転写因子
CD4陽性T細胞が活性化されると、NFκBともに産生される

普段は細胞質にあってセリン/スレオニンキナーゼにより核移行配列がリン酸化されており核移行が妨げられている。
細胞質の[Ca2+]↑によりカルモジュリンがCa2+を結合しコンフォメーションが変化する。
Ca2+を結合したカルモジュリンは、セリン/スレオニンホスファターゼであるカルシニューリンに結合する。
カルモジュリンとの結合によりカルシニューリンは活性化され、NFATを脱リン酸化する。
脱リン酸化されたNFATは核に移行し遺伝子発現を行う。
T細胞ではIL-2の転写に関わっている

Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/09/30 22:33:38」(JST)

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Nuclear factor of activated T-cells (NFAT) is a general name applied to a family of transcription factors shown to be important in immune response. One or more members of the NFAT family is expressed in most cells of the immune system. NFAT is also involved in the development of cardiac, skeletal muscle, and nervous systems.

The NFAT transcription factor family consists of five members NFATc1, NFATc2, NFATc3, NFATc4, and NFAT5.^[1] NFATc1 through NFATc4 are regulated by calcium signaling. Calcium signaling is critical to NFAT activation because calmodulin (CaM), a well-known calcium sensor protein, activates the serine/threonine phosphatase calcineurin (CN). Activated CN rapidly dephosphorylates the serine-rich region (SRR) and SP-repeats in the amino termini of NFAT proteins, resulting in a conformational change that exposes a nuclear localization signal, resulting in NFAT nuclear import.

Nuclear import of NFAT proteins is opposed by maintenance kinases in the cytoplasm and export kinases in the nucleus. Export kinases, such as PKA and GSK-3β, must be inactivated for NFAT nuclear retention.

NFAT proteins have weak DNA-binding capacity. Therefore, to effectively bind DNA, NFAT proteins must cooperate with other nuclear resident transcription factors generically referred to as NFATn.^[2] This important feature of NFAT transcription factors enables integration and coincidence detection of calcium signals with other signaling pathways such as ras-MAPK or PKC. In addition, this signaling integration is involved in tissue-specific gene expression during development. A screen of ncRNA sequences identified in EST sequencing projects^[3]^[4] discovered a 'ncRNA repressor of the nuclear factor of activated T cells' called NRON.^[5]

Breast cancer[edit]

NFAT transcription factors are implicated in breast cancer, more specifically in the process of cell motility at the basis of metastasis formation. Indeed NFAT1 (NFATC2) and NFAT5 are pro-invasive and pro-migratory in breast carcinoma ^[6]^[7] and NFAT3 (NFATc4) is an inhibitor of cell motility.^[8] NFAT1 regulates the expression of the TWEAKR and its ligand TWEAK with the Lipocalin 2 to increase breast cancer cell invasion ^[9] and NFAT3 inhibits Lipocalin 2 expression to blunt the cell invasion.^[8]

References[edit]

^ Crabtree GR, Olson EN (2002). "NFAT signaling: choreographing the social lives of cells". Cell. 109 Suppl (2): S67–79. doi:10.1016/S0092-8674(02)00699-2. PMID 11983154.
^ Macian F (2005). "NFAT proteins: key regulators of T-cell development and function". Nat. Rev. Immunol. 5 (6): 472–84. doi:10.1038/nri1632. PMID 15928679.
^ Okazaki Y, Furuno M, Kasukawa T, et al. (December 2002). "Analysis of the mouse transcriptome based on functional annotation of 60,770 full-length cDNAs". Nature 420 (6915): 563–73. doi:10.1038/nature01266. PMID 12466851.
^ Numata K, Kanai A, Saito R, Kondo S, Adachi J, Wilming LG, Hume DA, Hayashizaki Y, Tomita M, RIKEN GER Group, GSL Members (2003). "Identification of Putative Noncoding RNAs Among the RIKEN Mouse Full-Length cDNA Collection". Genome Res 13 (6B): 1301–6. doi:10.1101/gr.1011603. PMC 403720. PMID 12819127.
^ Willingham AT, Orth AP, Batalov S, et al. (September 2005). "A strategy for probing the function of noncoding RNAs finds a repressor of NFAT". Science 309 (5740): 1570–3. doi:10.1126/science.1115901. PMID 16141075.
^ Jauliac, S; López-Rodriguez, C, Shaw, LM, Brown, LF, Rao, A, Toker, A (2002 Jul). "The role of NFAT transcription factors in integrin-mediated carcinoma invasion.". Nature Cell Biology 4 (7): 540–4. doi:10.1038/ncb816. PMID 12080349.
^ Yoeli-Lerner, M; Yiu, GK, Rabinovitz, I, Erhardt, P, Jauliac, S, Toker, A (2005-11-23). "Akt blocks breast cancer cell motility and invasion through the transcription factor NFAT.". Molecular Cell 20 (4): 539–50. doi:10.1016/j.molcel.2005.10.033. PMID 16307918.
^ ^a ^b Fougère, M; Gaudineau, B, Barbier, J, Guaddachi, F, Feugeas, JP, Auboeuf, D, Jauliac, S (2010-04-15). "NFAT3 transcription factor inhibits breast cancer cell motility by targeting the Lipocalin 2 gene.". Oncogene 29 (15): 2292–301. doi:10.1038/onc.2009.499. PMID 20101218.
^ Gaudineau, B; Fougère, M, Guaddachi, F, Lemoine, F, de la Grange, P, Jauliac, S (2012-10-01). "Lipocalin 2 (LCN2), the TNF-like receptor TWEAKR and its ligand TWEAK act downstream of NFAT1 to regulate breast cancer cell invasion.". Journal of cell science 125 (19): 4475–4486. doi:10.1242/jcs.099879. PMID 22767506.

UpToDate Contents

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1. T細胞受容体シグナル伝達 t cell receptor signaling
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English Journal

Involvement of store-operated calcium signaling in EGF-mediated COX-2 gene activation in cancer cells.

Wang JY, Chen BK, Wang YS, Tsai YT, Chen WC, Chang WC, Hou MF, Wu YC, Chang WC.SourceDivision of Gastrointestinal and General Surgery, College of Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Cancer Center, College of Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Department of Surgery, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Medical Genetics, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Cellular signalling.Cell Signal.2012 Jan;24(1):162-169. Epub 2011 Sep 6.
Growing evidence shows that chronic inflammation drives the progression of colorectal cancer (CRC). Cyclooxygenase-2 (COX-2) is one of the most important inflammatory genes involved in solid tumor metastasis. Epidermal growth factor receptor (EGFR) also plays a key role in cancer cell development. W
PMID 21924350

Rate and irregularity of electrical activation during atrial fibrillation affect myocardial NGF expression via different signalling routes.

Saygili E, Rana OR, Günzel C, Rackauskas G, Saygili E, Noor-Ebad F, Gemein C, Zink MD, Schwinger RH, Mischke K, Weis J, Marx N, Schauerte P.SourceDepartment of Cardiology, University RWTH Aachen, Aachen, Germany.
Cellular signalling.Cell Signal.2012 Jan;24(1):99-105. Epub 2011 Aug 26.
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PMID 21889978

Effective inhibition of a Strongylocentrotus nudus eggs polysaccharide against hepatocellular carcinoma is mediated via immunoregulation in vivo.

Wang M, Wang H, Tang Y, Kang D, Gao Y, Ke M, Dou J, Xi T, Zhou C.SourceSchool of Life Science and Technology, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China.
Immunology letters.Immunol Lett.2011 Dec 30;141(1):74-82. Epub 2011 Aug 30.
This study was aimed at evaluating the inhibitory effect of a polysaccharide that was isolated from Strongylocentrotus nudus eggs (SEP) against hepatocellular carcinoma in H22-bearing mice and elucidating its immunological mechanisms by determining its effects on the growth of transplanted tumors an
PMID 21893096

Japanese Journal

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Satou Yorifumi,Yasunaga Jun-ichirou,Zhao Tiejun,Yoshida Mika,Miyazato Paola,Takai Ken,Shimizu Kei,Ohshima Koichi,Green Patrick L.,Ohkura Naganari,Yamaguchi Tomoyuki,Ono Masahiro,Sakaguchi Shimon,Matsuoka Masao
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… HBZ could physically interact with Foxp3 and NFAT, thereby impairing the suppressive function of Treg cells. …
NAID 120002807462

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NAID 40018761216

New Molecular Mechanisms for Cardiovascular Disease:Transcriptional Pathways and Novel Therapeutic Targets in Heart Failure

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Journal of Pharmacological Sciences 116(4), 337-342, 2011
… nuclear factor of activated T-cells (NFAT) signaling pathway, transient receptor potential cation channel, subfamily C, member 6 (TRPC6) is a key component of a Ca2+-dependent regulatory loop. …
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