Homeodomain-interacting protein kinase2 in human idiopathic pulmonary fibrosis
Homeodomain-interacting protein kinase2 in human idiopathic pulmonary fibrosis
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DOI：
10.1002/jcp.24129
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发表时间：
2013-01-01
影响因子：
5.6
通讯作者：
Mariotta, Salvatore
中科院分区：
文献类型：
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作者：
Ricci, Alberto;Cherubini, Emanuela;Mariotta, Salvatore
同源结构域相互作用蛋白激酶2 （Hipk2）在细胞对基因毒性药物的反应中是一个新兴的参与者，它有助于细胞在细胞周期阻滞或细胞凋亡之间做出决定。HIPK2作为越来越多的转录因子的共同调节剂，调节许多不同的基本细胞过程，如凋亡、增殖、DNA损伤反应、分化。特发性肺纤维化（IPF）的特点是由于成纤维细胞增殖、细胞外基质沉积和肺功能损害导致肺解剖紊乱。尽管炎症的作用仍有争议，但人们的注意力已经集中在肺细胞的功能上，如成纤维细胞的表型和活性。本研究的目的是利用半定量RT-PCR、Western blots和免疫组织化学分析人肺成纤维细胞中HIPK2位点7q32.34杂合性缺失（LOH）和15例IPF样本和4例IPF活检分离成纤维细胞培养物中HIPK2的表达。在IPF成纤维细胞中，内部D7S6440微卫星的LOH频率为46%，外部D7S2468微卫星的LOH频率为26.6%。此外，我们在IPF患者的成纤维细胞中证实了HIPK2蛋白的低表达。IPF来源细胞中HIPK2表达的恢复诱导顺铂治疗后化疗耐药的显著降低。获得的结果允许我们假设HIPK2功能障碍可能在成纤维细胞行为和IPF发病机制中发挥作用。HIPK2可能被认为是抗纤维化治疗的一个新的潜在靶点。j .细胞。物理学报，28(2):532 - 541,2013。(c) 2012 Wiley期刊有限公司
Homeodomain-interacting protein kinase 2 (Hipk2) is an emerging player in cell response to genotoxic agents that contributes to the cell's decision between cell cycle arrest or apoptosis. HIPK2 acts as co-regulator of an increasing number of transcription factors and modulates many different basic cellular processes such as apoptosis, proliferation, DNA damage response, differentiation. Idiopathic pulmonary fibrosis (IPF) is characterized by an anatomical disarrangement of the lung due to fibroblast proliferation, extracellular matrix deposition and lung function impairment. Although the role of inflammation is still debated, attention has been focused on lung cell functions as fibroblast phenotype and activity. Aim of the present study was to analyze the loss of heterozygosity (LOH) at HIPK2 locus 7q32.34 in human lung fibroblasts and the HIPK2 expression in 15 IPF samples and in four primary fibroblast cell cultures isolated from IPF biopsies using semi-quantitative RT-PCR, Western blots and immunohistochemistry. We demonstrated a frequency of LOH in IPF fibroblasts of 46% for the internal D7S6440 microsatellite and 26.6% for the external D7S2468 microsatellite. Furthermore, we demonstrated low HIPK2 protein expression in those fibroblasts from IPF patients that present the HIPK2 LOH. The restoration of HIPK2 expression in IPF derived cells induced a significant reduction of chemoresistance after treatment with cisplatin. The results obtained allow us to hypothesize that HIPK2 dysfunction may play a role in fibroblasts behavior and in IPF pathogenesis. HIPK2 may be considered as a novel potential target for anti-fibrosis therapy. J. Cell. Physiol. 228: 235241, 2013. (c) 2012 Wiley Periodicals, Inc.