Global expression profiling of fibroblast responses to transforming growth factor-β1 reveals the induction of inhibitor of differentiation-1 and provides evidence of smooth muscle cell phenotypic switching
Global expression profiling of fibroblast responses to transforming growth factor-β1 reveals the induction of inhibitor of differentiation-1 and provides evidence of smooth muscle cell phenotypic switching
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DOI：
10.1016/s0002-9440(10)63847-3
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发表时间：
2003-02-01
影响因子：
6
通讯作者：
Heller, RA
中科院分区：
文献类型：
--
作者：
Chambers, RC;Leoni, P;Heller, RA
转化生长因子-β（1）（TGF-β（1））通过促进成纤维细胞向肌成纤维细胞的转化，在促进细胞外基质蛋白沉积中起核心作用。为了获得有关转录程序的新见解，我们使用寡核苷酸微阵列分析了人胎儿肺成纤维细胞对TGF-β（1）长达24小时的反应的整体基因表达。在这份报告中，我们提供了在两个时间点上调至少两倍的146个基因的数据。这些基因分为几个主要功能类别，包括参与细胞骨架重组（n = 30）、基质形成（n = 25）、代谢和蛋白质生物合成（n = 27）、细胞信号传导（n = 21）、增殖和存活（n = 13）、基因转录（n = 9）和不确定功能（n = 21）的基因。对于这些基因中的80个，这是第一次报告它们是TGF-β（1）反应性的。早期诱导的两个成员的分化抑制剂（ID）家族的转录调节因子，ID 1和11133，其次是上调的一些基因，通常表达的高度分化的平滑肌细胞，包括平滑肌肌球蛋白重链，碱性钙蛋白，和smoothelin。这些发现在原代成人肺成纤维细胞的蛋白质水平得到证实。ID 1进一步表现为典型的立即早期基因，并且与ID 3不同，在蛋白质水平上表达和诱导。免疫组化分析表明，ID 1在实验诱导的肺纤维化中的纤维化灶内的（肌）成纤维细胞中高度表达。ID 1作为驱动细胞谱系定型和分化的碱性螺旋-环-螺旋转录因子的显性负性拮抗剂。这些发现对于我们理解成纤维细胞在发育、肿瘤发生、组织修复和纤维化过程中对TGF-β 1的转录编程具有重要意义。
Transforming growth factor-beta(1) (TGF-beta(1)) plays a central role in promoting extracellular matrix protein deposition by promoting the transformation of fibroblasts to myofibroblasts. To gain new insights into the transcriptional programs involved, we profiled human fetal lung fibroblast global gene expression in response to TGF-beta(1) up to 24 hours using oligonucleotide microarrays. In this report, we present data for 146 genes that were up-regulated at least twofold at two time points. These genes group into several major functional categories, including genes involved in cytoskeletal reorganization (n = 30), matrix formation (n = 25), metabolism and protein biosynthesis (n = 27), cell signaling (n = 21), proliferation and survival (n = 13), gene transcription (n = 9), and of uncertain function (n = 21). For 80 of these genes, this is the first report that they are TGF-beta(1)-responsive. The early induction of two members of the inhibitor of differentiation (ID) family of transcriptional regulators, ID1 and 11133, was followed by the up-regulation of a number of genes that are usually expressed by highly differentiated smooth muscle cells, including smooth muscle myosin heavy chain, basic calponin, and smoothelin. These findings were confirmed at the protein level for primary adult lung fibroblasts. ID1 further behaved like a typical immediate-early gene and, unlike ID3, was expressed and induced at the protein level. Immunohistochemical analysis showed that ID1 was highly expressed by (myo)-fibroblasts within fibrotic foci in experimentally induced pulmonary fibrosis. ID1 acts as a dominant-negative antagonist of basic helix-loop-helix transcription factors that drive cell lineage commitment and differentiation. These findings have important implications for our understanding of fibroblast transcriptional programming in response to TGF-beta(1) during development, oncogenesis, tissue repair, and fibrosis.