Title |
Acetyltransferases in Transformation by c-MYC
|
Institution |
THOMAS JEFFERSON UNIVERSITY, PHILADELPHIA, PA
|
Principal Investigator |
MCMAHON, STEVEN
|
NCI Program Director |
Judy Mietz
|
Cancer Activity |
DNA Chromosome Aberrations
|
Division |
DCB
|
Funded Amount |
$61,157
|
Project Dates |
05/01/2002 - 02/29/2008
|
Fiscal Year |
2007
|
Project Type |
Grant
|
Research Topics w/ Percent Relevance |
Cancer Types w/ Percent Relevance |
Gene Therapy (10.0%)
|
N/A
|
Research Type |
Endogenous Factors in the Origin and Cause of Cancer
|
Abstract |
DESCRIPTION (provided by applicant): We have isolated a novel transcriptional cofactor whose recruitment is essential for transformation by the c-MYC oncoprotein. This protein, TRRAP is a component of several histone acetyltransferase complexes that regulate transcription via chromatin modification. We also show for the first time that c-MYC itself is modified by acetylation in vitro and in vivo. Furthermore, both classes of TRRAP-associated acetyltransferase are capable of acetylating c-MYC in vivo. Guiding Hypothesis and Specific Aims: We hypothesize that the TRRAP cofactor complexes are critical for cellular transformation by c-MYC because together they regulate the expression of a subset of downstream target genes. The identification of this subset of genes is our primary goal. Once identified, we will define the mechanism by which these genes participate in c -MYC' s biological functions. In addition, we will biochemically characterized the c-MYC/TRRAP interaction. This will include defining the domain on the 434 kDa TRRAP protein bound by c-MYC and determining the role of TRRAP in the assembly and function of the acetyltransferase complexes themselves. Innovation and Significance: The identification of the TRRAP cofactor and the demonstration that it is recruited by c-MYC are novel observations that form the basis of this proposal. Because this recruitment appears critical for transformation, we will use specific mutants in c-MYC which are defective for TRRAP recruitment to probe the genetic cascade regulated by c-MYC in transformation. |