Cao Y, Liu X, Zhang W, Deng X, Zhang H, Liu Y, Chen L, Thompson E A, Townsend C M, Ko T C
Department of Surgery, University of Texas Health Science Center, Houston, TX 77030, USA.
Oncogene. 2009 Feb 26;28(8):1089-98. doi: 10.1038/onc.2008.456. Epub 2009 Jan 12.
Transforming growth factor-beta (TGF-beta) regulates epithelial tissue homeostasis by activating processes that control cell cycle arrest, differentiation and apoptosis. Disruption of the TGF-beta signaling pathway often occurs in colorectal cancers. Earlier, we have shown that TGF-beta induces apoptosis through the transcription factor Smad3. Affymetrix oligonucleotide microarrays were used to identify TGF-beta/Smad3 target genes that regulate apoptosis in rat intestinal epithelial cells (RIE-1). We found that TGF-beta repressed the expression of the inhibitor of differentiation (Id) gene family. Knockdown of Id1 and Id2 gene expression induced apoptosis in RIE-1 cells, whereas overexpression of Id2 attenuated TGF-beta-induced apoptosis. TranSignal Protein/DNA arrays were used to identify the hypoxia-inducing factor-1 (HIF-1) as a downstream target of TGF-beta. HIF-1 is a basic helix-loop-helix protein, and overexpression of Id2 blocked HIF-1 activation by TGF-beta. Furthermore, knockdown of HIF-1 blocked TGF-beta-induced apoptosis. Thus, we have identified HIF-1 as a novel mediator downstream of Id2 in the pathway of TGF-beta-induced apoptosis.
转化生长因子-β（TGF-β）通过激活控制细胞周期停滞、分化和凋亡的过程来调节上皮组织稳态。TGF-β信号通路的破坏在结直肠癌中经常发生。此前，我们已经表明TGF-β通过转录因子Smad3诱导凋亡。利用Affymetrix寡核苷酸微阵列来鉴定调节大鼠肠上皮细胞（RIE-1）凋亡的TGF-β/Smad3靶基因。我们发现TGF-β抑制分化抑制因子（Id）基因家族的表达。敲低Id1和Id2基因表达可诱导RIE-1细胞凋亡，而Id2的过表达则减弱TGF-β诱导的凋亡。利用TranSignal蛋白质/DNA阵列来鉴定缺氧诱导因子-1（HIF-1）作为TGF-β的下游靶点。HIF-1是一种碱性螺旋-环-螺旋蛋白，Id2的过表达可阻断TGF-β对HIF-1的激活。此外，敲低HIF-1可阻断TGF-β诱导的凋亡。因此，我们已经确定HIF-1是TGF-β诱导凋亡途径中Id2下游的一种新型介质。
