Fhit modulates the DNA damage checkpoint response
Fhit modulates the DNA damage checkpoint response
复制标题
DOI：
10.1158/0008-5472.can-06-2503
复制
发表时间：
2006-12-01
期刊：
影响因子：
11.2
通讯作者：
Huebner, Kay
中科院分区：
文献类型：
--
作者：
Ishii, Hideshi;Mimori, Koshi;Huebner, Kay
在癌前病变中，诱导DNA损伤检查点，并且在这些早期阶段中，FRA 3B/FHIT共同染色体脆性区的杂合性丢失先于检查点反应的激活或与检查点反应的激活一致。在体外将外源性Fhit引入细胞中导致在中间S检查点处检查点蛋白Husl和Chkl的表达的调节，该调节导致在食管癌细胞中诱导凋亡，但在非癌原代培养物中不诱导凋亡。保守的Fhit酪氨酸114的突变导致该功能的失败，证实了该残基的重要性。结果表明，DNA损伤敏感的FRA 3B/FHIT染色体脆性区，矛盾的是，编码的蛋白质，这是必要的保护细胞从积累的DNA损伤，通过其作用在检查点蛋白的调制，和失活的Fhit有助于积累异常检查点表型在癌症的发展。
In preneoplastic lesions, the DNA damage checkpoint is induced and loss of heterozygosity at the FRA3B/FHIT common chromosome fragile region precedes or is coincident with activation of the checkpoint response in these early stages. Introduction of exogenous Fhit into cells in vitro led to modulation of expression of checkpoint proteins Husl an Chkl at mid-S checkpoint, a modulation that led to induction of apoptosis in esophageal cancer cells but not in noncancerous primary cultures. Mutation of the conserved Fhit tyrosine 114 resulted in failure of this function, confirming the importance of this residue. The results suggest that the DNA damage-susceptible FRA3B/FHIT chromosome fragile region, paradoxically, encodes a protein that is necessary for protecting cells from accumulation of DNA damage through its role in modulation of checkpoint proteins, and inactivation of Fhit contributes to accumulation of abnormal checkpoint phenotypes in cancer development.