Identification and characterization of the intercellular adhesion molecule-2 gene as a novel p53 target.
Identification and characterization of the intercellular adhesion molecule-2 gene as a novel p53 target.
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DOI：
10.18632/oncotarget.11366
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发表时间：
2016-09-20
期刊：
影响因子：
--
通讯作者：
Tokino T
中科院分区：
文献类型：
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作者：
Sasaki Y;Tamura M;Takeda K;Ogi K;Nakagaki T;Koyama R;Idogawa M;Hiratsuka H;Tokino T
p53 肿瘤抑制因子通过激活细胞周期停滞和细胞凋亡来抑制细胞生长，从而维持基因组稳定性并防止癌症发展。在此，我们报道细胞间粘附分子-2 (ICAM2) 被 p53 转录激活。具体来说，ICAM2 由 p53 家族和 DNA 损伤以 p53 依赖性方式诱导。我们鉴定了位于 ICAM2 基因内的 p53 结合序列，该序列对野生型 p53、TAp73 和 TAp63 有反应。在功能方面，我们发现ICAM2的异位表达抑制了癌细胞的迁移和侵袭。此外，我们证明沉默癌细胞中的内源性ICAM2会导致细胞外信号调节激酶（ERK）磷酸化水平显着增加，这表明ICAM2通过抑制ERK信号传导来抑制癌细胞的迁移和侵袭。此外，与野生型p53相比，ICAM2在含有突变型p53的人类癌症组织中表达不足。值得注意的是，ICAM2 表达的降低与各种癌症患者的生存率较低有关。我们的研究结果表明，p53 诱导 ICAM2 在抑制迁移和侵袭方面具有关键作用。
The p53 tumor suppressor inhibits cell growth through the activation of both cell cycle arrest and apoptosis, which maintain genome stability and prevent cancer development. Here, we report that intercellular adhesion molecule-2 (ICAM2) is transcriptionally activated by p53. Specifically, ICAM2 is induced by the p53 family and DNA damage in a p53-dependent manner. We identified a p53 binding sequence located within the ICAM2 gene that is responsive to wild-type p53, TAp73, and TAp63. In terms of function, we found that the ectopic expression of ICAM2 inhibited cancer cell migration and invasion. In addition, we demonstrated that silencing endogenous ICAM2 in cancer cells caused a marked increase in extracellular signal-regulated kinase (ERK) phosphorylation levels, suggesting that ICAM2 inhibits migration and invasion of cancer cells by suppressing ERK signaling. Moreover, ICAM2 is underexpressed in human cancer tissues containing mutant p53 as compared to those with wild-type p53. Notably, the decreased expression of ICAM2 is associated with poor survival in patients with various cancers. Our findings demonstrate that ICAM2 induction by p53 has a key role in inhibiting migration and invasion.