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Thomas Robert Kadesch, Ph.D.

DECEASED

Thomas Robert Kadesch, Ph.D.

faculty photo
Department: Genetics

Contact information
475 Clinical Research Building
415 Curie Boulevard
Philadelphia, PA 19104-6145
Office: 215-898-1047
Fax: 215-573-7760
Education:
B.A. (Biochemistry)
University of California at Santa Barbara, 1975.
Ph.D. (Biochemistry)
University of California at Berkeley, 1980.
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Description of Research Expertise

Research Interests
Notch signaling and the transcriptional regulation of cellular differentiation and transformation.

Key words: Notch, Transcription, Transformation, Differentiation, Schwann Cells, Myoblasts, Stem cells.

Description of Research
Stem cells possess the capacity to both self-renew and differentiate into defined lineages. Satellite cells are stem cells of skeletal muscle that normally reside adjacent to muscle fibers. Upon muscle injury they proliferate and then a subset differentiate to form addition fibers, thus repairing the damage while maintaining the stem cell niche. Our long-standing interest in the Notch signaling pathway has led us recently into the study satellite cells since it is now known that Notch controls the propensity of these cells to either proliferate (Notch signaling on) or differentiate (Notch signaling off).

Notch signaling is generally viewed as a transcriptional cascade, with Notch itself functioning both as a receptor, poised at the plasma membrane, and as a transcription factor generated by proteolysis of the receptor after ligand engagement. Several of the gene targets of Notch are themselves transcription factors that control the expression of genes further downstream in the overall pathway. However, these more distal components of the pathway, and how they link Notch signaling to its phenotypic effects, are not well understood. A major goal of the lab is to identify the components of the Notch pathway that lead to the inhibition of satellite cell differentiation. Indeed, our current data support the presence of two arms — one that promotes proliferation and another that functions through the transcriptional repressor HRT1— that combine to elicit Notch’s overall effects.

Additional projects in the lab also focus on pathway building, but involve the study of Notch in two other cells types, Schwann cells and adipocytes. For the case of Schwann cells, which generate the myelin sheath that protects nerves of the PNS, we’ve shown that constitutively active Notch (the proteolytically cleaved form) functions as an oncogene, inducing cells to actually de-differentiate and become non-responsive to cell-cell contact. For adipocytes, which produce triglycerides, fatty acids and lipids (i.e. fat), we’ve shown that Notch signaling, through the activation of the transcriptional repressor Hes-1, blocks differentiation. The theme that runs through all three areas of study is the ability of Notch to maintain cells in an undifferentiated state. Our studies aim to determine ultimately if this is coincidental or tied to a shared signaling mechanism.

Rotation Projects for 2006-2007
Various aspects of the aforementioned studies.

Lab personnel:
Shara Kabak – Postdoc
Matt Buas – Grad Student
Ruth McCarrick-Walmsley - Technician

Selected Publications

Ross, D.A, Hannenhalli, S, Tobias, J.W., Cooch, N., Shiekhattar, R. and Kadesch, T.: Functional analysis of Hes-1 in preadipocytes. Mol. Endo 20: 698-705, 2006.

Kadesch, T.: Notch signaling: the demise of elegant simplicity. Curr. Opinions Gen. Dev. 14: 506-512, 2004.

Ross, D. and Kadesch, T.: Consequences of Notch-mediated induction of Jagged1. Exp. Cell. Research 296: 173-182, 2004.

Ross, D. and Kadesch, T.: Dual roles for the Notch target Hes1 in the differentiation of 3T3-L1 Preadipocytes. Mol. Cell. Biol. 24: 3505-3513, 2004.

Li, Y, Rao, P., Wen, R., Song, Y., Muir, D., Wallace, P., van Horne, S. Tennekoon, G. and Kadesch, T.: Notch and Schwann cell transformation. Oncogene 23: 1146-1152, 2004.

Rao, P. and Kadesch, T.: The Intracellular Form of Notch Abrogates TGF-ß-Mediated Growth Arrest. Mol. Cell. Biol 23: 6694-6701, 2003.

Zhao, F., McCarrick-Walmsley, R. Akerblad, P., Sigvardsson, M. and Kadesch, T.: Inhibition of p300/CBP by Early B-Cell Factor. Mol. Cell. Biol. (23), 3837-3846, 2003.

Ross, D.A. and Kadesch, T.: The Notch Intracellular Domain Can Function as a Coactivator for LEF-1. Mol. Cell. Biol. (21), 7537-7544, 2001.

Tang Z., Kadesch T.: Identification of a novel domain in the Notch-responsive transcription factor CSL. Nucl. Acids Res. In press 2001.

Kishi N., Tang Z., Maeda Y., Hirai A., Mo R., Ito M., Suzuki S., Kinoshita T., Kadesch T., Hui C., Artavanis-Tsakonas S., Matsuno K.: Murine homologs of deltex define a novel gene family involved in vertebrate notch signaling and neurogenesis. Internat'l J. Dev. Neurosci. 19: 21-35, 2001.

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Last updated: 03/15/2007
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