Multiple B-vitamin inadequacy amplifies alterations induced by folate depletion in p53 expression and its downstream effector MDM2†
Version of Record online: 22 MAY 2008
Copyright © 2008 Wiley-Liss, Inc.
International Journal of Cancer
Volume 123, Issue 3, pages 519–525, 1 August 2008
How to Cite
Liu, Z., Choi, S.-W., Crott, J. W., Smith, D. E. and Mason, J. B. (2008), Multiple B-vitamin inadequacy amplifies alterations induced by folate depletion in p53 expression and its downstream effector MDM2. Int. J. Cancer, 123: 519–525. doi: 10.1002/ijc.23599
Conflict of Interest: J.B.M. has served as a consultant to Wyeth Consumer Healthcare, a manufacturer of multivitamins.
Any opinions, findings, conclusions or recommendations expressed in this publication are those of the authors and do not necessarily reflect the view of the U.S. Department of Agriculture.
- Issue online: 28 MAY 2008
- Version of Record online: 22 MAY 2008
- Manuscript Accepted: 4 MAR 2008
- Manuscript Received: 20 NOV 2007
- National Institutes of Health. Grant Numbers: U54 CA10097, K05 CA100048, R21 AA016681
- Agricultural Research Service. Grant Number: 58-1950-7-707
- Cancer Research and Prevention Foundation
- strand breaks
Folate is required for biological methylation and nucleotide synthesis, aberrations of which are thought to be the mechanisms that enhance colorectal carcinogenesis produced by folate inadequacy. These functions of folate also depend on the availability of other B-vitamins that participate in “one-carbon metabolism,” including B2, B6 and B12. Our study therefore investigated whether combined dietary restriction of these vitamins amplifies aberrations in the epigenetic and genetic integrity of the p53 gene that is 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 4 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 1-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. © 2008 Wiley-Liss, Inc.