Transcriptional activation by Myc is under negative control by the transcription factor AP-2.

Abstract

The Myc protein binds to and transactivates the expression of genes via E‐box elements containing a central CAC(G/A)TG sequence. The transcriptional activation function of Myc is required for its ability to induce cell cycle progression, cellular transformation and apoptosis. Here we show that transactivation by Myc is under negative control by the transcription factor AP‐2. AP‐2 inhibits transactivation by Myc via two distinct mechanisms. First, high affinity binding sites for AP‐2 overlap Myc‐response elements in two bona fide target genes of Myc, prothymosin‐alpha and ornithine decarboxylase. On these sites, AP‐2 competes for binding of either Myc/Max heterodimers or Max/Max homodimers. The second mechanism involves a specific interaction between C‐terminal domains of AP‐2 and the BR/HLH/LZ domain of Myc, but not Max or Mad. Binding of AP‐2 to Myc does not preclude association of Myc with Max, but impairs DNA binding of the Myc/Max complex and inhibits transactivation by Myc even in the absence of an overlapping AP‐2 binding site. Taken together, our data suggest that AP‐2 acts as a negative regulator of transactivation by Myc.

Tuberous sclerosis complex is required for tumor maintenance in MYC‐driven Burkitt's lymphoma

“…PRC fragments were digested with KpnI and XhoI and cloned into the pGL3‐Basic Firefly luciferase vector (Promega). The pTK‐Ap2/E (renamed in E‐box Rep ) and pTK‐AP2/mut4 (renamed in E‐box RepMut ) E‐box luciferase reporter constructs were obtained from Martin Eilers (Gaubatz et al , 1995). 20 h before transfection, HeLa cells were seeded in a 96‐well plate (5,000 cells per well).…”

MSSP promotes ras/myc cooperative cell transforming activity by binding to c‐Myc

“…Complex formation with various proteins may realize versatile functions of c-Myc, and indeed several proteins have been identi®ed as associating with c-Myc. Max (Blackwood & Eisenman 1991;Blackwood et al 1992), Nmi (Bao & Zervos 1996), YY1 (Shrivastava et al 1993) AP2 (Gaubatz et al 1995), SNF5 (Cheng et al 1999) and CBF/NF-Y (Taira et al 1999) bind to the C-terminal region of c-Myc, while p107 (Beijersbergen et al 1994;Gu et al 1994;Hoang et al 1995), Bin1 (Sakamuro et al 1996), TBP (Hateboer et al 1993;Maheswaran et al 1994), a-tubulin (Alexandrova et al 1995), TRRAP (McMahon et al 1998), Pam (Guo et al 1998), AMY-1 ) and MM-1 (Mori et al 1998) bind to the N-terminal region. Max stimulates the activities of c-Myc in transcription and transformation by heterodimer formation via a leucine zipper (Blackwood & Eisenman 1991;Blackwood et al 1992).…”

DNA binding of USF is required for specific E-box dependent gene activation in vivo

“…In the genomic-sequence of prothymosin-a, the Mycresponsive E-box element (E1) is located 2 kb downstream from the start site of transcription (Gaubatz et al, 1995). We therefore repeated the experiment using a reporter plasmid in which the entire gene up to exon 2 is fused inframe to luciferase coding sequences within exon 2 (ProT-luc) ( Figure 4a).…”

“…IgH enhancer reporter plasmids and CMV-E47 were generously provided by Tom Kadesch and have been described (Carter et al, 1997), prothymosin receptor constructs are described elsewhere (Gaubatz et al, 1995). Details of the construction of the Gal4-E2 and Gal4-mutE2 and the mutE1/mutE2 reporter plasmids, and of the expression plasmids expressing Vp16-TFE-3, USF-1mutbr, USF-1Dbr, MaxDbr, Maxmutbr and USF-1 in an inducible manner will be provided upon request.…”

“…Nuclear extracts and electrophoretic mobility shift assays (EMSA) Nuclear extracts were prepared as described before (Gaubatz et al, 1995). Double stranded oligonucleotides used for EMSA analyses (top strand only shown) include MB2 5'-AGG GGA CAC GTG GCC CGG-; MB2.M1 (mutant Ebox) 5'-AGG GAC ACC TGG CCC GG- (Bello Fernandez et al, 1993); P9599 5' -GTG TAA ACA CGC CGT GGG AAA AA-and kB (Promega) 5'-AGT TGA GGGGAC TTT CCC AGG-.…”