Han Xiaobin, Xiao Zhousheng, Quarles L Darryl
From the Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163.
From the Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163
J Biol Chem. 2015 Apr 17;290(16):10447-59. doi: 10.1074/jbc.M114.609230. Epub 2015 Mar 9.
Fibroblastic growth factor receptor 1 (FGFR1) signaling pathways are implicated in the regulation of FGF-23 gene transcription, but the molecular pathways remain poorly defined. We used low molecular weight (LMW, 18 kDa) FGF-2 and high molecular weight (HMW) FGF-2 isoforms, which, respectively, activate cell surface FGF receptors and intranuclear FGFR1, to determine the roles of membrane FGFRs and integrative nuclear FGFR1 signaling (INFS) in the regulation of FGF-23 gene transcription in osteoblasts. We found that LMW-FGF-2 induced NFAT and Ets1 binding to conserved cis-elements in the proximal FGF-23 promoter and stimulated FGF-23 promoter activity through PLCγ/calcineurin/NFAT and MAPK pathways in SaOS-2 and MC3T3-E1 osteoblasts. In contrast, HMW-FGF-2 stimulated FGF-23 promoter activity in osteoblasts through a cAMP-dependent binding of FGFR1 and cAMP-response element-binding protein (CREB) to a conserved cAMP response element (CRE) contiguous with the NFAT binding site in the FGF-23 promoter. Mutagenesis of the NFAT and CRE binding sites, respectively, inhibited the effects of LMW-FGF-2 and HMW-FGF-23 to stimulate FGF-23 promoter activity. FGF-2 activation of both membrane FGFRs and INFS-dependent FGFR1 pathways may provide a means to integrate systemic and local regulation of FGF-23 transcription under diverse physiological and pathological conditions.
成纤维细胞生长因子受体1（FGFR1）信号通路与FGF - 23基因转录的调控有关，但分子机制仍不清楚。我们使用低分子量（LMW，18 kDa）FGF - 2和高分子量（HMW）FGF - 2亚型，它们分别激活细胞表面FGF受体和核内FGFR1，以确定膜FGFRs和整合核FGFR1信号（INFS）在成骨细胞中FGF - 23基因转录调控中的作用。我们发现，LMW - FGF - 2诱导NFAT和Ets1与FGF - 23近端启动子中的保守顺式元件结合，并通过PLCγ/钙调神经磷酸酶/NFAT和MAPK途径刺激SaOS - 2和MC3T3 - E1成骨细胞中的FGF - 23启动子活性。相比之下，HMW - FGF - 2通过FGFR1和环磷酸腺苷反应元件结合蛋白（CREB）与FGF - 23启动子中与NFAT结合位点相邻的保守环磷酸腺苷反应元件（CRE）的环磷酸腺苷依赖性结合，刺激成骨细胞中的FGF - 23启动子活性。分别对NFAT和CRE结合位点进行诱变，可抑制LMW - FGF - 2和HMW - FGF - 23刺激FGF - 23启动子活性的作用。FGF - 2对膜FGFRs和INFS依赖性FGFR1途径的激活可能为在不同生理和病理条件下整合FGF - 23转录的全身和局部调控提供一种手段。
