Shmt1 heterozygosity impairs folate-dependent thymidylate synthesis capacity and modifies risk of Apc(min)-mediated intestinal cancer risk.
Shmt1 heterozygosity impairs folate-dependent thymidylate synthesis capacity and modifies risk of Apc(min)-mediated intestinal cancer risk.
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DOI：
10.1158/0008-5472.can-10-1886
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发表时间：
2011-03-15
期刊：
影响因子：
11.2
通讯作者：
Stover PJ
中科院分区：
文献类型：
--
作者：
Macfarlane AJ;Perry CA;McEntee MF;Lin DM;Stover PJ
叶酸介导的单碳代谢是重新合成嘌呤、胸苷酸和s -腺苷蛋氨酸（主要的细胞甲基供体）所必需的。叶酸代谢障碍会降低细胞甲基化潜能和基因组稳定性，这是结直肠癌（CRC）的危险因素。细胞质丝氨酸羟甲基转移酶（SHMT1）调节叶酸活化的碳在胸苷酸和s -腺苷甲硫氨酸生物合成之间的分配。因此，SHMT1表达的变化可以确定胸苷酸和s -腺苷蛋氨酸生物合成对结直肠癌风险的具体贡献。Shmt1半合子性与胸腺嘧啶合成能力下降有关，这是由于其生物合成途径中的酶，即胸腺嘧啶合成酶和细胞质胸腺嘧啶激酶的下调。甲基化能力、基因表达和嘌呤合成方面未观察到明显的shmt1依赖性变化。Shmt1半合子性通过基因-饮食相互作用与Apcmin/+小鼠的肠癌风险增加相关，表明胸苷酸合成能力改变了Apcmin/+小鼠对肠癌的易感性。
Folate-mediated one-carbon metabolism is required for the de novo synthesis of purines, thymidylate, and S-adenosylmethionine, the primary cellular methyl donor. Impairments in folate metabolism diminish cellular methylation potential and genome stability, which are risk factors for colorectal cancer (CRC). Cytoplasmic serine hydroxymethyltransferase (SHMT1) regulates the partitioning of folate-activated one-carbons between thymidylate and S-adenosylmethionine biosynthesis. Therefore, changes in SHMT1 expression enable the determination of the specific contributions made by thymidylate and S-adenosylmethionine biosynthesis to CRC risk. Shmt1 hemizygosity was associated with a decreased capacity for thymidylate synthesis, due to down regulation of enzymes in its biosynthetic pathway, namely thymidylate synthase and cytoplasmic thymidine kinase. Significant Shmt1-dependent changes to methylation capacity, gene expression and purine synthesis were not observed. Shmt1 hemizygosity was associated with increased risk for intestinal cancer in Apcmin/+ mice through a gene-by-diet interaction, indicating that the capacity for thymidylate synthesis modifies susceptibility to intestinal cancer in Apcmin/+ mice.