PP2A as a New Player in Chronic Obstructive Pulmonary Disease.
PP2A as a New Player in Chronic Obstructive Pulmonary Disease.
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PP2A 作为慢性阻塞性肺疾病的新参与者。
DOI：
10.1165/rcmb.2018-0242ed
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发表时间：
2018
影响因子：
6.4
通讯作者：
Nyunoya,Toru
中科院分区：
文献类型：
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作者：
Li,Xiuying;Nyunoya,Toru
慢性阻塞性肺疾病（COPD）是一种常见的呼吸系统疾病，其特征是在长期暴露于有害刺激（如香烟烟雾）后发生不可逆的呼气流量限制[CS]。慢性阻塞性肺病现在是美国第三大死亡原因(1)。COPD是一种肺活量测定诊断，包含多种临床表型，包括肺气肿、慢性支气管炎和小气道疾病。关于COPD的分子发病机制，目前流行的理论包括：1)慢性炎症（2),2)蛋白酶/抗蛋白酶失衡（3),3）氧化应激（4),4）肺泡细胞凋亡（5),5）细胞衰老(6),6）自噬失调(7)。然而，这些进程并不一定是排他性的，可以是密切相关的。例如，与非吸烟者和非COPD吸烟者相比，持续性DNA损伤会导致COPD吸烟者肺部慢性炎症和氧化应激、细胞凋亡或衰老增加(8)。因此，将这些过程联系起来的统一病因学可能有潜在的靶向治疗。在其他统一的途径中，最有趣的目标之一存在于蛋白磷酸酶家族中。蛋白质的可逆磷酸化控制着基本的生物过程，并受激酶和磷酸酶的调节。真核细胞中的蛋白磷酸化位点主要有丝氨酸、苏氨酸和酪氨酸三个。人类基因组测序已经确定。500个蛋白激酶和z100个蛋白酪氨酸磷酸酶（PTPs），而只有z30个蛋白丝氨酸/苏氨酸磷酸酶。事实上，多种磷酸酶的失调，包括蛋白磷酸酶2A （PP2A）、双特异性丝裂原激活的蛋白激酶磷酸酶1、蛋白酪氨酸磷酸酶1B （PTP1B）以及10号染色体上缺失的磷酸酶和张力蛋白同源物（PTEN），都与COPD中多种生物功能的调节有关，包括炎症、蛋白水解和细胞命运（9-11）。PP2A属于PSP家族，是一种从酵母到人类高度保守的酶。PP2A由三个亚基组成——支架A亚基、催化亚基和可变调节B亚基——它们决定了它的酶促行为和亚细胞定位（12）。PP2A调节多种生命功能，包括细胞周期进程；细胞增殖、运动和寿命；以及细胞内信号的转导。在这期杂志中，Nath及其同事（第695-705页）报道，与不吸烟者和正常吸烟者相比，从COPD受试者获得的培养的原代人支气管上皮细胞（HBEs）中PP2A的活性降低，而不是细胞蛋白浓度降低（13）。作者评估了已知的内源性PP2A抑制剂，并观察到与不吸烟者和正常吸烟者相比，COPD患者培养的HBEs中PP2A癌性抑制剂（CIP2A）的mRNA和蛋白水平均有选择性地升高。虽然在培养的HBEs中，短期暴露于CS 2天不会对PP2A和CIP2A产生相同的影响，但一项小鼠体内研究表明，长时间暴露于CS 8周后，CIP2A的基因和蛋白质水平都增加了，同时PP2A的活性在4周达到峰值后下降。CIP2A敲低增加了非吸烟者和COPD吸烟者培养的HBEs中PP2A的活性，并调节了COPD患者培养的HBEs中细胞外信号调节激酶（ERK）激活和基质金属蛋白酶1 （MMP-1）和MMP-9表达的下游影响。此外，厄洛替尼……
Chronic obstructive pulmonary disease (COPD) is a prevalent respiratory disorder characterized by irreversible expiratory flow limitation that develops after chronic exposure to noxious stimuli (eg, cigarette smoke [CS]). COPD is now the third leading cause of death in the United States (1). COPD is a spirometric diagnosis that encompasses multiple clinical phenotypes, including emphysema, chronic bronchitis, and small airway disease. Prevailing theories regarding the molecular pathogenesis of COPD include 1) chronic inflammation (2), 2) an imbalance of proteases/antiproteases (3), 3) oxidative stress (4), 4) alveolar cell apoptosis (5), 5) cellular senescence (6), and 6) dysregulated autophagy (7). However, these processes are not necessarily exclusive and can be intimately linked. For example, persistent DNA damage contributes to increased chronic inflammation and oxidative stress, cell apoptosis, or senescence in the lungs of smokers with COPD relative to nonsmokers and smokers without COPD (8). Hence, a unifying etiology linking these processes could potentially be targeted therapeutically. Among other unifying pathways, one of the most intriguing targets exists within a family of protein phosphatases. Reversible phosphorylation of proteins governs fundamental biological processes and is regulated by kinases and phosphatases. There are three main protein phosphorylation sites, namely, serine, threonine, and tyrosine in eukaryotic cells. Human genome sequencing has identified. 500 protein kinases and z100 protein tyrosine phosphatases (PTPs), but only z30 protein serine/threonine phosphatases. Indeed, dysregulation of several phosphatases, including protein phosphatase 2A (PP2A), the dual-specificity mitogen-activated protein kinase phosphatase 1, protein tyrosine phosphatase 1B (PTP1B), and phosphatase and tensin homolog deleted from chromosome 10 (PTEN), has been implicated in the regulation of diverse biological functions in COPD, including inflammation, proteolysis, and cell fate (9–11). PP2A belongs to the PSP family and is a highly conserved enzyme from yeast to humans. PP2A consists of three subunits—a scaffold A subunit, a catalytic subunit, and a variable regulatory B subunit—that determine its enzymatic behavior and subcellular localization (12). PP2A regulates diverse life functions, including cell-cycle progression; cell proliferation, motility, and lifespan; and transduction of intracellular signals. In this issue, Nath and colleagues (pp. 695–705) report that the activity, but not the cellular protein concentration of PP2A, is decreased in cultured primary human bronchial epithelial cells (HBEs) obtained from subjects with COPD compared with nonsmokers and normal smokers (13). The authors evaluated known endogenous inhibitors of PP2A and observed that both the mRNA and protein levels of cancerous inhibitor of PP2A (CIP2A) were selectively increased in cultured HBEs from patients with COPD relative to nonsmokers and normal smokers. Although short-term exposure to CS for 2 days did not cause the same effects on PP2A and CIP2A in cultured HBEs, an in vivo mouse study demonstrated that prolonged exposure to CS increased both the gene and protein levels of CIP2A after 8 weeks, accompanied by a decrease in PP2A activity after peaking at 4 weeks. CIP2A knockdown increased PP2A activity in cultured HBEs isolated from both nonsmokers and smokers with COPD, and modulated downstream effects on extracellular signal-regulated kinase (ERK) activation and matrix metalloproteinase 1 (MMP-1) and MMP-9 expression in cultured HBEs isolated from patients with COPD. Furthermore, erlotinib …