Folate depletion in human lymphocytes up-regulates p53 expression despite marked induction of strand breaks in exons 5-8 of the gene
Folate depletion in human lymphocytes up-regulates p53 expression despite marked induction of strand breaks in exons 5-8 of the gene
复制标题
DOI：
10.1016/j.mrgentox.2006.10.001
复制
发表时间：
2007-01-10
影响因子：
1.9
通讯作者：
Mason, Joel B.
中科院分区：
文献类型：
--
作者：
Crott, Jimmy W.;Liu, Zhenhua;Mason, Joel B.
低膳食叶酸摄入量与致癌风险升高有关。叶酸耗竭促进癌发生的一种假定机制是诱导基因特异性链断裂和受影响基因的表达受损。在含有15、30或120 nM叶酸的培养基中培养原代人淋巴细胞。测定p53链断裂、基因和蛋白表达以及p21转录物。与30和120 W相比，在15 nM叶酸中生长的细胞发生了显著水平的p53链断裂，反映为来自p53外显子5-8（类似于40%损失，P < 0.0001）和外显子7-8（类似于26%损失，P < 0.0001）的可扩增DNA的减少。然而，与120 nM相比，15和30 nM中的稳态p53转录物升高两倍（P < 0.001）。p53蛋白丰度随着培养基叶酸的减少而增加，p21转录物也是如此。微核试验表明，在两个较低的叶酸浓度下，染色体损伤增加了3倍（P < 0.01）。在原代人淋巴细胞中，叶酸耗竭诱导p53外显子5-8断裂显著增加，但不降低p53 mRNA、蛋白质的稳态水平，也不损害下游信号传导。叶酸耗竭诱导p53链断裂不会损害所有人类细胞系中p53的表达或作用。(c)2006 Elsevier B. V.保留所有权利。
Low dietary folate intake is associated with an elevated risk for carcinogenesis. One putative mechanism by which folate depletion promotes carcinogenesis is by inducing gene-specific strand breakage and impaired expression of affected genes. Primary human lymphocytes were cultured in media containing 15, 30 or 120 nM folic acid. p53 strand breaks, gene and protein expression, and p21 transcript were determined. Cells grown in 15 nM folate developed significant levels of p53 strand breaks, reflected by reductions in amplifiable DNA from p53 exons 5-8 (similar to 40% loss, P < 0.0001) and exons 7-8 (similar to 26% loss, P < 0.0001) compared to 30 and 120W. Nevertheless, steady-statep53 transcript was elevated two-fold in 15 and 30 compared to 120nM (P < 0.001). p53 protein abundance increased with decreasing media folate, as did p21 transcript. The cytokinesis-block micronucleus assay demonstrated a three-fold increase in chromosomal damage at the two lower folate concentrations (P < 0.01). In primary human lymphocytes, folate depletion induces a marked increase in p53 exons 5-8 breaks, but does not reduce steady-state levels of p53 mRNA, protein, or impair downstream signaling. The induction of p53 strand breaks by folate depletion does not impair p53 expression or action within all human cell lines. (c) 2006 Elsevier B.V. All rights reserved.