Transforming growth factor-alpha-induced transcriptional activation of the vascular permeability factor (VPF/VEGF) gene requires AP-2-dependent DNA binding and transactivation
Transforming growth factor-alpha-induced transcriptional activation of the vascular permeability factor (VPF/VEGF) gene requires AP-2-dependent DNA binding and transactivation
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DOI：
10.1093/emboj/16.4.750
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发表时间：
1997-02-17
期刊：
影响因子：
11.4
通讯作者：
Caughman, SW
中科院分区：
文献类型：
--
作者：
Gille, J;Swerlick, RA;Caughman, SW
内皮细胞特异性促分裂原血管通透性因子/血管内皮生长因子（VPF/ VEGF）代表皮肤血管生成的中心调节因子。最近已经报道了在银屑病皮肤和愈合伤口中增加的VPF/VEGF表达，在这两种情况中转化生长因子-α（TGF α）及其配体表皮生长因子受体显著上调。由于TGF α强烈诱导角质形成细胞中的VPF/VEGF合成，因此TGF α介导的VPF/VEGF表达可能在皮肤生物学中血管通透性增加和过度增殖的起始和维持中起重要作用。本研究的目的是确定负责TGF α诱导的VPF/VEGF基因转录激活的分子机制。我们已经鉴定了VPF/VEGF启动子的-88 bp和-65 bp之间的富含GC的TGF α响应区，其对于组成型和TGF α诱导的转录激活是必需的。该区域组成性地结合Sp1依赖性蛋白复合物和不同于Sp1蛋白的另外的TGF α诱导性蛋白复合物。在supershift EMSA研究中，AP-2和Egr-1转录因子均被检测为TGF α诱导蛋白复合物的组分。在共转染研究中，AP-2而不是Egr-1表达载体激活VPF/ VEGF转录，因此表明AP-2蛋白在TGF α诱导的VPF/VEGF基因表达中具有重要的功能，通过阐明对皮肤中血管生成过程至关重要的调控机制，这些研究可能形成新的治疗策略的基础，以调节皮肤炎症和伤口愈合中的VPF/VEGF表达。
The endothelial cell-specific mitogen vascular permeability factor/vascular endothelial growth factor (VPF/ VEGF) represents a central regulator of cutaneous angiogenesis, Increased VPF/VEGF expression has recently been reported in psoriatic skin and healing wounds, both conditions in which transforming growth factor-alpha (TGF alpha) and its ligand, the epidermal growth factor receptor, are markedly up-regulated. Since TGF alpha strongly induces VPF/VEGF synthesis in keratinocytes, TGF alpha-mediated VPF/VEGF expression is likely to play a significant role in the initiation and maintenance of increased vascular hyperpermeability and hyperproliferation in skin biology. The objectives of the present studies were to determine the molecular mechanisms responsible for TGF alpha-induced transcriptional activation of the VPF/VEGF gene, We have identified a GC-rich TGF alpha-responsive region between -88 bp and -65 bp of the VPF/VEGF promoter that is necessary for constitutive and TGF alpha-inducible transcriptional activation, In electrophoretic mobility shift assays, this region binds Spl-dependent protein complexes constitutively and an additional TGF alpha-inducible protein complex that is distinct from Sp1 protein. Both AP-2 and Egr-1 transcription factors were detected as components of the TGF alpha-inducible protein complex in supershift EMSA studies, In co-transfection studies, an AP-2 but not an Egr-1 expression vector activated VPF/ VEGF transcription, thus indicating that AP-2 protein is functionally important in TGF alpha-induced VPF/VEGF gene expression, By clarifying regulatory mechanisms that are critical for angiogenic processes in the skin, these studies may form the basis for new therapeutic strategies to modulate VPF/VEGF expression in cutaneous inflammation and wound healing.