童雪梅
博士 研究员 博士生导师
上海交通大学 基础医学院
长期致力于研究细胞代谢和细胞死亡的生化和分子调节机制及其在防治代谢相关疾病如癌症、肥胖症、糖尿病中的应用。
个性化签名
- 姓名:童雪梅
- 目前身份:在职研究人员
- 担任导师情况:博士生导师
- 学位:博士
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学术头衔:
博士生导师
- 职称:高级-研究员
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学科领域:
肿瘤学
- 研究兴趣:长期致力于研究细胞代谢和细胞死亡的生化和分子调节机制及其在防治代谢相关疾病如癌症、肥胖症、糖尿病中的应用。
童雪梅,研究员,博士生导师。2006年获美国约翰霍普金斯大学医学院生物化学博士学位,之后在美国宾夕法尼亚大学医学院肿瘤生物学系进行博士后研究,2010年5月起全职在上海交通大学医学院工作,研究方向为细胞代谢和细胞死亡的生化和分子调节机制及其在防治代谢相关疾病如癌症、肥胖症、糖尿病中的应用。
博士后工作期间研究了转录因子ChREBP在调节肝癌和结肠癌细胞代谢、增殖和肿瘤生长中的生理功能和分子机理。首次发现调节代谢关键酶基因的转录因子ChREBP对于肿瘤细胞中葡萄糖依赖性代谢、细胞增殖及肿瘤生长起着关键作用。博士期间主要研究细胞凋亡调控毛发周期与脱发症的分子机制。迄今已在Genes & Development、PNAS、Journal of Investigative Dermatology、Current Opinion in Genetics & Development、Trends in Molecular Medicine、Oncogene、The FASEB Journal等期刊上发表多篇论文。获得教育部新世纪优秀人才计划、上海高层次人才和上海市青年科技启明星计划(A类)奖励。目前负责1项国家自然科学基金面上项目和1项上海市科委基础研究重点项目,参与1项科技部973重大研究计划。
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成果数
4
【期刊论文】The molecular determinants of de novo nucleotide biosynthesis in cancer cells
Current Opinion in Genetics & Development,2009,19(1):32-37
2009年02月01日
Tumor cells increase the use of anabolic pathways to satisfy the metabolic requirements associated with a high growth rate. Transformed cells take up and metabolize nutrients such as glucose and glutamine at high levels that support anabolic growth. Oncogenic signaling through the PI3K/Akt and Myc pathways directly control glucose and glutamine uptake, respectively. In order to achieve elevated rates of nucleotide biosynthesis, neoplastic cells must divert carbon from PI3K/Akt-induced glycolytic flux into the nonoxidative branch of the pentose phosphate pathway to generate ribose-5-phosphate. This redirection of glucose catabolism appears to be regulated by cytoplasmic tyrosine kinases. Myc-induced glutamine metabolism also increases the abundance and activity of different rate-limiting enzymes that produce the molecular precursors required for de novo nucleotide synthesis. In this review, we will focus on recent progress in understanding how glucose and glutamine metabolism is redirected by oncogenes in order to support de novo nucleotide biosynthesis during proliferation and how metabolic reprogramming can be potentially exploited in the development of new cancer therapies.
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Oncogene ,2010,29():2962–2972
2010年03月15日
As chronic myeloid leukemia (CML) progresses from the chronic phase to blast crisis, the levels of BCR-ABL increase. In addition, blast-transformed leukemic cells display enhanced resistance to imatinib in the absence of BCR-ABL-resistance mutations. In this study, we show that when BCR-ABL-transformed cell lines were selected for imatinib resistance in vitro, the cells that grew out displayed a higher BCR-ABL expression comparable to the increase seen in accelerated forms of the disease. This enhanced expression of BCR-ABL was associated with an increased rate of glycolysis but with a decreased rate of proliferation. The higher level of BCR-ABL expression in the selected cells correlated with a nonhypoxic induction of hypoxia-inducible factor-1α (HIF-1α) that was required for cells to tolerate enhanced BCR-ABL signaling. HIF-1α induction resulted in an enhanced rate of glycolysis but with reduced glucose flux through both the tricarboxylic acid cycle and the oxidative arm of the pentose phosphate pathway (PPP). The reduction in oxidative PPP-mediated ribose synthesis was compensated by the HIF-1α-dependent activation of the nonoxidative PPP enzyme, transketolase, in imatinib-resistant CML cells. In both primary cultures of cells from patients exhibiting blast transformation and in vivo xenograft tumors, use of oxythiamine, which can inhibit both the pyruvate dehydrogenase complex and transketolase, resulted in enhanced imatinib sensitivity of tumor cells. Together, these results suggest that oxythiamine can enhance imatinib efficacy in patients who present an accelerated form of the disease.
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Proc Natl Acad Sci U S A. ,2009,106(51):21660-2166
2009年12月22日
Tumor cells are metabolically reprogrammed to fuel cell proliferation. Most transformed cells take up high levels of glucose and produce ATP through aerobic glycolysis. In cells exhibiting aerobic glycolysis, a significant fraction of glucose carbon is also directed into de novo lipogenesis and nucleotide biosynthesis. The glucose-responsive transcription factor carbohydrate responsive element binding protein (ChREBP) was previously shown to be important for redirecting glucose metabolism in support of lipogenesis in nonproliferating hepatocytes. However, whether it plays a more generalized role in reprogramming metabolism during cell proliferation has not been examined. Here, we demonstrated that the expression of ChREBP can be induced in response to mitogenic stimulation and that the induction of ChREBP is required for efficient cell proliferation. Suppression of ChREBP resulted in diminished aerobic glycolysis, de novo lipogenesis, and nucleotide biosynthesis, but stimulated mitochondrial respiration, suggesting a metabolic switch from aerobic glycolysis to oxidative phosphorylation. Cells in which ChREBP was suppressed by RNAi exhibited p53 activation and cell cycle arrest. In vivo, suppression of ChREBP led to a p53-dependent reduction in tumor growth. These results demonstrate that ChREBP plays a key role both in redirecting glucose metabolism to anabolic pathways and suppressing p53 activity.
cancer biology, cell biology, metabolis
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Proc Natl Acad Sci U S A.,2012,109(18):6904-6909
2012年05月01日
Despite the fact that most cancer cells display high glycolytic activity, cancer cells selectively express the less active M2 isoform of pyruvate kinase (PKM2). Here we demonstrate that PKM2 expression makes a critical regulatory contribution to the serine synthetic pathway. In the absence of serine, an allosteric activator of PKM2, glycolytic efflux to lactate is significantly reduced in PKM2-expressing cells. This inhibition of PKM2 results in the accumulation of glycolytic intermediates that feed into serine synthesis. As a consequence, PKM2-expressing cells can maintain mammalian target of rapamycin complex 1 activity and proliferate in serine-depleted medium, but PKM1-expressing cells cannot. Cellular detection of serine depletion depends on general control nonderepressible 2 kinase-activating transcription factor 4 (GCN2-ATF4) pathway activation and results in increased expression of enzymes required for serine synthesis from the accumulating glycolytic precursors. These findings suggest that tumor cells use serine-dependent regulation of PKM2 and GCN2 to modulate the flux of glycolytic intermediates in support of cell proliferation.
amino acid synthesis, glucose, metabolism, nucleotide biosynthesis
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