Transforming growth factor-beta-induced apoptosis is mediated by Smad-dependent expression of GADD45b through p38 activation.
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.
Yoo
Jiyun
J
Laboratory of Cell Regulation and Carcinogenesis, National Instituts of Health, Bethesda, MD 20892-5055, USA.
Ghiassi
Mayshan
M
Jirmanova
Ludmila
L
Balliet
Arthur G
AG
Hoffman
Barbara
B
Fornace
Albert J
AJ
Liebermann
Dan A
DA
Bottinger
Erwin P
EP
Roberts
Anita B
AB
D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism*; D017209:Apoptosis; D015152:Blotting, Northern; D002460:Cell Line; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004789:Enzyme Activation; D022781:Hepatocytes / Q000378:metabolism; D008024:Ligands; D020935:MAP Kinase Signaling System; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D041681:NIH 3T3 Cells; D016376:Oligonucleotides, Antisense / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases; D000097642:GADD45 Proteins
D000943:Antigens, Differentiation; D004268:DNA-Binding Proteins; D008024:Ligands; D020928:Mitogen-Activated Protein Kinases; D016376:Oligonucleotides, Antisense; D016212:Transforming Growth Factor beta; D048051:p38 Mitogen-Activated Protein Kinases; C490125:Gadd45b protein, mouse; D000097642:GADD45 Proteins