Mechanisms of notch signaling / Peter Ordentlich.

Format:

Book

Manuscript

Microformat

Thesis/Dissertation

Author/Creator:

Ordentlich, Peter.

Contributor:

University of Pennsylvania.

Language:

English

Subjects (All):

Penn dissertations--Immunology.

Immunology--Penn dissertations.

Allergy and Immunology.

Academic Dissertations as Topic.

Medical Subjects:

Allergy and Immunology.

Academic Dissertations as Topic.

Local Subjects:

Penn dissertations--Immunology.

Immunology--Penn dissertations.

Physical Description:

x, 143 pages : illustrations ; 29 cm

Production:

1997.

Summary:

The B cell specific immunoglobulin heavy chain (IgH) intronic enhancer has been widely studied as a paradigm for understanding tissue specific and developmentally regulated transcription. Regulation of the enhancer has been used to identify transcription factors that may be important in the commitment to and differentiation of the B cell lineage. The E2A encoded basic-Helix-Loop-Helix (bHLH) proteins E12 and E47 have been shown to bind to the $\mu$E5 site of the IgH enhancer. Through knockout analysis in mice these factors have been demonstrated to be essential for early B cell development. Our lab has previously shown that although E47 is a ubiquitously expressed protein it binds DNA as a homodimer in a B cell restricted manner. We have sought to identify post-translational mechanisms by which E47 transcription activity may be regulated, in order to understand better the regulation of early B cell development.

The work in this thesis describes the regulation of E47 through a novel Notch mediated signal transduction pathway. Both human Notch and a human homologue of Deltex, a component of Notch signaling in Drosophila, have been shown here to inhibit E47 activity. This inhibition is independent of CBF1/RBP-J$\sb{\kappa}$, the only known downstream effector of Notch signaling, representing the identification of a novel aspect of the mechanism of Notch function.

Investigation into the mechanism of Notch activation of CBF1/RBP-J$\sb{\kappa}$ has led to the identification of SMRT as a corepressor for CBF1/RBP-J$\sb{\kappa}$ mediated repression and a regulator of Notch signaling. Additionally it has been demonstrated that Notch activation of CBF1/RBP-J$\sb{\kappa}$ can be regulated by components of the Wnt/Wingless signaling pathway and to potentially require the coactivator p300/CBP for efficient activation. This thesis therefore demonstrates that various signaling pathways can regulate E47 activity and provides insight into the mechanism of how these signaling pathways function. It will be interesting to determine if the findings presented here can be applied to the understanding of the process of B cell development.

Notes:

Thesis (Ph.D. in Immunology) -- University of Pennsylvania, 1997.

Includes bibliographical references.

Local Notes:

University Microfilms order no.: 98-14897.

OCLC:

187457369