Yoo Jiyun, Ghiassi Mayshan, Jirmanova Ludmila, Balliet Arthur G, Hoffman Barbara, Fornace Albert J, Liebermann Dan A, Bottinger Erwin P, Roberts Anita B
Laboratory of Cell Regulation and Carcinogenesis, National Instituts of Health, Bethesda, MD 20892-5055, USA.
J Biol Chem. 2003 Oct 31;278(44):43001-7. doi: 10.1074/jbc.M307869200. Epub 2003 Aug 21.
Transforming growth factor-beta (TGF-beta)-dependent apoptosis is important in the elimination of damaged or abnormal cells from normal tissues in vivo. In this report, we identify GADD45b as an effector of TGF-beta-induced apoptosis. GADD45b has been shown to be a positive mediator of apoptosis induced by certain cytokines and oncogenes. We show that Gadd45b is an immediateearly response gene for TGF-beta and that the proximal Gadd45b promoter is activated by TGF-beta through the action of Smad2, Smad3, and Smad4. We show that ectopic expression of GADD45b in AML12 murine hepatocytes is sufficient to activate p38 and to trigger apoptotic cell death, whereas antisense inhibition of Gadd45b expression blocks TGF-beta-dependent p38 activation and apoptosis. Furthermore, we also show that TGF-beta can activate p38 and induce apoptosis in mouse primary hepatocytes from wild-type mice, but not from Gadd45b-/- mice. All of these findings suggest that GADD45b participates in TGF-beta-induced apoptosis by acting upstream of p38 activation.
转化生长因子-β（TGF-β）依赖性凋亡在体内正常组织清除受损或异常细胞过程中起重要作用。在本报告中，我们确定生长停滞和DNA损伤诱导蛋白45b（GADD45b）是TGF-β诱导凋亡的效应分子。GADD45b已被证明是某些细胞因子和癌基因诱导凋亡的正向介质。我们发现Gadd45b是TGF-β的即时早期反应基因，并且近端Gadd45b启动子通过Smad2、Smad3和Smad4的作用被TGF-β激活。我们表明，在AML12小鼠肝细胞中异位表达GADD45b足以激活p38并触发凋亡性细胞死亡，而反义抑制Gadd45b表达则阻断TGF-β依赖性p38激活和凋亡。此外，我们还表明，TGF-β可激活野生型小鼠原代肝细胞中的p38并诱导凋亡，但不能激活Gadd45b基因敲除小鼠的原代肝细胞。所有这些发现表明，GADD45b通过在p38激活的上游发挥作用参与TGF-β诱导的凋亡。
