Transforming Growth Factor-beta Directly Induces p53-up-regulated Modulator of Apoptosis (PUMA) during the Rapid Induction of Apoptosis in Myc-driven B-cell Lymphomas
- Author(s)
- Spender, LC; Carter, MJ; O'Brien, DI; Clark, LJ; Yu, J; Michalak, EM; Happo, L; Cragg, MS; Inman, GJ;
- Details
- Publication Year 2013-02-15,Volume 288,Issue #7,Page 5198-5209
- Journal Title
- JOURNAL OF BIOLOGICAL CHEMISTRY
- Publication Type
- Journal Article
- Abstract
- c-Myc transformed human Burkitt's lymphoma (BL) cells are highly sensitive to TGF-beta-induced apoptosis. Previously we demonstrated that TGF-beta-mediated cell death in BL cells is regulated via the mitochondrial intrinsic apoptosis pathway, which is dependent on the activation of BAX and/or BAK. TGF-beta directly induces transcription of the BH3-only protein BIK and represses expression of the pro-survival factor BCL-X-L but has no effect on the direct BAX/BAK "activators" BIM or BID (tBID). Here we show that TGF-beta induces the BH3-only activator PUMA to aid induction of the intrinsic cell death pathway. TGF-beta also induced PUMA in normal germinal center CD77-positive centroblasts isolated from human tonsil tissue. PUMA was a direct TGF-beta target gene in B-cells, and we identify a putative Smad-binding region within the human PUMA promoter that recruits Smad3 and Smad4 in cells in response to TGF-beta signaling. Constitutive activity of the isolated Smadbinding region in luciferase reporter assays was dependent on Smad consensus sequences and was partially dependent on endogenous TGF-beta signaling and Smad4. Knockdown ofPUMA in BL cells using lentiviral shRNA resulted in slower kinetics of the TGF-beta -mediated apoptotic response. Analysis of E mu-Myc cell lines demonstrated that c-myc-driven murine lymphomas are also sensitive to TGF-beta-mediated apoptosis. Moreover, Puma(-/-) E mu-Myc lines demonstrated significantly delayed kinetics of the apoptotic response when compared with wild type lymphomas. TGF-beta therefore induces a polygenic response in Myc-driven lymphomas involving transcription of PUMA, which is necessary for the rapid induction of cell death.
- Publisher
- AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
- Keywords
- BH3-ONLY PROTEIN PUMA; BCL-2 FAMILY-MEMBERS; UP-REGULATION; CANCER CELLS; GENE-EXPRESSION; BAX ACTIVATION; X-L; RESPONSES; BH3; P53
- Research Division(s)
- Stem Cells And Cancer
- Link To PubMed Central Version
- http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3576124/
- Publisher's Version
- https://doi.org/10.1074/jbc.M112.410274
- Terms of Use/Rights Notice
- Copyright © 2013 by American Society for Biochemistry and Molecular Biology
Creation Date: 2013-02-15 12:00:00