Notch signaling pathways are important for several crucial decisions during lymphocyte development. The basic helix-loop-helix E2A transcription factors (E12/E47) are also essential for the development for both B and T lymphocytes. Our recent findings suggest that E2A transcription factors may be downstream effectors of Notch signaling for lymphocyte development. Specifically, we have shown that signaling through Notch modulates the turnover of E2A proteins, which requires the phosphorylation of these proteins by p42/p44 MAP kinases. Expression of activated Notch l enhanced the association of E47 with the SCFSkp2 E3 ubiquitin ligase and its ubiquitination. Notch-induced degradation of E2A proteins occurred in B but not T cells studied. However, this correlated with the level of MAP kinase activity in these cells. Therefore, differences in the level of MAP kinase activity may be an effective regulatory mechanism to control E2A turnover. In this proposal, we first hypothesize that accelerated E2A degradation by Notch signals may play an important role in Notch-mediated T versus B lineage choice by blocking B cell development in the thymus. We then propose that Notch signals may be responsible for reducing E2A levels in T cells once functional pre-TCR and TCR are formed, and lower E2A levels are necessary for T cells to go through proper selections during maturation. These hypotheses will be tested by measuring E 2A degradation in progenitor B cells and in T cells upon activation of MAP kinases. Furthermore, mutations will be introduced into the E2A genome to encode E2A proteins resistant to Notch induced degradation. The knock-in mice will be used to determine if expression of the mutant protein allows B cell formation in the thymus, renders resistance to Notch-mediated inhibition of B cell development in the bone mar row, and impacts on T cell selection, as well as positive and negative selection. Finally, we propose to understand how Notch signals induce the ubiquitination and degradation of E2A proteins. Perhaps, Notch signals facilitate expression of unknown genes involved in the ubiquitination of E2A proteins, which will be identified by examination of proteins associated with the ubiquitination machinery of E2A proteins. In summary, studies outlined here expand our investigation on a novel function of Notch signaling, i.e., induction of ubiquitin-mediated E2A degradation, and evaluate the biological significance of this function in the context of lymphocyte development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI056129-01
Application #
6675261
Study Section
Immunobiology Study Section (IMB)
Program Officer
Mallia, Conrad M
Project Start
2003-07-01
Project End
2007-12-31
Budget Start
2003-07-01
Budget End
2003-12-31
Support Year
1
Fiscal Year
2003
Total Cost
$173,250
Indirect Cost
Name
Oklahoma Medical Research Foundation
Department
Type
DUNS #
077333797
City
Oklahoma City
State
OK
Country
United States
Zip Code
73104
Zhao, Ying; Ling, Flora; Griffin, Timothy M et al. (2014) Up-regulation of the Sirtuin 1 (Sirt1) and peroxisome proliferator-activated receptor ? coactivator-1? (PGC-1?) genes in white adipose tissue of Id1 protein-deficient mice: implications in the protection against diet and age-induced glucose intolerance. J Biol Chem 289:29112-22
Liu, Chen; Wang, Hong-Cheng; Yu, Sen et al. (2014) Id1 expression promotes T regulatory cell differentiation by facilitating TCR costimulation. J Immunol 193:663-672
Liu, Chen; Jin, Rong; Wang, Hong-Cheng et al. (2013) Id1 expression promotes peripheral CD4+ T cell proliferation and survival upon TCR activation without co-stimulation. Biochem Biophys Res Commun 436:47-52
Zhao, Ying; Ling, Flora; Wang, Hong-Cheng et al. (2013) Chronic TLR signaling impairs the long-term repopulating potential of hematopoietic stem cells of wild type but not Id1 deficient mice. PLoS One 8:e55552
Hu, Taishan; Wang, Hongcheng; Simmons, Amie et al. (2013) Increased level of E protein activity during invariant NKT development promotes differentiation of invariant NKT2 and invariant NKT17 subsets. J Immunol 191:5065-73
Zhang, Ping; Zhao, Ying; Sun, Xiao-Hong (2013) Notch-regulated periphery B cell differentiation involves suppression of E protein function. J Immunol 191:726-36
Wang, Hong-Cheng; Peng, Vincent; Zhao, Ying et al. (2012) Enhanced Notch activation is advantageous but not essential for T cell lymphomagenesis in Id1 transgenic mice. PLoS One 7:e32944
Wu, Wei; Sun, Xiao-Hong (2012) Janus kinase 3: the controller and the controlled. Acta Biochim Biophys Sin (Shanghai) 44:187-96
Nie, Lei; Zhao, Ying; Wu, Wei et al. (2011) Notch-induced Asb2 expression promotes protein ubiquitination by forming non-canonical E3 ligase complexes. Cell Res 21:754-69
Wu, Wei; Sun, Xiao-Hong (2011) A mechanism underlying NOTCH-induced and ubiquitin-mediated JAK3 degradation. J Biol Chem 286:41153-62

Showing the most recent 10 out of 19 publications