The calcineurin-responsive nuclear factor of activated T cells (NFAT) family of transcription factors was originally identified as a group of inducible nuclear proteins, which regulate transcription during T lymphocyte activation. However, following their initial discovery, a multitude of studies quickly established that NFAT proteins are also expressed in cells outside the immune system, where they participate in the regulation of the expression of genes influencing cell growth and differentiation. Ectopic activation of individual NFAT members is now recognized as an important aspect for oncogenic transformation in several human malignancies, most notably in pancreatic cancer. Sustained activation of the Ca2+/calcineurin/NFAT signaling pathway has emerged as a powerful regulatory principle governing pancreatic cancer cell growth. Activated NFAT proteins form complexes with key oncogenic proteins to regulate the transcription of master cell cycle regulators and proteins with functions in cell survival, migration and angiogenesis. This review pays particular attention to recent advances in our understanding of how the NFAT transcription pathway controls gene expression during development and progression of pancreatic cancer.

1.
Graef IA, Chen F, Crabtree GR: NFAT signaling in vertebrate development. Curr Opin Genet Dev 2001;11:505–512.
2.
Crabtree GR, Olson EN: NFAT signaling: choreographing the social lives of cells. Cell 2002;109(suppl):S67–S79.
3.
Schulz RA, Yutzey KE: Calcineurin signaling and NFAT activation in cardiovascular and skeletal muscle development. Dev Biol 2004;266:1–16.
4.
Macian F: NFAT proteins: key regulators of T-cell development and function. Nat Rev Immunol 2005;5:472–484.
5.
Sitara D, Aliprantis AO: Transcriptional regulation of bone and joint remodeling by NFAT. Immunol Rev 2010;233:286–300.
6.
Jauliac S, López-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;4:540–544.
7.
Mancini M, Toker A: NFAT proteins: emerging roles in cancer progression. Nat Rev Cancer 2009;9:810–820.
8.
Buchholz M, Schatz A, Wagner M, Michl P, Linhart T, Adler G, Gress TM, Ellenrieder V: Overexpression of c-myc in pancreatic cancer caused by ectopic activation of NFATc1 and the Ca2+/calcineurin signaling pathway. EMBO J 2006;25:3714–3724.
9.
Graef IA, Chen F, Crabtree GR: NFAT signaling in vertebrate development. Curr Opin Genet Dev 2001;11:505–512.
10.
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.
11.
Buchholz M, Ellenrieder V: An Emerging Role for Ca2+/calcineurin/NFAT signaling in cancerogenesis. Cell Cycle 2007;6:16–19.
12.
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.
13.
Lai MM, Burnett PE, Wolosker H, Blackshaw S, Snyder SH: Cain, a novel physiologic protein inhibitor of calcineurin. J Biol Chem 1998;273:18325–18331.
14.
Sun L, Youn HD, Loh C, Stolow M, He W, Liu JO: Cabin 1, a negative regulator for calcineurin signaling in T lymphocytes. Immunity 1998;8:703–711.
15.
Klauck TM, Faux MC, Labudda K, Langeberg LK, Jaken S, Scott JD: Coordination of three signaling enzymes by AKAP79, a mammalian scaffold protein. Science 1996;271:1589–1592.
16.
Shaw KT, Ho AM, Raghavan A, Kim J, Jain J, Park J, Sharma S, Rao A, Hogan PG: Immunosuppressive drugs prevent a rapid dephosphorylation of transcription factor NFAT1 in stimulated immune cells. Proc Natl Acad Sci USA 1995;92:11205–11209.
17.
Neal JW, Clipstone NA: Glycogen synthase kinase-3 inhibits the DNA binding activity of NFATc. J Biol Chem 2001;276:3666–3673.
18.
Aramburu J, Garcia-Cózar F, Raghavan A, Okamura H, Rao A, Hogan PG: Selective inhibition of NFAT activation by a peptide spanning the calcineurin targeting site of NFAT. Mol Cell 1998;1:627–637.
19.
Aramburu J, Yaffe MB, López-Rodríguez C, Cantley LC, Hogan PG, Rao A: Affinity-driven peptide selection of an NFAT inhibitor more selective than cyclosporin A. Science 1999;285:2129–2133.
20.
Shibasaki F, Price ER, Milan D, McKeon F: Role of kinases and the phosphatase calcineurin in the nuclear shuttling of transcription factor NF-AT4. Nature 1996;382:370–373.
21.
Choo MK, Yeo H, Zayzafoon M: NFATc1 mediates HDAC-dependent transcriptional repression of osteocalcin expression during osteoblast differentiation. Bone 2009;45:579–589.
22.
Koenig A, Linhart T, Schlengemann K, Reutlinger K, Wegele J, Adler G, Singh G, Hofmann L, Kunsch S, Büch T, Schäfer E, Gress TM, Fernandez-Zapico ME, Ellenrieder V: NFAT-induced histone acetylation relay switch promotes c-Myc-dependent growth in pancreatic cancer cells. Gastroenterology 2010;138:1189–1199.
23.
Darnell JE Jr: STATs and gene regulation. Science 1997;277:1630–1635.
24.
Yu H, Jove R: The STATs of cancer – new molecular targets come of age. Nat Rev Cancer 2004;4:97–105.
25.
Lagunas L, Clipstone NA: Deregulated NFATc1 activity transforms murine fibroblasts via an autocrine growth factor-mediated Stat3-dependent pathway. J Cell Biochem 2009;108:237–248.
26.
Crabtree GR: Contingent genetic regulatory events in T lymphocyte activation. Science 1989;243:355–361.
27.
Woodrow M, Clipstone NA, Cantrell D: p21ras and calcineurin synergize to regulate the nuclear factor of activated T cells. J Exp Med 1993;178:1517–1522.
28.
Nayak A, Glöckner-Pagel J, Vaeth M, Schumann JE, Buttmann M, Bopp T, Schmitt E, Serfling E, Berberich-Siebelt F: Sumoylation of the transcription factor NFATc1 leads to its subnuclear relocalization and interleukin-2 repression by histone deacetylase. J Biol Chem 2009;284:10935–10946.
29.
Olabisi OA, Soto-Nieves N, Nieves E, Yang TT, Yang X, Yu RY, Suk HY, Macian F, Chow CW: Regulation of transcription factor NFAT by ADP-ribosylation. Mol Cell Biol 2008;28:2860–2871.
30.
Gwack Y, Sharma S, Nardone J, Tanasa B, Iuga A, Srikanth S, Okamura H, Bolton D, Feske S, Hogan PG, Rao A: A genome-wide Drosophila RNAi screen identifies DYRK-family kinases as regulators of NFAT. Nature 2006;441:646–650.
31.
Kuhn C, Frank D, Will R, Jaschinski C, Frauen R, Katus HA, Frey N: DYRK1A is a novel negative regulator of cardiomyocyte hypertrophy. J Biol Chem 2009;284:17320–17327.
32.
Beals CR, Sheridan CM, Turck CW, Gardner P, Crabtree GR: Nuclear export of NF-ATc enhanced by glycogen synthase kinase-3. Science 1997;275:1930–1934.
33.
Porter CM, Havens MA, Clipstone NA: Identification of amino acid residues and protein kinases involved in the regulation of NFATc subcellular localization. J Biol Chem 2000;275:3543–3551.
34.
Zhu J, Shibasaki F, Price R, Guillemot JC, Yano T, Dötsch V, Wagner G, Ferrara P, McKeon F: Intramolecular masking of nuclear import signal on NF-AT4 by casein kinase I and MEKK1. Cell 1998;93:851–861.
35.
Neal JW, Clipstone NA: A constitutively active NFATc1 mutant induces a transformed phenotype in 3T3-L1 fibroblasts. J Biol Chem 2003;278:17246–17254.
36.
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;28:7168–7181.
37.
Caetano MS, Vieira-de-Abreu A, Teixeira LK, Werneck MB, Barcinski MA, Viola JP: NFATC2 transcription factor regulates cell cycle progression during lymphocyte activation: evidence of its involvement in the control of cyclin gene expression. FASEB J 2002;16:1940–1942.
38.
Ellenrieder V, Hendler SF, Ruhland C, Boeck W, Adler G, Gress TM: TGF-beta-induced invasiveness of pancreatic cancer cells is mediated by matrix metalloproteinase-2 and the urokinase plasminogen activator system. Int J Cancer 2001;93:204–211.
39.
Velupillai P, Sung CK, Tian Y, Dahl J, Carroll J, Bronson R, Benjamin T: Polyoma virus-induced osteosarcomas in inbred strains of mice: host determinants of metastasis. PLoS Pathog 2010;22:e1000733.
40.
Ellenrieder V, Hendler SF, Boeck W, Seufferlein T, Menke A, Ruhland C, Adler G, Gress TM: Transforming growth factor beta1 treatment leads to an epithelial-mesenchymal transdifferentiation of pancreatic cancer cells requiring extracellular signal-regulated kinase 2 activation. Cancer Res 2001;61:4222–4228.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.