NFAT蛋白復(fù)合體的核重新定位，刺激β細(xì)胞分化和胰島素分泌,。
哺乳動物胰腺β細(xì)胞是胰島素的唯一來源,，它們按照特定方式生長，生長速度反映了懷孕,、衰老,、肥胖等生理變化導(dǎo)致的機(jī)體對胰島素需求情況的改變。盡管研究人員對transcription factor calcineurin/nuclear factor of activated T-cells (NFAT)信號傳遞途徑確切的分子機(jī)制還不是很清楚,，但是有研究顯示此途徑傳遞的信號與胰島素調(diào)節(jié)有關(guān),。倫敦大學(xué)國王學(xué)院（King's College London）MRC Centre for Developmental Neurobiology研究人員Jeremy J. Heit等發(fā)現(xiàn)calcineurin介導(dǎo)的NFAT核定位調(diào)節(jié)β細(xì)胞分化。文章發(fā)表于9月21日NATURE,，標(biāo)題為“Calcineurin/NFAT signalling regulates pancreatic β-cell growth and function”,。
淋巴細(xì)胞、肌細(xì)胞和神經(jīng)元細(xì)胞發(fā)生的生理學(xué)變化刺激了Ca2+入胞,，導(dǎo)致絲氨酸/蘇氨酸的鈣調(diào)神經(jīng)磷酸酶（calcineurin）被激活,。Calcineurin誘導(dǎo)NFAT轉(zhuǎn)錄復(fù)合物的快速核定位。以前一直認(rèn)為,，胰島素和葡萄糖能夠提高胞內(nèi)Ca2+的濃度,，激活β細(xì)胞內(nèi)NFAT蛋白符合體，因此研究人員一直希望能夠弄清NFAT在β細(xì)胞分化中的特殊角色,。研究人員利用基因工程手段得到calcineurin磷酸酶調(diào)節(jié)亞基缺陷小鼠模型——calcineurin b1 (Cnb1),。
結(jié)果發(fā)現(xiàn)Cnb1KO小鼠β細(xì)胞中幾乎沒有NFATc1聚集，胰島素分泌減少了85％,，β細(xì)胞數(shù)量減少到原來的50％,，小鼠伴隨有嚴(yán)重的高血糖癥并在10周后糖尿病加重。胰島β細(xì)胞的葡萄糖轉(zhuǎn)運(yùn)蛋白2(Glucose Transporter 2,GluT2)是β細(xì)胞特異轉(zhuǎn)錄因子受體,，并且有調(diào)節(jié)細(xì)胞周期的作用,。Cnb1KO小鼠β細(xì)胞中GluT2的mRNA數(shù)量下降、蛋白表達(dá)量下降,。綜合這些實驗結(jié)果,，似乎提示我們Cnb1的缺失導(dǎo)致胰島素合成量下降，是因為β細(xì)胞的分化能力下降,。
染色質(zhì)免疫沉淀(chromatin immunoprecipitation, ChIP)實驗發(fā)現(xiàn)Ins1, Hnf4a, Gck, Glut2 和Cdk.等基因的啟動子區(qū)都含有NFATc1的結(jié)合位點,。用環(huán)孢霉素A（cyclosporine A，一種calcineurin的抑制劑）處理后,，結(jié)合作用消失,。一種calcineurin依賴型的結(jié)構(gòu)性核NFAT突變能夠使小鼠β細(xì)胞Ins1等特異基因的mRNA水平、血清中胰島素的水平和胰腺大小恢復(fù)正常,。
研究人員認(rèn)為，NFAT蛋白復(fù)合體的核定位對刺激調(diào)節(jié)β細(xì)胞分化和功能的基因的表達(dá)是充分必要條件。因此NFAT不僅是治療糖尿病的候選靶標(biāo),，而且是治療β細(xì)胞生長紊亂引發(fā)的疾病,，如胰島瘤和胰島母細(xì)胞瘤（nesidioblastosis）的候選靶標(biāo)。
部分英文原文：
Calcineurin/NFAT signalling regulates pancreatic β-cell growth and function
The growth and function of organs such as pancreatic islets adapt to meet physiological challenges and maintain metabolic balance, but the mechanisms controlling these facultative responses are unclear. Diabetes in patients treated with calcineurin inhibitors such as cyclosporin A indicates that calcineurin/nuclear factor of activated T-cells (NFAT) signalling might control adaptive islet responses, but the roles of this pathway in β-cells in vivo are not understood. Here we show that mice with a β-cell-specific deletion of the calcineurin phosphatase regulatory subunit, calcineurin b1 (Cnb1), develop age-dependent diabetes characterized by decreased β-cell proliferation and mass, reduced pancreatic insulin content and hypoinsulinaemia. Moreover, β-cells lacking Cnb1 have a reduced expression of established regulators of β-cell proliferation. Conditional expression of active NFATc1 in Cnb1-deficient β-cells rescues these defects and prevents diabetes. In normal adult β-cells, conditional NFAT activation promotes the expression of cell-cycle regulators and increases β-cell proliferation and mass, resulting in hyperinsulinaemia. Conditional NFAT activation also induces the expression of genes critical for β-cell endocrine function, including all six genes mutated in hereditary forms of monogenic type 2 diabetes. Thus, calcineurin/NFAT signalling regulates multiple factors that control growth and hallmark β-cell functions, revealing unique models for the pathogenesis and therapy of diabetes.
