This resubmission focuses on signaling by Notch, a transmembrane receptor that influences cell fate choices in lower eukaryotes and which can alter proper development of particular cell lineages in higher eukaryotes, including T lymphocytes. The proposed experiments stem from the investigator's observation that Notch signaling can inhibit E47, a transcription factor that plays a critical role in early B cell development. He proposes, by extension, that Notch may also influence B cell development. The proposal takes a broad view and attempts to understand Notch from the phenotypic consequences of its activation to its molecular mechanisms of action. A combination of cell culture systems and transgenic mice will be used to investigate the effects of Notch signaling on gene expression in and development of B cells. Transgenic mice harboring a Notch responsive reporter will be generated in order to identify particular cells in the developing embryo and the adult that undergo Notch signaling. These latter experiments may provide insights into the mechanisms that govern cell fate decisions in a variety of cell developmental contexts. Finally, experiments are proposed to elucidate the molecular details of Notch's activation of the transcription factor CBF1. Recent results have shown that Notch inhibition of E47 does not involve signaling to CBF1 and, instead, may involve a novel pathway involving a second Notch-interacting protein called Deltex. Experiments are proposed to characterize signaling through Deltex.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM058228-03
Application #
6384313
Study Section
Allergy and Immunology Study Section (ALY)
Program Officer
Marino, Pamela
Project Start
1999-05-01
Project End
2003-04-30
Budget Start
2001-05-01
Budget End
2002-04-30
Support Year
3
Fiscal Year
2001
Total Cost
$317,387
Indirect Cost
Name
University of Pennsylvania
Department
Genetics
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Li, Yiwen; Rao, Prakash K; Wen, Rong et al. (2004) Notch and Schwann cell transformation. Oncogene 23:1146-52
Ross, David A; Rao, Prakash K; Kadesch, Tom (2004) Dual roles for the Notch target gene Hes-1 in the differentiation of 3T3-L1 preadipocytes. Mol Cell Biol 24:3505-13
Ross, David A; Kadesch, Tom (2004) Consequences of Notch-mediated induction of Jagged1. Exp Cell Res 296:173-82
Rao, Prakash; Kadesch, Tom (2003) The intracellular form of notch blocks transforming growth factor beta-mediated growth arrest in Mv1Lu epithelial cells. Mol Cell Biol 23:6694-701
Tang, Z; Kadesch, T (2001) Identification of a novel activation domain in the Notch-responsive transcription factor CSL. Nucleic Acids Res 29:2284-91
Ross, D A; Kadesch, T (2001) The notch intracellular domain can function as a coactivator for LEF-1. Mol Cell Biol 21:7537-44
Rao, P K; Dorsch, M; Chickering, T et al. (2000) Isolation and characterization of the notch ligand delta4. Exp Cell Res 260:379-86