TRRAP-dependent and TRRAP-independent transcriptional activation by Myc family oncoproteins.
We demonstrate that transformation-transactivation domain-associated protein (TRRAP) binding and the recruitment of histone H3 and H4 acetyltransferase activities are required for the transactivation of a silent telomerase reverse transcriptase (TERT) gene in exponentially growing human fibroblasts by c-Myc or N-Myc protein. However, recruitment of TRRAP by c- or N-Myc is dispensable for the partial induction of several basally expressed genes in exponentially growing primary and immortalized fibroblasts. Furthermore, recruitment of TRRAP is required for c-Myc- or N-Myc-mediated oncogenic transformation but not for the partial restoration of the growth defect in myc-null fibroblasts. A segment of the adenovirus E1A protein fused to a transformation-defective N-Myc protein carrying a small deletion in the transactivation domain specifically restores interaction with TRRAP, activates the silent TERT gene, induces acetylation of histones H3 and H4 at the TERT promoter, and transforms primary cells. Accordingly, wild-type L-Myc is much less efficient in TRRAP binding, activation of the silent TERT gene, and transformation of primary fibroblasts. Nevertheless, L-Myc is a potent activator of several basally expressed genes and can fully restore the growth defect of myc-null cells. These results suggest a differential requirement for TRRAP for several Myc-mediated activities.
Nikiforov
Mikhail A
MA
Department of Molecular Biology, Princeton University, Washington Road, Princeton, NJ 08544-1014, USA.
Chandriani
Sanjay
S
Park
Jeonghyeon
J
Kotenko
Iulia
I
Matheos
Dina
D
Johnsson
Anna
A
McMahon
Steven B
SB
Cole
Michael D
MD
D000123:Acetyltransferases / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing; D017500:Adenovirus E1A Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D051548:Histone Acetyltransferases; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D016271:Proto-Oncogene Proteins c-myc / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins; D019098:Telomerase / Q000235:genetics*; D015533:Transcriptional Activation
D048868:Adaptor Proteins, Signal Transducing; D017500:Adenovirus E1A Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D016271:Proto-Oncogene Proteins c-myc; D011993:Recombinant Fusion Proteins; D029701:Saccharomyces cerevisiae Proteins; C113829:transformation-transcription domain-associated protein; D000123:Acetyltransferases; D051548:Histone Acetyltransferases; C509186:TERT protein, human; D019098:Telomerase