内源性代谢产物X通过激活ERK通路上调cyclinD1促进C_2C_（12）细胞增殖
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摘要
1923年,Warburg发现快速增殖的肿瘤细胞主要通过糖酵解的方式进行代谢,被称为Warburg理论。近年来Warburg理论越来越被人们所接受,寻找和发现内源性代谢产物或者相关酶新的生物学功能已成为当今生命科学研究的热点。
本实验室最近对生长速度存在显著差异的蛋鸡与肉鸡的蛋白质组以及转录组学的比较研究发现,快速生长的肉鸡肌肉组织中调控X代谢的酶Z的表达以及酶活性显著高于蛋鸡,由于肌肉是利用内源性代谢产物X的主要器官,该结果提示内源性代谢产物X可能与个体发育过程中的骨骼肌生长速度有一定联系。因此,本论文研究了内源性代谢产物X对骨骼肌细胞增殖的影响以及可能的分子机制。
细胞生物学实验结果表明,内源性代谢产物X促进成肌细胞C2C12的增殖,进一步研究发现X可能通过激活ERK通路在转录和翻译水平上上调cyclinD1的表达,从而起到促进细胞增殖的作用。更为重要的是,内源性代谢产物X可以协同IGF1对细胞增殖起到进一步的促进作用,同时,X也可以拮抗MSTN对细胞增殖的抑制作用。本研究利用不表达Z酶的HepG2细胞和X的下游产物A初步探讨了X促进细胞增殖是否依赖于其代谢功能。结果表明,内源性代谢产物X可以促进不表达Z酶的HepG2细胞的增殖,而其下游代谢产物A对C2C12细胞的增殖没用表现出促进作用。以上结果提示,X可能通过不依赖其自身代谢通路的方式促进骨骼肌细胞的增殖。综上所述,我们的实验结果表明,内源性代谢产物X可能在骨骼肌发生和再生过程中具有十分重要的调控功能,有望发展成为治疗骨骼肌及代谢性疾病的一个潜在药物。
In the 1920s, Otto Warburg demonstrated that tumor cells had high rates of glycolysis, lactate production, and biosynthesis of lipids and other macromolecules which have been regarded as the Warburg's effect. Recently, Warburg's effect is being greatly recongnized and identification of novel functional roles of endogenous metabolites is the hot spot in biomedical research.
Recently, enzyme Z was identified in a screen for genes whose expression was differentially regulated in the skeletal muscle tissue between broiler and layer chickens by transcriptom and proteomics analysis. In addtiton, our previously unpublished data also demonstrated that the enzymatic activity of the enzyme Z and concerntration of its substrate X were higher in the skeletal muscle tissue of the rapidly growthing broiler than in that of layer chicken. Considering the skeletal muscle is the major organ for utilizing the intrinsic metabolite X, these observations suggest that the intrinsic metabolite X play regulatory roles during skeletal muscle development. Therefore, in the present study, we investigated the effect of the X on muscle cell proliferation and the possible moleculear mechanisms for its function.
Herein we provided experimental evidence to show that the intrinsic metabolite X promoted the C2C12 cell proliferation in vitro by upregulating expression of the cyclinD1 via ERK signaling pathway. More interestingly, we found that the X agonized IGF function and antagonized myostatin inhibitory effect on muscle cell proliferation. To ask whether the molecular action of X was dependent on its enzyme Z, the HepG2 cells (an enzyme Z deficiency cell line) was treated by the X and the results indicated that X can still promote HepG2 cell proliferation. In addation, we also investigated the effect of X's product and found that X's product had no effect on C2C12 cell proliferation. Taken together, our findings indicated that the intrinsic metabolite X plays regulatory roles in cell proliferation in the way of independent on its metabolism. Our work highlights the potential application of using the X to cure human diseases, such as muscular dystrophy and atrophy.
本实验室最近对生长速度存在显著差异的蛋鸡与肉鸡的蛋白质组以及转录组学的比较研究发现,快速生长的肉鸡肌肉组织中调控X代谢的酶Z的表达以及酶活性显著高于蛋鸡,由于肌肉是利用内源性代谢产物X的主要器官,该结果提示内源性代谢产物X可能与个体发育过程中的骨骼肌生长速度有一定联系。因此,本论文研究了内源性代谢产物X对骨骼肌细胞增殖的影响以及可能的分子机制。
细胞生物学实验结果表明,内源性代谢产物X促进成肌细胞C2C12的增殖,进一步研究发现X可能通过激活ERK通路在转录和翻译水平上上调cyclinD1的表达,从而起到促进细胞增殖的作用。更为重要的是,内源性代谢产物X可以协同IGF1对细胞增殖起到进一步的促进作用,同时,X也可以拮抗MSTN对细胞增殖的抑制作用。本研究利用不表达Z酶的HepG2细胞和X的下游产物A初步探讨了X促进细胞增殖是否依赖于其代谢功能。结果表明,内源性代谢产物X可以促进不表达Z酶的HepG2细胞的增殖,而其下游代谢产物A对C2C12细胞的增殖没用表现出促进作用。以上结果提示,X可能通过不依赖其自身代谢通路的方式促进骨骼肌细胞的增殖。综上所述,我们的实验结果表明,内源性代谢产物X可能在骨骼肌发生和再生过程中具有十分重要的调控功能,有望发展成为治疗骨骼肌及代谢性疾病的一个潜在药物。
In the 1920s, Otto Warburg demonstrated that tumor cells had high rates of glycolysis, lactate production, and biosynthesis of lipids and other macromolecules which have been regarded as the Warburg's effect. Recently, Warburg's effect is being greatly recongnized and identification of novel functional roles of endogenous metabolites is the hot spot in biomedical research.
Recently, enzyme Z was identified in a screen for genes whose expression was differentially regulated in the skeletal muscle tissue between broiler and layer chickens by transcriptom and proteomics analysis. In addtiton, our previously unpublished data also demonstrated that the enzymatic activity of the enzyme Z and concerntration of its substrate X were higher in the skeletal muscle tissue of the rapidly growthing broiler than in that of layer chicken. Considering the skeletal muscle is the major organ for utilizing the intrinsic metabolite X, these observations suggest that the intrinsic metabolite X play regulatory roles during skeletal muscle development. Therefore, in the present study, we investigated the effect of the X on muscle cell proliferation and the possible moleculear mechanisms for its function.
Herein we provided experimental evidence to show that the intrinsic metabolite X promoted the C2C12 cell proliferation in vitro by upregulating expression of the cyclinD1 via ERK signaling pathway. More interestingly, we found that the X agonized IGF function and antagonized myostatin inhibitory effect on muscle cell proliferation. To ask whether the molecular action of X was dependent on its enzyme Z, the HepG2 cells (an enzyme Z deficiency cell line) was treated by the X and the results indicated that X can still promote HepG2 cell proliferation. In addation, we also investigated the effect of X's product and found that X's product had no effect on C2C12 cell proliferation. Taken together, our findings indicated that the intrinsic metabolite X plays regulatory roles in cell proliferation in the way of independent on its metabolism. Our work highlights the potential application of using the X to cure human diseases, such as muscular dystrophy and atrophy.
引文
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2 DeBerardinis, R. J., Lum, J. J., Hatzivassiliou, G. and Thompson, C. B. (2008) The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab.7,11-20
3 Bauer, D. E., Harris, M. H., Plas, D. R., Lum, J. J., Hammerman, P. S., Rathmell, J. C., Riley, J. L. and Thompson, C. B. (2004) Cytokine stimulation of aerobic glycolysis in hematopoietic cells exceeds proliferative demand. FASEB J.18,1303-1305
4 Warburg, O. (1956) On respiratory impairment in cancer cells. SCIENCE.124,269-270
5 Warburg, O. (1956) On the origin of cancer cells. SCIENCE.123,309-314
6 Izyumov, D. S., Avetisyan, A. V., Pletjushkina, O. Y., Sakharov, D. V., Wirtz, K. W., Chernyak, B. V. and Skulachev, V. P. (2004) "Wages of fear": transient threefold decrease in intracellular ATP level imposes apoptosis. Biochim Biophys Acta.1658,141-147
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