The induction of microRNA-16 in colon cancer cells by protein arginine deiminase inhibition causes a p53-dependent cell cycle arrest.
The induction of microRNA-16 in colon cancer cells by protein arginine deiminase inhibition causes a p53-dependent cell cycle arrest.
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通过蛋白质精氨酸脱亚胺酶抑制诱导结肠癌细胞中的 microRNA-16 导致 p53 依赖性细胞周期停滞
DOI：
10.1371/journal.pone.0053791
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Hofseth LJ
中科院分区：
文献类型：
--
作者：
Cui X;Witalison EE;Chumanevich AP;Chumanevich AA;Poudyal D;Subramanian V;Schetter AJ;Harris CC;Thompson PR;Hofseth LJ
蛋白质精氨酸脱亚胺酶（PAD）在钙依赖性不可逆反应中催化肽基精氨酸翻译后转化为肽基瓜氨酸。有证据表明PAD在致癌作用中发挥作用。为了确定PAD的癌症相关功能影响，我们设计了一种小分子PAD抑制剂（称为Chor-amidine或Cl-amidine），并测试了这种药物对细胞周期的影响。来自结肠癌细胞实验的数据表明，Cl-脒导致G1期阻滞，这是p53依赖性的。在另一组实验中，我们发现Cl-脒导致microRNA-16（miRNA-16）显著增加，并且这种增加也是p53依赖性的。由于miRNA-16是一种假定的肿瘤抑制miRNA，并且其他人已经发现miRNA-16抑制增殖，因此我们假设与PAD抑制相关的p53依赖性G1期阻滞反过来依赖于miRNA-16的表达。结果与这一假设是一致的。同样，我们发现G1期阻滞至少部分是由于Cl-脒介导的miRNA-16表达抑制其G1期相关靶点：细胞周期蛋白D1、D2、D3、E1和cdk6的能力。我们的研究揭示了PAD抑制可以预防或治疗结肠癌的机制。
Protein Arginine Deiminases (PADs) catalyze the post-translational conversion of peptidyl-Arginine to peptidyl-Citrulline in a calcium-dependent, irreversible reaction. Evidence is emerging that PADs play a role in carcinogenesis. To determine the cancer-associated functional implications of PADs, we designed a small molecule PAD inhibitor (called Chor-amidine or Cl-amidine), and tested the impact of this drug on the cell cycle. Data derived from experiments in colon cancer cells indicate that Cl-amidine causes a G1 arrest, and that this was p53-dependent. In a separate set of experiments, we found that Cl-amidine caused a significant increase in microRNA-16 (miRNA-16), and that this increase was also p53-dependent. Because miRNA-16 is a putative tumor suppressor miRNA, and others have found that miRNA-16 suppresses proliferation, we hypothesized that the p53-dependent G1 arrest associated with PAD inhibition was, in turn, dependent on miRNA-16 expression. Results are consistent with this hypothesis. As well, we found the G1 arrest is at least in part due to the ability of Cl-amidine-mediated expression of miRNA-16 to suppress its' G1-associated targets: cyclins D1, D2, D3, E1, and cdk6. Our study sheds light into the mechanisms by which PAD inhibition can protect against or treat colon cancer.
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DOI：
10.1158/1940-6207.capr-09-0117
发表时间：
2010-04
期刊：
Cancer prevention research (Philadelphia, Pa.)
影响因子：
--
作者：
Cui X;Jin Y;Hofseth AB;Pena E;Habiger J;Chumanevich A;Poudyal D;Nagarkatti M;Nagarkatti PS;Singh UP;Hofseth LJ
通讯作者：
Hofseth LJ
影响因子：
3.8
作者：
Chang X;Han J;Pang L;Zhao Y;Yang Y;Shen Z
通讯作者：
Shen Z
影响因子：
5.3
作者：
Li, Pingxin;Yao, Hongjie;Wang, Yanming
通讯作者：
Wang, Yanming
影响因子：
82.9
作者：
Bonci, Desiree;Coppola, Valeria;De Maria, Ruggero
通讯作者：
De Maria, Ruggero
影响因子：
2.9
作者：
Knuckley, Bryan;Causey, Corey P.;Jones, Justin E.;Bhatia, Monica;Dreyton, Christina J.;Osborne, Tanesha C.;Takahara, Hidenari;Thompson, Paul R.
通讯作者：
Thompson, Paul R.