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Recruitment of TRRAP required for oncogenic transformation by E1A
L Deleu1, S Shellard, K Alevizopoulos
1Department of Biomedical Genetics, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA.
Abstract:
TRRAP links Myc with histone acetylases and appears to be an important mediator of its oncogenic function. Here we show that interaction with TRRAP is required for cellular transformation not only by Myc, but also by the adenovirus E1A protein. Substitution of the 262 N-terminal residues of Myc with a small domain of E1A (residues 12-54) restores Myc transforming function. E1A(12-54) contains a TRRAP-interaction domain, that recruits TRRAP to either E1A-Myc chimeras, or the native 12S E1A protein. Overexpression of a competing TRRAP fragment in vivo blocks interaction of cellular TRRAP with either E1A-Myc or E1A, and suppresses cellular transformation by both oncoproteins. Moreover, E1A(Delta26-35) that fails to bind TRRAP but is capable of binding the Retinoblastoma (Rb)-family and p300/CBP proteins is defective in cellular immortalization, transformation and cell cycle deregulation. Thus in addition to disrupting Rb and p300/CBP functions, E1A must recruit TRRAP to transform cells.
Insights
TRAP155 (TRRAP) is crucial for cellular transformation mediated by Myc and adenovirus E1A. This protein recruits TRRAP, essential for these oncoproteins to induce cell cycle deregulation and transformation.
Area of Science:
- Molecular Biology
- Oncology
- Virology
Background:
- TRRAP (Transformation/Transcription domain-associated protein) is a key mediator of Myc's oncogenic function by linking it to histone acetyltransferases.
- The adenovirus E1A protein is a potent oncoprotein involved in cellular transformation.
Purpose of the Study:
- To investigate the role of TRRAP in cellular transformation induced by Myc and adenovirus E1A.
- To elucidate the mechanism by which E1A interacts with TRRAP and its functional consequences.
Main Methods:
- Chimeric protein construction (Myc-E1A) to identify functional domains.
- In vivo overexpression of TRRAP fragments to block protein interactions.
- Analysis of cellular immortalization, transformation, and cell cycle deregulation.
Main Results:
- Interaction with TRRAP is essential for cellular transformation by both Myc and E1A.
- A specific domain of E1A (residues 12-54) mediates TRRAP recruitment and restores Myc transforming function.
- Overexpression of a TRRAP fragment inhibits E1A and Myc-mediated transformation.
- E1A mutants defective in TRRAP binding show impaired cellular immortalization and transformation.
Conclusions:
- TRRAP recruitment is a critical step in cellular transformation mediated by Myc and E1A.
- E1A utilizes TRRAP, in addition to disrupting Retinoblastoma (Rb) family and p300/CBP interactions, to achieve cellular transformation.