The E2A gene products belong to a class of helix-loop-helix (HLH) proteins, also named E-proteins. Members of the E-proteins include E12, E47, E2-2 and HEB. The DNA binding activities of the E- proteins are regulated by a distinct class of antagonistic HLH proteins, named Id gene products. Four Id genes are present in the mammalian genome, designated as Id1-4. E47 levels are high in T cell progenitors where they act to promote TCR? gene rearrangement, induce the expression of genes involved in pre-TCR signaling and suppress proliferation. Once a pre-TCR has been generated, E47 levels decrease to permit developmental progression and cellular expansion. E47 expression also prevents the development of lymphoma in thymocyte progenitors. In this grant application we would examine how E- and Id protein activities are regulated to control developmental progression and suppress the development of lymphoma.

Public Health Relevance

During previous studies we have demonstrated that a class of DNA binding proteins, named E- proteins. are important for the development of white blood cells. We have also shown that the E- proteins make sure that white blood cells do not multiply inappropriately in healthy individuals. But mutations can make the E-proteins inactive. Such mutations can ultimately result in the development of lymphoid malignancies. The proposed studies would provide insight into how mutations in the genome of white blood cells lead to the development of lymphoma and should provide novel strategies for the treatment of human T cell leukemias.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA078384-15
Application #
8433486
Study Section
Hematopoiesis Study Section (HP)
Program Officer
Howcroft, Thomas K
Project Start
1999-04-01
Project End
2014-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
15
Fiscal Year
2013
Total Cost
$374,134
Indirect Cost
$131,976
Name
University of California San Diego
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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Lucas, Joseph S; Bossen, Claudia; Murre, Cornelis (2011) Transcription and recombination factories: common features? Curr Opin Cell Biol 23:318-24
Miyazaki, Masaki; Rivera, Richard R; Miyazaki, Kazuko et al. (2011) The opposing roles of the transcription factor E2A and its antagonist Id3 that orchestrate and enforce the naive fate of T cells. Nat Immunol 12:992-1001
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Heinz, Sven; Benner, Christopher; Spann, Nathanael et al. (2010) Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol Cell 38:576-89