Liu Zhipei, Shen Jia, Pu Kui, Katus Hugo A, Plöger Frank, Tiefenbacher Christiane P, Chen Xiaobo, Braun Thomas
Department of Cardiac Development and Remodeling, Max-Planck Institute for Heart and Lung Research, Parkstr. 1, 61231 Bad Nauheim, Germany.
Biochim Biophys Acta. 2009 Dec;1793(12):1819-27. doi: 10.1016/j.bbamcr.2009.09.012. Epub 2009 Sep 24.
GDF5 and BMP2, members of the TGF-beta superfamily of growth factors, are known to regulate apoptosis in different cell types either positively or negatively. We wanted to investigate the effects of GDF5 and BMP2 on vascular smooth muscle cells and mouse embryonic fibroblasts and disclose the mechanism by which GDF5 and BMP2 might exert anti-apoptotic effects. The effect of GDF5 and BMP2 on proliferation and/or programmed cells death was assessed in isolated human vascular smooth muscle cells and mouse embryonic fibroblasts. We demonstrate that GDF5 and BMP2 prevent apoptosis induced by serum starvation in mouse embryonic fibroblasts but not in smooth muscle cells via the BMP receptor 2 (BMPR2), which is often mutated in hereditary cases of primary pulmonary hypertension. GDF5 and BMP2 stimulate the interaction of BMPR-2 with XIAP thereby reducing the ubiquitination of XIAP, which results in enhanced protein stability. The increased concentration of XIAP counteracts apoptosis by binding and inactivating activated caspases. We conclude that the inhibition of apoptosis in mouse embryonic fibroblasts by BMP2 and GDF5 does not depend on more complex signal transduction pathways such as smad and MAPK signaling but on direct stabilization of XIAP by BMPR2.
生长分化因子5（GDF5）和骨形态发生蛋白2（BMP2）是转化生长因子-β（TGF-β）超家族生长因子的成员，已知它们可正向或负向调节不同细胞类型中的细胞凋亡。我们想研究GDF5和BMP2对血管平滑肌细胞和小鼠胚胎成纤维细胞的影响，并揭示GDF5和BMP2可能发挥抗凋亡作用的机制。在分离的人血管平滑肌细胞和小鼠胚胎成纤维细胞中评估了GDF5和BMP2对增殖和/或程序性细胞死亡的影响。我们证明，GDF5和BMP2可通过骨形态发生蛋白受体2（BMPR2）防止血清饥饿诱导的小鼠胚胎成纤维细胞凋亡，但不能防止平滑肌细胞凋亡，BMPR2在原发性肺动脉高压的遗传病例中常发生突变。GDF5和BMP2刺激BMPR-2与X连锁凋亡抑制蛋白（XIAP）的相互作用，从而减少XIAP的泛素化，这导致蛋白质稳定性增强。XIAP浓度的增加通过结合并使活化的半胱天冬酶失活来抵消细胞凋亡。我们得出结论，BMP2和GDF5对小鼠胚胎成纤维细胞凋亡的抑制不依赖于更复杂的信号转导途径，如smad和丝裂原活化蛋白激酶（MAPK）信号传导，而是依赖于BMPR2对XIAP的直接稳定作用。
