Potential role of peptidylarginine deiminase enzymes and protein citrullination in cancer pathogenesis.
Potential role of peptidylarginine deiminase enzymes and protein citrullination in cancer pathogenesis.
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DOI：
10.1155/2012/895343
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发表时间：
2012
影响因子：
3
通讯作者：
Coonrod SA
中科院分区：
文献类型：
--
作者：
Mohanan S;Cherrington BD;Horibata S;McElwee JL;Thompson PR;Coonrod SA
肽基精氨酸脱亚胺酶(PADS)是一类翻译后修饰酶，催化带正电的蛋白质结合的精氨酸和甲基精氨酸残基转化为不带电荷的非标准氨基酸瓜氨酸。这种酶活性被称为瓜氨酸化或脱亚胺。瓜氨酸化可以通过改变目标蛋白的结构和功能来显著影响生化途径。5个哺乳动物PAD家族成员(PAD 1-4和6)已被描述，并显示出组织特异性分布。最近对PAD的综述主要集中在它们在自身免疫性疾病中的作用。在这里，我们将讨论PADS在肿瘤进展和肿瘤相关炎症中的潜在作用。在癌症的背景下，越来越多的临床证据表明PAD4(可能还有PAD2)在肿瘤进展中起着重要作用。最近的研究结果表明，用PAD抑制剂治疗细胞系和小鼠显著抑制了肿瘤生长，有趣的是，炎症症状也得到了抑制，这加强了PADS和癌症之间的联系。在分子水平上，转录因子、辅调节因子和组蛋白是PADS进行瓜氨酸化的功能靶点，这些靶点的瓜氨酸化可以影响多种肿瘤细胞系的基因表达。下一代同工酶特异性PAD抑制剂可能具有调节炎性肿瘤微环境和肿瘤细胞生长的治疗潜力。
The peptidylarginine deiminases (PADs) are a family of posttranslational modification enzymes that catalyze the conversion of positively charged protein-bound arginine and methylarginine residues to the uncharged, nonstandard amino acid citrulline. This enzymatic activity is referred to as citrullination or, alternatively, deimination. Citrullination can significantly affect biochemical pathways by altering the structure and function of target proteins. Five mammalian PAD family members (PADs 1–4 and 6) have been described and show tissue-specific distribution. Recent reviews on PADs have focused on their role in autoimmune diseases. Here, we will discuss the potential role of PADs in tumor progression and tumor-associated inflammation. In the context of cancer, increasing clinical evidence suggests that PAD4 (and possibly PAD2) has important roles in tumor progression. The link between PADs and cancer is strengthened by recent findings showing that treatment of cell lines and mice with PAD inhibitors significantly suppresses tumor growth and, interestingly, inflammatory symptoms. At the molecular level, transcription factors, coregulators, and histones are functional targets for citrullination by PADs, and citrullination of these targets can affect gene expression in multiple tumor cell lines. Next generation isozyme-specific PAD inhibitors may have therapeutic potential to regulate both the inflammatory tumor microenvironment and tumor cell growth.