Cadmium induces Wnt signaling to upregulate proliferation and survival genes in sub-confluent kidney proximal tubule cells.
Cadmium induces Wnt signaling to upregulate proliferation and survival genes in sub-confluent kidney proximal tubule cells.
复制标题
DOI：
10.1186/1476-4598-9-102
复制
发表时间：
2010-05-08
期刊：
影响因子：
37.3
通讯作者：
Thévenod F
中科院分区：
文献类型：
--
作者：
Chakraborty PK;Lee WK;Molitor M;Wolff NA;Thévenod F
1类致癌物质镉(Cd~(2+))破坏上皮细胞黏附连接(AJ)的E-钙粘蛋白/β-连环蛋白复合体，导致肾癌。已知E-钙粘附素黏附的解除调节和Wnt/β-连环蛋白信号的改变与肿瘤的发生有关。我们研究了Cd~(2+)诱导的肾近端小管上皮细胞(PTC)上E-钙粘素中断后的Wnt信号转导。TOPFlash检测显示，Cd~(2+)(25μM，3~9h)可引起β-连环蛋白的核转位，并触发WNT反应。Cd~(2+)降低β-连环蛋白与AJ组分(E-钙粘连蛋白、α-连环蛋白)的相互作用，增加与WNT途径转录因子TCF4的结合，该转录因子上调并移位到细胞核。Cd~(2+)上调WNT靶基因c-Myc、Cyclin D_1和ABCB1，电迁移率漂移分析显示Cd~(2+)增加TCF4与Cyclin D_1和ABCB1启动子序列的结合。野生型和突变型TCF4的过表达证实了Cd~(2+)诱导的Wnt信号。Cd~(2+)诱导的WNT信号在融合的非增殖细胞中未观察到，表现为E-钙粘蛋白表达增加。E-钙粘蛋白的过表达降低了Wnt信号、PTC增殖和Cd~(2+)毒性。Cd~(2+)还可诱导促凋亡的内质网应激标志物和Wnt抑制因子CHOP/GADD153的活性氧种依赖性表达，但这并不能消除WNT反应和细胞活力。Cd~(2+)在PTC中诱导Wnt信号转导。因此，Cd~(2+)可能通过促进Wnt途径介导的肿瘤前细胞的增殖和存活来促进PTC的癌变。
The class 1 carcinogen cadmium (Cd2+) disrupts the E-cadherin/β-catenin complex of epithelial adherens junctions (AJs) and causes renal cancer. Deregulation of E-cadherin adhesion and changes in Wnt/β-catenin signaling are known to contribute to carcinogenesis. We investigated Wnt signaling after Cd2+-induced E-cadherin disruption in sub-confluent cultured kidney proximal tubule cells (PTC). Cd2+ (25 μM, 3-9 h) caused nuclear translocation of β-catenin and triggered a Wnt response measured by TOPflash reporter assays. Cd2+ reduced the interaction of β-catenin with AJ components (E-cadherin, α-catenin) and increased binding to the transcription factor TCF4 of the Wnt pathway, which was upregulated and translocated to the nucleus. While Wnt target genes (c-Myc, cyclin D1 and ABCB1) were up-regulated by Cd2+, electromobility shift assays showed increased TCF4 binding to cyclin D1 and ABCB1 promoter sequences with Cd2+. Overexpression of wild-type and mutant TCF4 confirmed Cd2+-induced Wnt signaling. Wnt signaling elicited by Cd2+ was not observed in confluent non-proliferating cells, which showed increased E-cadherin expression. Overexpression of E-cadherin reduced Wnt signaling, PTC proliferation and Cd2+ toxicity. Cd2+ also induced reactive oxygen species dependent expression of the pro-apoptotic ER stress marker and Wnt suppressor CHOP/GADD153 which, however, did not abolish Wnt response and cell viability. Cd2+ induces Wnt signaling in PTC. Hence, Cd2+ may facilitate carcinogenesis of PTC by promoting Wnt pathway-mediated proliferation and survival of pre-neoplastic cells.
登录
查看更多内容
影响因子：
4.8
作者：
Giannini, AL;Vivanco, MDM;Kypta, RM
通讯作者：
Kypta, RM
DOI：
10.1083/jcb.129.2.489
发表时间：
1995-04
期刊：
The Journal of cell biology
影响因子：
--
作者：
Hermiston ML;Gordon JI
通讯作者：
Gordon JI
DOI：
10.1083/jcb.200402153
发表时间：
2004-10-25
期刊：
The Journal of cell biology
影响因子：
--
作者：
Gottardi CJ;Gumbiner BM
通讯作者：
Gumbiner BM
影响因子：
4.8
作者：
Block, Karen;Eid, Assaad;Gorin, Yves
通讯作者：
Gorin, Yves
影响因子：
5.1
作者：
Hu, J;Mao, Y;White, K
通讯作者：
White, K