Abstract/Details

Notch functions from the cytoplasm to the nucleus during T cell activation


2007 2007

Other formats: Order a copy

Abstract (summary)

Notch1 specifically upregulates expression of the cytokine interferon-γ in peripheral T cells through activation of NF-κB. However, how Notch mediates NF-κB activation remains unclear. NF-κB activation occurs within minutes of TCR engagement and this activation is sustained for at least 48 hours following TCR signaling. We used either γ-secretase inhibitor (GSI) to prevent the cleavage and subsequent activation of Notch family members or siRNA against Notch1 to reduce endogenous expression of Notch1 specifically. We demonstrate that GSI blocked the later, sustained NF-κB activation, but did not affect the initial activation of NF-κB. Using biochemical approaches, as well as confocal microscopy, we show that the intracellular domain of Notch1 (N1IC) directly interacts with NF-κB and competes with IκBα, leading to retention of NF-κB in the nucleus, and that N1IC can directly regulate IFN-γ expression through complexes formed on the IFN-γ promoter. Additionally, within the immunological synapse, cytosolic Notch1 associates with CARMA1 and BCL10, mediating a direct interaction among them. Upon TCR and CD28 stimulation, Notch1 directly interacts with PKC&thetas; and the IKK complex, leading to IKK-mediated activation of NF-κB. In the absence of Notch1, there is no formation of CARMA1/BCL10/Malt1 complex, which is required for IKK activation. Taken together, these data suggest that Notch1 plays two roles during T cell activation: as an activation scaffold in the cytoplasm and as a transcriptional activator in the nucleus.

Indexing (details)


Subject
Molecular biology;
Immunology
Classification
0307: Molecular biology
0982: Immunology
Identifier / keyword
Health and environmental sciences; Biological sciences; Cytoplasm; Notch; Nucleus; T cell activation
Title
Notch functions from the cytoplasm to the nucleus during T cell activation
Author
Shin, Hyun Mu
Number of pages
128
Publication year
2007
Degree date
2007
School code
0118
Source
DAI-B 68/07, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
ISBN
9780549175506
Advisor
Osborne, Barbara A.
University/institution
University of Massachusetts Amherst
Department
Molecular & Cellular Biology
University location
United States -- Massachusetts
Degree
Ph.D.
Source type
Dissertations & Theses
Language
English
Document type
Dissertation/Thesis
Dissertation/thesis number
3275792
ProQuest document ID
304838205
Copyright
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
http://search.proquest.com/docview/304838205
Access the complete full text

You can get the full text of this document if it is part of your institution's ProQuest subscription.

Try one of the following:

  • Connect to ProQuest through your library network and search for the document from there.
  • Request the document from your library.
  • Go to the ProQuest login page and enter a ProQuest or My Research username / password.