NDLI: Runx1 Is a Co-activator with FOXO3 to Mediate Transforming Growth Factor β (TGFβ)-induced Bim Transcription in Hepatic Cells*

Content Provider	PubMed Central
Author	Wildey, Gary M. Howe, Philip H.
Abstract	Transforming growth factor β (TGFβ) regulates essential cellular functions such as cellular proliferation, differentiation, and apo pto sis. The Bcl-2 family of proteins has been implicated as mediators of TGFβ-induced apo pto sis. We demonstrated previously that TGFβ induces the expression of Bim (Bcl-2-interacting mediator of cell death), a member of the BH3-only family of pro-apo pto tic Bcl-2 proteins, to induce cell death in B-lymphocytes. Here, we investigated the mechanism of TGFβ-mediated Bim expression in two hepatocyte cell lines that undergo apo pto sis with TGFβ, AML-12 and Hep3B. We show that TGFβ induces Bim protein and mRNA levels, and its expression is sufficient to induce cell death. Gene array results revealed that Runx1, a member of the Runx family of transcription factors, was induced by TGFβ, and this induction was confirmed at the mRNA and protein levels. Interestingly, TGFβ specifically induced the expression of Runx1 protein from an internal ribosome entry site (IRES)-dependent, cap-independent, mRNA transcript, and its overexpression was sufficient to induce hepatocyte apo pto sis. Deletion and mutation analyses of the murine Bim promoter identified a putative forkhead binding element, at position −174 to −168 from the transcription start site, as the mediator of Runx1 induction. Co-immunoprecipitation, electrophoretic mobility shift assays, and chromatin immunoprecipitation assays demonstrated that Runx1 does not bind directly to the identified forkhead binding element but rather binds the transcriptional regulator FOXO3, which occupies this site. Finally, small interfering RNA knockdown of Runx1 or FOXO3 decreased TGFβ-induced Bim expression. Our results support a mechanism in which TGFβ stimulates Bim transcription by up-regulating Runx1 expression, which binds FOXO3, and the two cooperate in the transcriptional induction of Bim.
Related Links	http://dx.doi.org/10.1074/jbc.M109.027201
Starting Page	20227
File Format	PDF
ISSN	1083351X
e-ISSN	1083351X
Journal	The Journal of Biological Chemistry
Issue Number	30
Volume Number	284
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2009-07-24
Access Restriction	Open
Rights Holder	American Society for Biochemistry and Molecular Biology
Subject Keyword	Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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Runx1 Is a Co-activator with FOXO3 to Mediate Transforming Growth Factor β (TGFβ)-induced Bim Transcription in Hepatic Cells

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Runx1 Is a Co-activator with FOXO3 to Mediate Transforming Growth Factor β (TGFβ)-induced Bim Transcription in Hepatic Cells*

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Runx1 Is a Co-activator with FOXO3 to Mediate Transforming Growth Factor β (TGFβ)-induced Bim Transcription in Hepatic Cells

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