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Philip H. Howe, Ph.D.StaffDepartment of Cancer Biology |
Area of general research interest:
Molecular mechanism of Transforming Growth Factor Beta (TGFbeta) growth action
Current program:
- TGF beta-mediated growth arrest and apoptosis
- Signal transduction/cell cycle
- Genetic selection of TGF beta-signaling mutants
Investigators:
- Praveen Chander, Graduate Student
- Arindam Chaudhury, Graduate Student
- George S. Hussey , Graduate Student
- Yong Jiang, Ph.D., Research Fellow
- Sneha Ramesh, Ph.D., Research Fellow
- Gary Wildey, Ph.D., Project Scientist
Collaborators:
- Edward Leof, Ph.D., Department of Biochemistry, Mayo Clinic, Rochester MN
- Xiangxi Xu, Ph.D., Department of Biochemistry, Emory Univeristy, Atlanta, GA
Brief Description:
Our laboratory focuses on understanding signaling mechanisms of transforming growth factor-β1 (TGF-β1) in three major projects. In Project 1, we study the role of the adaptor molecule Dab2 in several differentiation models, where we observe that Dab2 protein expression is induced during the differentiation process. Since mRNA levels remain unchanged, it is possible that during differentiation there is increased Dab2 translation or, alternatively, a decrease in Dab2 degradation. We are investigating the degradation of Dab2 protein with specific emphasis on its GSK3β-dependent phosphorylation and subsequent ubiquitination and degradation through the proteasomal pathway.
In Project 2, our focus is on the signaling pathways by which TGF-β mediates apoptosis in B-lymphocyte cells. We have determined previously that TGF-β-induced apoptosis in these cells is mediated by Smad regulatory proteins and the Bcl-2 interacting mediator of cell death (Bim): TGF-β induces the Smad3-dependent transcription of Bim, which heterodimerizes and neutralizes the anti-apoptotic effects of Bcl-2, releasing cytochrome c from the mitochondria and inducing apoptosis through activation of the caspase cascade. Current studies investigate the phosphorylation/degradation of Bim, as well as the transcriptional mechanism through which TGF-β mediates Bim induction.
In Project 3, we have initiated a small chemical compound screen for modulators of TGF-β signaling, aiming to isolate chemical modulators of TGF-β signaling that can be used as early- and late-stage therapeutics for epithelium-derived carcinomas.
Selected References:
Ramesh, S., Wildey, G.M., Qi, X-J., Robinson, J., Molkentin, J.D., Letterio, J.J., and Howe, P.H. (2008). TGFβ-mediated Bim expression and apoptosis is regulated through Smad3-dependent expression of MAPK phosphatase MKP2. EMBO Reports
9(10): 990-997.
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, X.J., Wildey, G.M., and Howe, P.H. (2006). Evidence that Ser87 of BimEL is phosphorylated by Akt and regulates BimEL apoptotic function. J. Biol. Chem. 281, 813-823.
Hocevar, B.A., Prunier, C., and Howe, P.H. (2005). Disabled-2 (Dab2) mediates transforming growth factor {beta} (TGF{beta})-stimulated fibronectin synthesis through TGF{beta}-activated kinase 1 and activation of the JNK pathway. J. Biol. Chem. 280, 25920-25927.
Prunier, C., and Howe, P.H. (2005). Disabled-2 (Dab2) is required for transforming growth factor {beta}-induced epithelial to mesenchymal transition (EMT). J. Biol. Chem. 280, 17540-17548.
Lu, T., Burdelya, L.G., Swiatkowski, S.M., Boiko, A.D., Howe, P.H., Stark, G.R., and Gudkov, A.V. (2004). Secreted transforming growth factor {beta}2 activates NF-{kappa}B, blocks apoptosis, and is essential for the survival of some tumor cells. Proc. Natl. Acad. Sci. U. S. A. 101, 7112-7117.
Prunier, C., Hocevar, B.A., and Howe, P.H. (2004). Wnt signaling: physiology and pathology. Growth Factors 22, 141-150.
Hocevar, B.A., Mou, F., Rennolds, J.L., Morris, S.M., Cooper, J.A., and Howe, P.H. (2003). Regulation of the Wnt signaling pathway by disabled-2 (Dab2). EMBO J. 22, 3084-3094.
Wildey, G.M., Patil, S., and Howe, P.H. (2003). Smad3 potentiates transforming growth factor beta (TGF beta)- induced apoptosis and expression of the BH3-only protein bim in WEHI 231 B lymphocytes. J. Biol. Chem. 278, 18069-18077.
Prunier, C., Pessah, M., Ferrand, N., Seo, S.R., Howe, P., and Atfi, A. (2003). The oncoprotein ski acts as an antagonist of transforming growth factor-beta signaling by suppressing Smad2 phosphorylation. J. Biol. Chem. 278, 26249-26257.
Hocevar, B.A., Smine, A., Xu, X.X., and Howe, P.H. (2001). The adaptor molecule Disabled-2 links the transforming growth factor beta receptors to the Smad pathway. EMBO J. 20, 2789-2801.
Brown, T.L., Patil, S., and Howe, P.H. (2000). Analysis of TGF-beta-inducible apoptosis. Methods Mol. Biol. 142, 149-167.
Hocevar, B.A., and Howe, P.H. (2000). Regulation of AP-1 activity by TGF-beta. Methods Mol. Biol. 142, 97-108.
Hocevar, B.A., and Howe, P.H. (2000). Analysis of TGF-beta-mediated synthesis of extracellular matrix components. Methods Mol. Biol. 142, 55-65.
Howe, P.H. (2000). Transforming growth factor-beta protocols (Totowa, NJ: Humana Press).
Jin, G., and Howe, P.H. (2000). Promoter analysis of TGF-beta responsive genes by transient transfection and deletional/mutational analysis. Methods Mol. Biol. 142, 79-95.
Patil, S., Wildey, G.M., Brown, T.L., Choy, L., Derynck, R., and Howe, P.H. (2000). Smad7 is induced by CD40 and protects WEHI 231 B-lymphocytes from transforming growth factor-beta-induced growth inhibition and apoptosis. J. Biol. Chem. 275, 38363-38370.
Brown, T.L., Patil, S., Cianci, C.D., Morrow, J.S., and Howe, P.H. (1999). Transforming growth factor beta induces caspase 3-independent cleavage of alpha II-spectrin (alpha-fodrin) coincident with apoptosis. J. Biol. Chem. 274, 23256-23262.
Hocevar, B.A., Brown, T.L., and Howe, P.H. (1999). TGF-beta induces fibronectin synthesis through a c-Jun N- terminal kinase-dependent, Smad4-independent pathway. EMBO J. 18, 1345-1356.
Jin, G., and Howe, P.H. (1999). Transforming growth factor beta regulates clusterin gene expression via modulation of transcription factor c-Fos. Eur. J. Biochem. 263, 534-542.
Brown, T.L., and Howe, P.H. (1998). MADD is highly homologous to a Rab3 guanine nucleotide exchange protein (Rab3-GEP). Curr. Biol. 8, R191-R191.
Brown, T.L., Patil, S., Basnett, R.K., and Howe, P.H. (1998). Caspase inhibitor BD-fmk distinguishes transforming growth factor beta- induced apoptosis from growth inhibition. Cell Growth Differ. 9, 869-875.
Hocevar, B.A., and Howe, P.H. (1998). Mechanisms of TGF-beta-induced cell cycle arrest. Miner. Electrolyte Metab. 24, 131-135.
Jin, G., and Howe, P.H. (1997). Regulation of clusterin gene expression by transforming growth factor beta. J. Biol. Chem. 272, 26620-26626.
Lee, Y.J., Han, Y.L., Lu, H.T., Nguyen, V., Qin, H.W., Howe, P.H., Hocevar, B.A., Boss, J.M., Ransohoff, R.M., and Benveniste, E.N. (1997). TGF-beta suppresses IFN-gamma induction of class II MHC gene expression by inhibiting class II transactivator messenger RNA expression. J. Immunol. 158, 2065-2075.
Hocevar, B.A., and Howe, P.H. (1996). Isolation and characterization of mutant cell lines defective in transforming growth factor beta signaling. Proc. Natl. Acad. Sci. U. S. A. 93, 7655-7660.
Mal, A., Poon, R.Y.C., Howe, P.H., Toyoshima, H., Hunter, T., and Harter, M.L. (1996). Inactivation of p27Kip1 by the viral E1A oncoprotein in TGFbeta- treated cells. Nature 380, 262-265.
Reddy, K.B., Jin, G., Karode, M.C., Harmony, J.A.K., and Howe, P.H. (1996). Transforming growth factor beta (TGF beta)-induced nuclear localization of apolipoprotein J/clusterin in epithelial cells. Biochemistry 35, 6157-6163.
Reddy, K.B., Karode, M.C., Harmony, A.K., and Howe, P.H. (1996). Interaction of transforming growth factor beta receptors with apolipoprotein J/clusterin. Biochemistry 35, 309-314.
Reddy, K.B., Hocevar, B.A., and Howe, P.H. (1994). Inhibition of G1 phase cyclin dependent kinases by transforming growth factor beta 1. J. Cell. Biochem. 56, 418-425.
Devajyothi, C., Kalvakolanu, I., Babcock, G.T., Vasavada, H.A., Howe, P.H., and Ransohoff, R.M. (1993). Inhibition of interferon-gamma-induced major histocompatibility complex class II gene transcription by interferon-beta and type beta 1 transforming growth factor in human astrocytoma cells. Definition of cis-element. J. Biol. Chem. 268, 18794-18800.
Howe, P.H., Dobrowolski, S.F., Reddy, K.B., and Stacey, D.W. (1993). Release from G1 growth arrest by transforming growth factor beta 1 requires cellular ras activity. J. Biol. Chem. 268, 21448-21452.
Reddy, K.B., and Howe, P.H. (1993). Transforming growth factor beta 1-mediated inhibition of smooth muscle cell proliferation is associated with a late G1 cell cycle arrest. J. Cell. Physiol. 156, 48-55.