近日，国际著名杂志PNAS刊登了德国慕尼黑大学等机构的研究人员的最新研究成果“The c-MYC oncoprotein, the NAMPT enzyme, the SIRT1-inhibitor DBC1, and the SIRT1 deacetylase form a positive feedback loop。”，文章中，研究人员揭示了癌细胞无限分裂的一种分子机制。
癌细胞最显著的特征就是无限分裂、永不停止，而正常细胞则不会无限生长。什么原因导致癌细胞的“疯狂”？德国研究人员最新发现，一种核蛋白和一种酶会在癌细胞中“狼狈为奸”，形成反馈回路，助长癌细胞无限分裂。
德国慕尼黑大学的研究人员发现，这是因为一种名为c－Myc的核蛋白可摆脱细胞内的控制机制，促使癌细胞分裂。这种蛋白可调节细胞的生长和分裂，合成这种蛋白的基因本应在造血、胚胎发育等情况下“工作”，在不需要时受细胞抑制而“休息”。但是，在癌细胞中这种基因却摆脱抑制、放肆表达，在淋巴癌、乳腺癌等癌症中甚至扮演了“制造者”的角色。
研究人员发现，高度聚集的c－Myc蛋白可激活一种抑制细胞衰老和死亡的酶SIRT1，而这种酶又可反作用于c－Myc蛋白，如此形成一个回路，令c－Myc蛋白和SIRT1酶越来越多，最终促使癌细胞无限分裂。
研究人员表示，发现这一反馈回路有助于研究治疗癌症的新方法。用药物等手段阻断这一回路中的某个或某几个环节，或许可以抑制癌细胞分裂。（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, Jörg 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.
