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United States Department of Agriculture

Agricultural Research Service

Research Project: NUTRITION AND CANCER PREVENTION

Location: Human Nutrition Research Center on Aging

Title: Multiple B-vitamin inadequacy amplifies alterations induced by folate depletion in p53 expression and its downstream effector MDM2

Authors
item Liu, Zhenhua - JM USDA HNRCA @ TUFTS
item Choi, Sang-Woon
item Crott, Jimmy - JM USDA HNRCA @ TUFTS
item Smith, Donald
item Mason, Joel

Submitted to: International Journal of Cancer
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: March 4, 2008
Publication Date: August 1, 2008
Citation: Liu, Z., Choi, S., Crott, J.W., Smith, D., Mason, J.B. 2008. Multiple B-vitamin inadequacy amplifies alterations induced by folate depletion in p53 expression and its downstream effector MDM2. International Journal of Cancer. 123(3):519-525.

Interpretive Summary: Folate is required for biological methylation and nucleotide synthesis, and it is aberrations in these processes that are thought to be the mechanisms that enhance colorectal carcinogenesis produced by folate inadequacy. These functions of folate also depend on availability of other B-vitamins, including B2, B6 and B12. This study therefore investigated whether combined dietary restriction of these vitamins amplifies aberrations in a key tumor suppressor, p53 gene, that are induced by folate depletion alone. Ninety-six mice were group pair-fed diets with different combinations of B-vitamin depletion over 10 weeks. DNA and RNA were extracted from epithelial cells isolated from the colon. Region-specific DNA methylation and breaks on p53 were observed to be induced by folate combined with B2, B6, and B12 restriction. Furthermore, the expression of p53 downstream gene and MDM2 were also significantly altered by the combined depletion state but not by folate depletion alone. These data indicate that inadequacies of other one-carbon vitamins may amplify aberrations of the p53 gene induced by folate depletion alone, implying that concurrent inadequacies in several of these vitamins may have added tumorigenic potential beyond that observed with isolated folate depletion.

Technical Abstract: Folate is required for biological methylation and nucleotide synthesis, and it is aberrations in these processes that are thought to be the mechanisms that enhance colorectal carcinogenesis produced by folate inadequacy. These functions of folate also depend on availability of other B-vitamins that participate in ‘one-carbon metabolism’, including B2, B6 and B12. This study therefore investigated whether combined dietary restriction of these vitamins amplifies aberrations in the epigenetic and genetic integrity of the p53 gene that are induced by folate depletion alone. Ninety-six mice were group pair-fed diets with different combinations of B-vitamin depletion over 10 weeks. DNA and RNA were extracted from epithelial cells isolated from the colon. Within the hypermutable region of p53 (exons 5-8), DNA strand breaks were induced within exons 6 and 8 by folate combined with B2, B6, and B12 restriction (p < 0.05); such effects were not significantly induced by mild folate depletion alone. Similarly, a minor degree of hypomethylation of exon 6 produced by isolated folate depletion was significantly amplified (P </- 0.05) by simultaneous depletion of all four B vitamins. Furthermore, the expression of p53 and MDM2 were significantly decreased (p </- 0.05) by the combined depletion state but not by folate depletion alone. These data indicate that inadequacies of other one-carbon vitamins may amplify aberrations of the p53 gene induced by folate depletion alone, implying that concurrent inadequacies in several of these vitamins may have added tumorigenic potential beyond that observed with isolated folate depletion.

Last Modified: 10/1/2014
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