Suppression of p53 and p21CIP1/WAF1 reduces arsenite-induced aneuploidy.
Suppression of p53 and p21CIP1/WAF1 reduces arsenite-induced aneuploidy.
复制标题
DOI：
10.1021/tx900353v
复制
发表时间：
2010-02-15
影响因子：
4.1
通讯作者：
States, J. Christopher
中科院分区：
文献类型：
--
作者：
Maria Salazar, Ana;Miller, Heather L.;McNeely, Samuel C.;Sordo, Monserrat;Ostrosky-Wegman, Patricia;States, J. Christopher
非整倍体和广泛的染色体重排在人类肿瘤中很常见。利用siRNA抑制p53和p21 CIP 1/WAF 1，研究了DNA损伤反应蛋白p53和p21 CIP 1/WAF 1在端粒酶永生化二倍体人成纤维细胞非整倍体发生和染色体断裂中的作用。将细胞暴露于环境致癌物亚砷酸钠（15和20 µM），并使用微核阻断试验在双核细胞中评价微核（MN）诱导。为了确定MN是否由染色体的错误分离或染色体片段引起，我们使用了荧光原位杂交与着丝粒DNA探针。无论p53或p21 CIP 1/WAF 1表达如何，对照细胞中的细胞核主要为致染色体断裂来源。转染NSC siRNA或Mock的细胞中具有着丝粒信号的MN在砷暴露后增加30%，表明砷诱导tGM 24细胞的非整倍体。虽然p53的抑制增加了亚砷酸盐处理的细胞与MN的分数，它引起了减少与centeromeric DNA的分数。抑制p21 CIP 1/WAF 1类似于p53抑制，降低了着丝粒DNA的分数。我们的研究结果表明，缺乏正常p53功能的细胞不能成为非整倍体，因为它们死于有丝分裂阻滞相关的细胞凋亡，而具有正常p53功能的细胞能够从有丝分裂阻滞中退出，可以成为非整倍体。此外，我们目前的结果支持p21 CIP 1/WAF 1的这一作用。由于p21 CIP 1/WAF 1的抑制导致了砷诱导的非整倍体的减少，这表明p21 CIP 1/WAF 1在有丝分裂退出中起作用。
Aneuploidy and extensive chromosomal rearrangements are common in human tumors. The role of DNA damage response proteins p53 and p21CIP1/WAF1 in aneugenesis and clastogenesis was investigated in telomerase immortalized diploid human fibroblasts using siRNA suppression of p53 and p21CIP1/WAF1. Cells were exposed to the environmental carcinogen sodium arsenite (15 and 20 µM), and the induction of micronuclei (MN) was evaluated in binucleated cells using the cytokinesis-block assay. To determine whether MN resulted from missegregation of chromosomes or from chromosomal fragments, we used a fluorescent in situ hybridization with a centromeric DNA probe. Micronuclei were predominantly of clastogenic origin in control cells regardless of p53 or p21CIP1/WAF1 expression. MN with centromere signals in cells transfected with NSC siRNA or Mock increased 30% after arsenite exposure, indicating that arsenite induced aneuploidy in the tGM24 cells. Although suppression of p53 increased the fraction of arsenite-treated cells with MN, it caused a decrease in the fraction of with centeromeric DNA. Suppression of p21CIP1/WAF1 like p53 suppression decreased the fraction of with centromeric DNA. Our results suggest that cells lacking normal p53 function cannot become aneuploid because they die by mitotic arrest-associated apoptosis, whereas cells with normal p53 function that are able to exit from mitotic arrest can become aneuploid. Furthermore our current results support this role for p21CIP1/WAF1. Since suppression of p21CIP1/WAF1 caused a decrease in aneuploidy induced by arsenite suggesting that p21CIP1/WAF1 plays a role in mitotic exit.
登录
查看更多内容
影响因子：
8.3
作者：
Coronado-Gonzalez, Jose Antonio;Del Razo, Luz Maria;la Pena, Jorge Escobedo-de
通讯作者：
la Pena, Jorge Escobedo-de
影响因子：
5.3
作者：
Lanni, JS;Jacks, T
通讯作者：
Jacks, T
影响因子：
3.8
作者：
Porter, PC;Clark, DR;States, JC
通讯作者：
States, JC
影响因子：
5.8
作者：
Huang, SC;Huang, CYF;Lee, TC
通讯作者：
Lee, TC
影响因子：
3.2
作者：
Chou, WC;Dang, CV
通讯作者：
Dang, CV