日前,，德國研究人員在國際權(quán)威雜志PNAS上發(fā)表了他們最新的發(fā)現(xiàn)"The c-MYC oncoprotein, the NAMPT enzyme, the SIRT1-inhibitor DBC1, and the SIRT1 deacetylase form a positive feedback loop",，科學(xué)家證實(shí)了一種核蛋白和一種酶會(huì)在癌細(xì)胞中“狼狽為奸”,，形成反饋回路，助長癌細(xì)胞無限分裂,。
癌細(xì)胞最顯著的特征就是無限分裂,、永不停止,，而正常細(xì)胞則不會(huì)無限生長,。什么原因?qū)е掳┘?xì)胞的“瘋狂”,？德國慕尼黑大學(xué)的研究人員發(fā)現(xiàn)，這是因?yàn)橐环N名為c-Myc的核蛋白可擺脫細(xì)胞內(nèi)的控制機(jī)制,，促使癌細(xì)胞分裂。這種蛋白可調(diào)節(jié)細(xì)胞的生長和分裂,，合成這種蛋白的基因本應(yīng)在造血,、胚胎發(fā)育等情況下“工作”，在不需要時(shí)受細(xì)胞抑制而“休息”,。但是,，在癌細(xì)胞中這種基因卻擺脫抑制、放肆表達(dá),，在淋巴癌,、乳腺癌等癌癥中甚至扮演了“制造者”的角色。
研究人員發(fā)現(xiàn),，高度聚集的c-Myc蛋白可激活一種抑制細(xì)胞衰老和死亡的酶SIRT1,，而這種酶又可反作用于c-Myc蛋白，如此形成一個(gè)回路,，令c-Myc蛋白和SIRT1酶越來越多,，最終促使癌細(xì)胞無限分裂。
研究人員表示,，發(fā)現(xiàn)這一反饋回路有助于研究治療癌癥的新方法,。用藥物等手段阻斷這一回路中的某個(gè)或某幾個(gè)環(huán)節(jié)，或許可以抑制癌細(xì)胞分裂,。（生物谷Bioon.com）
doi:10.1073/pnas.1105304109
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The c-MYC oncoprotein, the NAMPT enzyme, the SIRT1-inhibitor DBC1, and the SIRT1 deacetylase form a positive feedback loop
Antje Menssena,1, Per Hydbringb,2,3, Karsten Kapellec,2, J.rg Vervoortsc, Joachim Dieboldd, Bernhard Lüscherc,Lars-Gunnar Larssonb, and Heiko Hermekinga,1
Silent information regulator 1 (SIRT1) represents an NAD+-dependent deacetylase that inhibits proapoptotic factors including p53. Here we determined whether SIRT1 is downstream of the prototypic c-MYC oncogene, which is activated in the majority of tumors. Elevated expression of c-MYC in human colorectal cancer correlated with increased SIRT1 protein levels. Activation of a conditional c-MYC allele induced increased levels of SIRT1 protein, NAD+, and nicotinamide-phosphoribosyltransferase (NAMPT) mRNA in several cell types. This increase in SIRT1 required the induction of the NAMPT gene by c-MYC. NAMPT is the rate-limiting enzyme of the NAD+ salvage pathway and enhances SIRT1 activity by increasing the amount of NAD+. c-MYC also contributed to SIRT1 activation by sequestering the SIRT1 inhibitor deleted in breast cancer 1 (DBC1) from the SIRT1 protein. In primary human fibroblasts previously immortalized by introduction of c-MYC, down-regulation of SIRT1 induced senescence and apoptosis. In various cell lines inactivation of SIRT1 by RNA interference, chemical inhibitors, or ectopic DBC1 enhanced c-MYC-induced apoptosis. Furthermore, SIRT1 directly bound to and deacetylated c-MYC. Enforced SIRT1 expression increased and depletion/inhibition of SIRT1 reduced c-MYC stability. Depletion/inhibition of SIRT1 correlated with reduced lysine 63-linked polyubiquitination of c-Myc, which presumably destabilizes c-MYC by supporting degradative lysine 48-linked polyubiquitination. Moreover, SIRT1 enhanced the transcriptional activity of c-MYC. Taken together, these results show that c-MYC activates SIRT1, which in turn promotes c-MYC function. Furthermore, SIRT1 suppressed cellular senescence in cells with deregulated c-MYC expression and also inhibited c-MYC–induced apoptosis. Constitutive activation of this positive feedback loop may contribute to the development and maintenance of tumors in the context of deregulated c-MYC.
