Mouse models to elucidate mechanisms of folate-related cancer pathologies

摘要: Perturbations in folate metabolism are associated with risk for colon cancer, although the underlying mechanisms remain to be established. It is not known if associations between disruptions and cancer result from altered S-adenosylmethionine (SAM; also known/abbreviated as AdoMet) synthesis and/or deoxythymidylic acid (dTMP) synthesis. Cytoplasmic serine hydroxymethyltransferase (cSHMT) a metabolic switch that directs partitioning of folate-activated one-carbon units dTMP SAM biosynthesis. cSHMT expressed tissues folate-related pathologies, including colon. Therefore, gain-of-function loss-of-function mouse models can used elucidate contributions biosynthetic pathways cancer. Nutrition genetics interact contribute initiation progression carcinogenesis. Molecular antecedents promote development sporadic include DNA damage (single point mutations, loss heterozygosity microsatellite instability), epigenetic alterations chromatin methylation, which affect both genome stability gene expression. Implicated function tumor suppressor genes adenomatous polyposis coli (APC) p53 , well alterations, such methylation acts silence genes. Dietary deficiency critical nutrients, folate, generation oxidative stress, increase rates thereby have potential induce genetic mutations instability responsible carcinogenesis. Tetrahydrofolate (THF) serves cofactor chemically activates carries at three different oxidation levels network reactions metabolism, occurs mitochondria cytoplasm (Figure 1).1,2 The primary role mitochondrial generate glycine formate serine.1,2 Mitochondrial-derived traverses where …