Transforming growth factor beta (TGFbeta) is prototypic of a family of cytokines with immunoregulatory properties that are critical to the maintenance of normal immunological homeostasis. Targeted disruption of the TGFbeta gene in mice results in a phenotype characterized as a progressive multifocal inflammatory process typical of autoimmune disease with increased circulating autoantibodies and immune complex deposition, increased expression of both classes of MHC antigens, and increased numbers of circulating immature neutrophils and lymphocytes. The inflammatory response in the TGFbeta-knockout is lymphocyte mediated demonstrating the vital role of TGFbeta in regulating lymphocyte proliferation and activation, which contribute to the maintenance of self tolerance. In this proposal we wish to determine the molecular mechanism by which TGFbeta induces apoptosis in immature B cells thus resulting in clonal deletion and maintenance of self tolerance. We hypothesize that there are distinct intracellular domains of either a homo and/or heteromeric TGFbeta receptor complex which mediate apoptosis in the WEHI-231 B lymphocyte cells. We also propose that a distinct and previously unidentified caspase protease(s) is responsible for mediating the apoptotic actions of TGFbeta. It is the goal of this application to determine the type of TGFbeta-receptor complex and the intracellular regions of this complex necessary for TGFbeta-induced apoptosis in WEHI-231 cells. We also propose to isolate and characterize the caspase protease(s) which is activated by TGFbeta in these cells.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Metabolic Pathology Study Section (MEP)
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Finerty, John F
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Cleveland Clinic Lerner
United States
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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
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; 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
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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