Phf14, a Novel Regulator of Mesenchyme Growth via Platelet-derived Growth Factor (PDGF) Receptor-α
Phf14, a Novel Regulator of Mesenchyme Growth via Platelet-derived Growth Factor (PDGF) Receptor-α
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DOI：
10.1074/jbc.m112.350074
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发表时间：
2012-08-10
影响因子：
4.8
通讯作者：
Era, Takumi
中科院分区：
文献类型：
--
作者：
Kitagawa, Michinori;Takebe, Atsushi;Era, Takumi
信号分子对间充质细胞生长的调控在维持组织功能方面起着重要作用。这一调控过程的中断导致间充质细胞的异常增殖，导致纤维化等致病事件。在目前的研究中，我们发现了一种新的核因子Phf14，它通过调节PDGFRα的表达来控制间充质细胞的增殖。Phf14基因缺失的小鼠出生后不久就死于呼吸衰竭。这些小鼠的肺组织学分析显示，间质增生，PDGFRα(+)间充质细胞数量增加。在Phf14缺失的间充质成纤维细胞中，PDGFRα的表达增加，导致增殖增加。我们证明了Phf14作为一个转录因子直接抑制PDGFRα的表达。基于这些结果，我们使用了一种针对PDGFRα的抗体成功地治疗了小鼠肺纤维化。这项研究表明，在正常和异常增殖的间质细胞中，Phf14作为PDGFRα表达的负调控因子，是肺纤维化新治疗的潜在靶点。
The regulation of mesenchymal cell growth by signaling molecules plays an important role in maintaining tissue functions. Aberrant mesenchymal cell proliferation caused by disruption of this regulatory process leads to pathogenetic events such as fibrosis. In the current study we have identified a novel nuclear factor, Phf14, which controls the proliferation of mesenchymal cells by regulating PDGFR alpha expression. Phf14-null mice died just after birth due to respiratory failure. Histological analyses of the lungs of these mice showed interstitial hyperplasia with an increased number of PDGFR alpha(+) mesenchymal cells. PDGFR alpha expression was elevated in Phf14-null mesenchymal fibroblasts, resulting in increased proliferation. We demonstrated that Phf14 acts as a transcription factor that directly represses PDGFR alpha expression. Based on these results, we used an antibody against PDGFR alpha to successfully treat mouse lung fibrosis. This study shows that Phf14 acts as a negative regulator of PDGFR alpha expression in mesenchymal cells undergoing normal and abnormal proliferation, and is a potential target for new treatments of lung fibrosis.