GDF5 and BMP2 inhibit apoptosis via activation of BMPR2 and subsequent stabilization of XIAP.
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.
Department of Cardiac Development and Remodeling, Max-Planck Institute for Heart and Lung Research, Parkstr. 1, 61231 Bad Nauheim, Germany.
Zhipei
Z
Liu
Jia
J
Shen
Kui
K
Pu
Hugo A
HA
Katus
Frank
F
Plöger
Christiane P
CP
Tiefenbacher
Xiaobo
X
Chen
Thomas
T
Braun
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics / Q000378:metabolism*; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D055428:Growth Differentiation Factor 5 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D009154:Mutation; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism; D055550:Protein Stability; D054875:Ubiquitination / Q000235:genetics; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics / Q000378:metabolism*
C525718:BMP2 protein, human; C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; C525893:GDF5 protein, human; C525894:Gdf5 protein, mouse; D055428:Growth Differentiation Factor 5; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C498218:BMPR2 protein, human; C498219:Bmpr2 protein, mouse; D052006:Bone Morphogenetic Protein Receptors, Type II