Growth factors, growth factor response elements, and the cardiac phenotype.
Growth factors, growth factor response elements, and the cardiac phenotype.
复制标题
生长因子、生长因子反应元件和心脏表型。
DOI：
10.1007/978-3-642-72477-0_4
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发表时间：
1992
影响因子：
9.5
通讯作者：
Parker,TG
中科院分区：
文献类型：
--
作者：
Schneider,MD;McLellan,WR;Black,FM;Parker,TG
成纤维细胞生长因子（FGF）和β-1型转化生长因子（TGFβ1）是一种多效调节肽，在心肌中以精确的发育和空间程序表达，在成人心脏中受缺血或血流动力学负荷的上调。主动脉结扎后营养因子的积累支持了自分泌或旁分泌途径可能起介导作用的假设，部分是机械负荷的后果。我们的实验室已经证明心肌细胞是肽类生长因子作用的靶细胞，更具体地说，碱性成纤维细胞生长因子（bFGF）和转化生长因子β 1对心脏表型的调节与胎儿心脏基因（包括骨骼α-肌动蛋白（SkA）、β-肌球蛋白重链和心房利钠因子）的诱导非常相似，这些基因是压力超负荷性肥大的特征。出乎意料的是，尽管碱性成纤维细胞生长因子对其他五个心脏基因的影响，酸性成纤维细胞生长因子（aFGF）被发现抑制，而不是刺激，在新生儿心肌细胞中的SkA转录。异源SkA启动子的近端200个核苷酸足以用于基础组织特异性转录、bFGF诱导和aFGF抑制。因此，肽生长因子的正调控和负调控都可以定位于近端SkA启动子。完整的启动子活性需要三个CC[A/T] 6 GG基序中的每一个，类似于用于激活c-fos原癌基因的血清反应元件（SRE），如先前在骨骼肌背景中的SkA转录所示。最近的SRE，SRE 1，是足够的，在其他SkA启动子序列的情况下，在心肌细胞（相对于心脏成纤维细胞）的有效组织特异性表达，并刺激bFGF的全长启动子和内源性基因的相同程度。尽管aFGF能够抑制SkA启动子，但对SRE 1没有显著影响。两种FGF均上调经典fos SRE，达到相当的程度。因此，SRE 1可以区分由bFGF和aFGF在心肌细胞中产生的信号。在心肌细胞提取物中，两种主要蛋白质接触SRE 1：血清反应因子（SRF）和第二种蛋白质F-ACT-1。因此，血清反应因子和F-ACT-1是心肌细胞中SkA基因基础转录和bFGF诱导SkA以及潜在的其他营养信号的候选反式作用因子。
Fibroblast growth factors (FGF) and typeβ-1 transforming growth factor (TGFβ1) are pleiotropic regulatory peptides which are expressed in myocardium in a precise developmental and spatial program and are up-regulated, in the adult heart, by ischemia or a hemodynamic burden. The accumulation of trophic factors after aortic banding supports the hypothesis that autocrine or paracrine pathways might function to mediate, in part, the consequences of mechanical load. Our laboratory has demonstrated that cardiac muscle cells are targets for the action of peptide growth factors and, more specifically, that modulation of the cardiac phenotype by basic FGF (bFGF) and TGFβ1strongly resembles the induction of fetal cardiac genes — including skeletal α-actin (SkA),β-myosin heavy chain, and atrial natriuretic factor — which are characteristic of pressure-overload hypertrophy. Unexpectedly, and despite effects like those of bFGF on five other cardiac genes, acidic FGF (aFGF) was found to repress, rather than stimulate, SkA transcription in neonatal cardiac muscle cells. The proximal 200 nucleotides of a heterologous SkA promoter were sufficient for basal tissue-specific transcription, for induction by bFGF, and for inhibition by aFGF. Thus, both positive and negative regulation by peptide growth factors can be localized to the proximal SkA promoter. Full promoter activity required each of three CC[A/T]6GG motifs similar to the serum response element (SRE) for activation of the c-fos proto-oncogene, as previously shown for SkA transcription in a skeletal muscle background. The most proximal SRE, SRE1, was sufficient in the absence of other SkA promoter sequences for efficient tissue-specific expression in cardiac myocytes (versus cardiac fibroblasts), and was stimulated by bFGF to the same extent as the full-length promoter and endogeneous gene. Despite its ability to repress the SkA promoter, aFGF had no significant effect on SRE1. Both FGFs up-regulated the canonical fos SRE, to a comparable degree. Thus, SRE1 can discriminate between signals generated in cardiac myocytes by bFGF and aFGF. In cardiac myocyte extracts, two predominant proteins contact SRE1: serum response factor (SRF) and a second protein, F-ACT-1. Thus, serum response factor and F-ACT-1 are candidate trans-acting factors for basal transcription of the SkA gene in cardiac muscle cells and for induction of SkA by bFGF and, potentially, other trophic signals.