The E2A gene is altered in the leukemic cells of high-risk patients with pre-B acute lymphoblastic leukemia (ALL) by virtue of the (1;19) (q23;p13) chromosome translocation.As a consequence of this translocation, a chimeric gene is generated which encodes a fusion protein comprised of amino-terminal E2A sequences linked to the homeodomain of the PBX1 gene. E2A-PBX1 fusion polypeptides presumably promote pre-B ALL by inducing inappropriate expression of PBX1-responsive genes. The preliminary data of the investigators indicate that the amino terminal region of E2A, including its transcription activation domain, is phosphorylated at multiple sites in vivo. Since protein phosphorylation is a common mechanism for the post-translational control of transcription factors, they will investigate how phosphorylation of these sites influences E2A function. The long-term objectives are to determine whether the leukemic properties of E2A-BPX1 fusion proteins are modulated by protein phosphorylation, and, if so, whether the malignant potential of these proteins can be mitigated by controlling their phosphorylation state. Accordingly, the specific aims of the project are (1) to identify the in vivo phosphorylation sites of E2A by tryptic mapping and phosphoaminoacid analysis of mutagenized E2A polypeptides; (2) to identify the protein kinases that mediate phosphorylation of E2A polypeptides in vitro and in vivo; (3) to determine the effect of protein phosphorylation on the transactivation potential of E2A polypeptides; and (4) to evaluate the effect of protein phosphorylation on properties of the leukemic E2A-PBX1 fusion proteins, including their in vitro transformation potential, their in vivo tumorigenicity, and their ability to induce RNA transcription.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA061011-02
Application #
2101784
Study Section
Pathology A Study Section (PTHA)
Project Start
1993-08-01
Project End
1998-05-31
Budget Start
1994-08-01
Budget End
1995-05-31
Support Year
2
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Dallas
State
TX
Country
United States
Zip Code
75390
Jin, Y; Xu, X L; Yang, M C et al. (1997) Cell cycle-dependent colocalization of BARD1 and BRCA1 proteins in discrete nuclear domains. Proc Natl Acad Sci U S A 94:12075-80