.
72. Pollak MR, Schlondorff J, del Camino D, Carrasquillo R, Lacey V. TRPC6 mutations associated with focal segmental glomerulosclerosis cause constitutive activation of NFAT-dependent transcription. Am J Physiol-Cell Physiol 2009; 296: C558-C569.
73. Wang Y, Jarad G, Tripathi P, et al. Activation of NFAT signaling in podocytes causes glomerulosclerosis. J Am Soc Nephrol 2010; 21: 1657-66.
74. Nijenhuis T, Sloan AJ, Hoenderop JG, et al. Angiotensin II contributes to podocyte injury by inceasing TRPC6 expression via an NFAT-mediated positive feedback signaling pathway. Am J Pathol 2011; 179: 1719-32.
75. Guo S, Lopex-Ilasaca M, Dzau VJ. Identification of calcium-modulating cyclophilin ligand (CAML) as transducer of angiotensin II-mediated nuclear factor of activated T cells (NFAT) activation. J Biol Chem 2005; 280: 12536-41.
76. Zanoni I, Ostuni R, Capuano G, et al. CD14 regulates the dendritic cell life cycle after LPS exposure through NFAT activation. Nature 2009; 460: 264-8.
77. Crist SA, Sprague DL, Ratliff TL. Nuclear factor of activated T cells (NFAT) mediates CD154 expression in megakaryocytes. Blood 2008; 111: 3553-61.
78. Winslow MM, Pan M, Starbuck M, Gallo EM, Karsentry G, Crabtree GR. Calcineurin/NFAT signaling in osteoblasts regulates bone mass. Dev Cell 2006; 10: 771-82.
79. Pan M, Winslow M, Keum JS, Crabtree GR. Stringent control of NFAT nuclear occupancy is critical for maintaining balanced immune response. Gene Ther Mol Biol 2007; 11: 171-6.
80. Baek KH, Zaslavsky A, Lynch RC, et al. Down's syndrome suppression of tumour growth and the role of the calcineurin inhibitor. Nature 2009; 459: 1126-30.
81. Szuhai K, Ijszenga M, de Jong D, Karseladze A, Tanke HJ, Hogendoorn PC. The NFATc2 gene is involved in a novel cloned translocation in a Ewing sarcoma variant that couples its function in immunology to oncology. Clin Cancer Res 2009; 15: 2259-68.
82. Greten FR, Eckman L, Greten TF, et al. IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell 2004; 118: 285-96.
83. Karin M. Nuclear factor-kappaB in cancer development and progression. Nature 2006; 441: 431-6.
84. Neal JW, Clipstone NA. A constitutively active NFATc1 mutant induces a transformed phenotype in 3T3-L1 fibroblasts. J Biol Chem 2003; 278: 17246-54.
85. Lagunas L, Clipstone NA. Deregulated NFATc1 activity transforms murine fibroblasts via an autocrine growth factor-mediated Stat3-dependent pathway. J Cell Biochem 2009; 108: 237-48.
86. Greenhough A, Smartt HJ, Moore AE, et al. The COX-2/PGE2 pathway: key roles in the hallmarks of cancer and adaptation to the tumour microenvironment. Carcinogenesis 2009; 30: 377-86.
87. Yan Y, Li J, Ouyang W, et al. NFAT3 is specifically required for TNF-alpha-induced cyclooxygenase-2 (COX-2) expression and transformation of Cl41 cells. J Cell Sci 2006; 119: 2985-94.
88. Flockhart RJ, Armstrong JL, Reynolds NJ, Lovat PE. NFAT signalling is a novel target of oncogenic BRAF in metastatic melanoma. Br J Cancer 2009; 101: 1448-55.
89. Sales KJ, Maldonado-Perez D, Grant V, et al. Prostaglandin F(2alpha)-F-prostanoid receptor regulates CXCL8 expression in endometrial adenocarcinoma cells via the calcium-calcineurin-NFAT pathway. Biochim Biophys Acta 2009; 1793: 1917-28.
90. Sales KJ, Grant V, Cook IH, et al. Interleukin-11 in endometrial adenocarcinoma is regulated by prostaglandin F2alpha-F-prostanoid receptor interaction via the calcium-calcineurin-nuclear factor of activated T cells pathway and negatively regulated by the regulator of calcineurin-1. Am J Pathol 2010; 176: 435-45.
91. (2+)/NFAT-dependent pathways. Oncogene 2007; 26: 7380-5.
92. Werneck MB, Vieira-de-Abreu A, Chammas R, Viola JP. NFAT1 transcription factor is central in the regulation of tissue microenvironment for tumor metastasis. Cancer Immunol Immunother 2011; 60: 537-46.
93. 2+/calcineurin signaling pathway. EMBO J 2006; 25: 3714-24.
94. Köenig A, Linhart T, Schlengemann K, et al. NFAT-induced histone acetylation relay switch promotes c-Myc-dependent growth in pancreatic cancer cells. Gastroenterol 2010; 138: 1189-99.
95. Singh G, Singh SK, Konig A, et al. Sequential activation of NFAT and c-Myc transcription factors mediates the TGF-beta switch from a suppressor to a promoter of cancer cell proliferation. J Biol Chem 2010; 285: 27241-50.
96. Gregory MA, Phang TL, Neviani P, et al. Wnt/Ca2+/NFAT signaling maintains survival of Ph+ leukemia cells upon inhibition of Bcr-Abl. Cancer Cell 2010; 18: 74-87.
97. Marafioti T, Pozzobon M, Hansmann ML, et al. 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 2005; 128: 333-42.
98. Medyouf H, Alcalde H, Berthier C, et al. Targeting calcineurin activation as a therapeutic strategy for T-cell acute lymphoblastic leukemia. Nat Med 2007; 13: 736-41.
99. Pham LV, Tamayo AT, Yoshimura LC, Lin-Lee YC, Ford RJ. Constitutive NF-kappaB and NFAT activation in aggressive B-cell lymphomas synergistically activates the CD154 gene and maintains lymphoma cell survival. Blood 2005; 106: 3940-7.
100. Pham, LV, Tamayo AT, Li C, Bueso-Ramos C, Ford RJ. An epigenetic chromatin remodeling role for NFATc1 in transcriptional regulation of growth and survival genes in diffuse large B-cell lymphomas. Blood 2010; 116: 3899-906.
101. Bultman S, Gebuhr T, Yee D, et al. A Brg1 null mutation in the mouse reveals functional differences among mammalian SWI/SNF complexes. Mol Cell 2000; 6: 1287-95.
102. Bultman SJ, Herschkowitz JI, Godfrey V, et al. Characterization of mammary tumors from Brg1 heterozygous mice. Oncogene 2008; 27: 460-8.
103. Naidu SR, Love IM, Imbalzano AN, Grossman SR, Androphy EJ. The SWI/SNF chromatin remodeling subunit BRG1 is a critical regulator of p53 necessary for proliferation of malignant cells. Oncogene 2009; 28: 2492-501.
104. Pan M. Expression of calcium/calcineurin pathway-regulated transcription factor NFATc1 and chromatin-remodelling genes BRG1 and BRM in invasive breast cancer. Eur J Cancer 2011; 9: 18.
105. Jauliac S, Lopez-Rodriguez C, Shaw LM, Brown LF, Rao A, Toker A. The role of NFAT transcription factors in integrin-mediated carcinoma invasion. Nat Cell Biol 2002; 4: 540-44.
106. Yoeli-Lerner M, Yiu GK, Rabinovitz I, Erhardt P, Jauliac S, Toker A. Akt blocks breast cancer cell motility and invasion through the transcription factor NFAT. Mol Cell 2005; 20: 539-50.
107. Yiu GK, Toker, A. NFAT induces breast cancer cell invasion by promoting the induction of cyclooxygenase-2. J Biol Chem 2006; 281: 12210-7.
108. Yiu GK, Kaunisto A, Chin Y, Toker A. NFAT promotes carcinoma invasive migration through glypican-6. Biochem J 2011; 440: 157-66.
109. Foldynova-Trantirkova S, Sekyrova P, Tmejova K, et al. Breast cancer-specific mutations in CK1epsilon inhibit Wnt/beta-catenin and activate the Wnt/Rac1/JNK and NFAT pathways to decrease cell adhesion and promote cell migration. Breast Cancer Res 2010; 12: R30.
110. Chigurupati S, Venkataraman R, Barrera D, et al. Receptor channel TRPC6 is a key mediator of Notch-driven glioblastoma growth and invasiveness. Cancer Res 2010; 70: 418-27.
111. Graef IA, Chen F, Chen L, Kuo A, Crabtree GR. Signals transduced by Ca(2+)/calcineurin and NFATc3/c4 pattern the developing vasculature. Cell 2001; 105: 863-75.
112. Bhati R, Patterson C, Livasy CA, et al. Molecular characterization of human breast tumor vascular cells. Am J Pathol 2008; 172: 1381-90.
113. Courtwright A, Siamakpour-Reihani S, Arbiser JL, et al. SFRP2 Stimulates Angiogenesis via a Calcineurin/NFAT Signaling Pathway. Cancer Res 2009; 69: 4621-8.
114. Siamakpour-Reihani S, Caster J, Bandhu Nepal D, et al. The role of calcineurin/NFAT in SFRP2 induced angiogenesis-a rationale for breast cancer treatment with the calcineurin inhibitor tacrolimus. PLoS One 2011; 6: e20412.
115. Ryeom S, Greenwald RJ, Sharpe AH, McKeon F. The threshold pattern of calcineurin-dependent gene expression is altered by loss of the endogenous inhibitor calcipressin. Nat Immunol 2003; 4: 874-81.
116. Hesser BA, Liang XH, Camenisch G, et al. Down syndrome critical region protein 1 (DSCR1), a novel VEGF target gene that regulates expression of inflammatory markers on activated endothelial cells. Blood 2004; 104: 149-58.
117. Armesilla AL, Lorenzom E, Gómez del Arco P, Martínez-Martínez S, Alfranca A, Redondo JM. Vascular endothelial growth factor activates nuclear factor of activated T cells in human endothelial cells: a role for tissue factor gene expression. Mol Cell Biol 1999; 19: 2032-43.
118. Hernández GL, Volpert OV, Iñiguez MA, et al. Selective inhibition of vascular endothelial growth factor-mediated angiogenesis by cyclosporin A: roles of the nuclear factor of activated T cells and cyclooxygenase 2. J Exp Med 2001; 193: 607-20.
119. Zaichuk TA, Shroff EH, Emmanuel R, Filleur S, Nelius T, Volpert OV. Nuclear activator of T cells balances angiogenesis activation and inhibition. J Exp Med 2004; 199: 1513-22.
120. Robbs BK, Cruz AL, Werneck MB, Mognol GP, Viola JP. Dual roles for NFAT transcription factor genes as oncogenes and tumor suppressors. Mol Cell Biol 2008; 28: 7168-81.
121. Glud SZ, Sørensen AB, Andrulis M, et al. A tumor-suppressor function for NFATc3 in T-cell lymphomagenesis by murine leukemia virus. Blood 2005; 106: 3546-52.
122. Zheng J, Fang F, Zeng X, Medler TR, Fiorillo AA, Clevenger CV. Negative cross talk between NFAT1 and Stat5 signaling in breast cancer. Mol Endocrinol 2011; 25: 2054-64.