c-Myc Transformation Domain Recruits the Human STAGA Complex and Requires TRRAP and GCN5 Acetylase Activity for Transcription Activation

Abstract

The c-Myc protein (Myc) is the most widely expressed member of a small family of highly related cellular oncoproteins that includes L-Myc and N-Myc. Myc is essential for early embryogenesis and regulates cell growth, proliferation, differentiation, and apoptosis. Deregulated Myc expression contributes to tumorigenesis in animal models and is associated with many types of cancer in humans. Most of the biological effects of Myc, including its cellular transformation properties, result from its gene-specific transcription regulatory functions. Myc has a complex N-terminal transcription regulatory domain with both transcription activating and repressive functions and a C-terminal basic helix-loop-helix leucine zipper (bHLHZip) 1 domain, which is required for heterodimerization with its obligatory bHLHZip partner Max and for binding to E-box DNA sequences (consensus CACGTG). The domains of Myc that are essential for cell transformation correspond to domains also required for transcription activation by Myc. These include the bHLHZip domain and two essential amino acid regions within the Myc N-terminal regulatory domain: amino acids 1-110 and 129 -145, which contain, respectively, the two phylogenetically conserved Myc box 1 (MB1) and Myc box 2 (MB2) sequences (reviewed in Refs. 1 and 2). Several different proteins that associate with the N-terminal regulatory domain of Myc have been identified (3). However, generally the precise role(s) of these interactions in Myc functions is still unclear. Of the various Myc-interacting proteins identified so far, the so-called transformation-transactivation domain-associated protein (TRRAP), the human histone acetyltransferase (HAT) GCN5, TIP48, TIP49, and BAF53 proteins appear to play essential roles in Myc-dependent cell transformation (4 -7). These proteins are part of a variety of both shared and distinct multiprotein complexes involved in regulation of chromatin structure via either ATP-dependent nucleosome remodeling (e.g. BAF53-containing SWI/SNF-like complexes) or histone acetylation. In particular, TRRAP is a subunit of the TIP48/TIP49-containing TIP60 HAT complex, which preferentially acetylates histone H4 (and H2A) within nucleosomes (8), a related p400 complex that appears to lack TIP60 and HAT activity (9), a novel TRRAP-BAF53 HAT complex that acetylates preferentially nucleosomal histones H4 and H2A (7), and at least three distinct human complexes related to the yeast SAGA coactivator complex that preferentially acetylate nucleosomal histone H3: the PCAF (p300/CBPassociated factor) complex (10), and the two distinct human GCN5-containing complexes STAGA (11) and TFTC (12). Some of these TRRAP-containing complexes have been implicated in transcription regulation and/or DNA repair within chromatin, although the detailed mechanisms are still unclear. Thus, the essential role of TRRAP in transformation by Myc may result from its possible function as an adaptor linking Myc to one or several of the above HAT complexes and cognate activities. Indeed, TRRAP has been shown t...

PARP-10, a novel Myc-interacting protein with poly(ADP-ribose) polymerase activity, inhibits transformation

“…These HAT enzymes function at least in part by acetylating core histones, a mechanism that has been linked to chromatin opening and gene activation (Sterner and Berger, 2000;Strahl and Allis, 2000;Jenuwein and Allis, 2001). In agreement, binding of Myc/Max heterodimers to E-box elements correlates with altered core histone acetylation at target promoters and increased transcription (Bouchard et al, 2001;Frank et al, 2001;Park et al, 2001;Xu et al, 2001;Nikiforov et al, 2002;Frank et al, 2003;Liu et al, 2003). In addition to HATs, c-Myc has been reported to recruit an SWI/SNF complex that affects chromatin structure by remodeling nucleosomes (Cheng et al, 1999;Park et al, 2002) as well as a number of other proteins that may affect Myc-dependent transcription (Oster et al, 2002).…”

Deregulated expression of a novel component of TFTC/STAGA histone acetyltransferase complexes, rat SGF29, in hepatocellular carcinoma: possible implication for the oncogenic potential of c-Myc

“…The recruitment of STAGA but not TFTC complex to the c-Myc N-terminal MbII domain is critical for cMyc-dependent transactivation and transformation (McMahon et al, 2000;Liu et al, 2003). TRRAP, an integral component of GCN5 HAT complexes including STAGA, is the first factor shown to associate with MbII, and is required for the c-Myc-mediated oncogenic transformation .…”

“…TRRAP is a part of at least four classes of histone acetyltransferase (HAT) complexes such as SPT3-TAF9-GCN5-acetyltransferase (STAGA) complex, TATA-binding protein-free TAF-containing (TFTC) complex, p300/CBP-associated factor (PCAF) complex and the TIP60-containing complex (Martinez et al, 1998;Ogryzko et al, 1998;Brand et al, 1999;Ikura et al, 2000). c-Myc, through MbI and MbII domains, recruits these HAT complexes, except for TFTC complex, to regulate transcription (McMahon et al, 2000;Liu et al, 2003).…”

The conserved Myc box 2 and Myc box 3 regions are important, but not essential, for Myc function in vivo

“…Myc's N-terminal 143 amino acids contain a transcriptional regulatory domain (Kato et al, 1990) that interacts with different co-factors, such as TRRAP, a component of several histone acetyltransferase (HAT) complexes (McMahon et al, 1998), the STAGA HAT Liu et al, 2003;Liu et al, 2008), the DNA helicases Tip48 and Tip49 that also belong to different HAT and chromatin remodeling complexes , and the elongation factor P-TEFb (Eberhardy and Farnham, 2002). Accordingly, a version of c-Myc that lacks the first 100 amino acids is inefficient in trans-activating its target genes (Spotts et al, 1997;Xiao et al, 1998;Hirst and Grandori, 2000), and it is unable to transform primary cells in culture (Xiao et al, 1998) or promote cell cycle re-entry of serumstarved fibroblasts (Hirst and Grandori, 2000).…”