Transforming growth factor ? (TGF?) and the pro-apoptotic Bcl-2 family member Bim, Bcl-2 interacting mediator of cell death, play critical roles in the development and homeostasis of the immune system. Targeted disruption, in mice, of either the TGF? or Bim gene results in an accumulation of lymphoid and myeloid cells, a perturbation of T cell development, and ultimately, the animals succumb to systemic autoimmune diseases. These phenotypes underscore the essential roles of TGF? and Bim in T cell development and in the negative selection or clonal deletion of autoreactive B cells that is critical for normal B lymphocyte development and the maintenance of self tolerance. We have investigated the molecular mechanisms by which TGF? aids in maintenance of self tolerance through its induction of apoptosis in B lymphocytes. We have demonstrated that TGF?-induced cell death is mediated through its induction of Bim, providing the first evidence that Bim expression levels are directly influenced by a pro-apoptotic cytokine rather than being upregulated in response to pro-survival factor (i.e. IL-3, IL-7) withdrawal or stress induction. TGF? induction of Bim was shown to be Smad3-dependent and abrogated by activation of survival pathways. Our preliminary data has identified two potential modulators of TGF?-mediated Bim induction, the immediate early gene MAPK phosphatase 2 (MKP2) and the transcriptional co-regulator Runx1/AML1. Herein, we wish to test the hypotheses that TGF? induces MKP2 to rapidly target existing Bim levels by inactivation of the MAP kinase Erk, resulting in dephosphorylation and escape of Bim from ubiquitin-mediated proteasomal decay. Additionally, and for sustained modulation of Bim, we postulate that TGF? induces the transcriptional co-regulator Runx1/AML1, which interacts with Fox03 to transactivate Bim mRNA expression. Interestingly, Runx1 induction by TGF? is mediated through a non-transcriptional mechanism involving translational regulation through an internal ribosome entry (IRES) mechanism. Thus, TGF? not only induces de novo Bim mRNA transcription but also assures that the pathway that results in degradation of its product is inhibited, resulting in Bim protein accumulation and ultimately mitochondrial-mediated cell death.

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The pro-apoptotic protein Bim is a key regulator of cell death in B lymphocytes and its deregulated expression underlies many hematological malignancies. The successful pursuit of these aims will lead to a better understanding of the regulation of Bim at both the transcriptional and post-translational mechanisms. Our research may identify factors and important regulatory pathways that could be used therapeutically to modulate Bim expression in vivo.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Tumor Cell Biology Study Section (TCB)
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Howcroft, Thomas K
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Medical University of South Carolina
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Chaudhury, Arindam; Hussey, George S; Ray, Partho S et al. (2010) TGF-beta-mediated phosphorylation of hnRNP E1 induces EMT via transcript-selective translational induction of Dab2 and ILEI. Nat Cell Biol 12:286-93
Chaudhury, Arindam; Chander, Praveen; Howe, Philip H (2010) Heterogeneous nuclear ribonucleoproteins (hnRNPs) in cellular processes: Focus on hnRNP E1's multifunctional regulatory roles. RNA 16:1449-62
Ramesh, Sneha; Wildey, Gary M; Howe, Philip H (2009) Transforming growth factor beta (TGFbeta)-induced apoptosis: the rise & fall of Bim. Cell Cycle 8:11-7
Wildey, Gary M; Howe, Philip H (2009) Runx1 is a co-activator with FOXO3 to mediate transforming growth factor beta (TGFbeta)-induced Bim transcription in hepatic cells. J Biol Chem 284:20227-39
Jiang, Y; Luo, W; Howe, P H (2009) Dab2 stabilizes Axin and attenuates Wnt/beta-catenin signaling by preventing protein phosphatase 1 (PP1)-Axin interactions. Oncogene 28:2999-3007
Chaudhury, Arindam; Howe, Philip H (2009) The tale of transforming growth factor-beta (TGFbeta) signaling: a soigné enigma. IUBMB Life 61:929-39
Ramesh, Sneha; Qi, Xiao-Jun; Wildey, Gary M et al. (2008) TGF beta-mediated BIM expression and apoptosis are regulated through SMAD3-dependent expression of the MAPK phosphatase MKP2. EMBO Rep 9:990-7
Jiang, Y; Prunier, C; Howe, P H (2008) The inhibitory effects of Disabled-2 (Dab2) on Wnt signaling are mediated through Axin. Oncogene 27:1865-75
Qi, Xiao-Jun; Wildey, Gary M; Howe, Philip H (2006) Evidence that Ser87 of BimEL is phosphorylated by Akt and regulates BimEL apoptotic function. J Biol Chem 281:813-23
Hocevar, Barbara A; Prunier, Celine; Howe, Philip H (2005) Disabled-2 (Dab2) mediates transforming growth factor beta (TGFbeta)-stimulated fibronectin synthesis through TGFbeta-activated kinase 1 and activation of the JNK pathway. J Biol Chem 280:25920-7

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