Transforming Growth Factor-β-induced Apoptosis Is Mediated by Smad-dependent Expression of GADD45b through p38 Activation

Jiyun Yoo, Mayshan Ghiassi, Ludmila Jirmanova, Arthur G. Balliet, Barbara Hoffman, Albert J. Fornace, Dan A. Liebermann, Erwin P. Böttinger, Anita B. Roberts

Research output: Contribution to journalArticlepeer-review

221 Scopus citations

Abstract

Transforming growth factor-β (TGF-β)-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-β-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 immediate-early response gene for TGF-β and that the proximal Gadd45b promoter is activated by TGF-β 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-β-dependent p38 activation and apoptosis. Furthermore, we also show that TGF-β 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-β-induced apoptosis by acting upstream of p38 activation.

Original languageEnglish
Pages (from-to)43001-43007
Number of pages7
JournalJournal of Biological Chemistry
Volume278
Issue number44
DOIs
StatePublished - 31 Oct 2003
Externally publishedYes

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