Transcriptional activation by Myc is under negative control by the transcription factor AP-2.
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.
Gaubatz
S
S
Zentrum für Molekulare Biologie Heidelberg (ZMBH), Germany.
Imhof
A
A
Dosch
R
R
Werner
O
O
Mitchell
P
P
Buettner
R
R
Eilers
M
M
D000818:Animals; D001358:Avian Sarcoma Viruses; D001483:Base Sequence; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D050976:Basic-Leucine Zipper Transcription Factors; D001665:Binding Sites; D002460:Cell Line; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000378:metabolism*; D005786:Gene Expression Regulation; D018257:Helix-Loop-Helix Motifs; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009955:Ornithine Decarboxylase / Q000096:biosynthesis*; D011498:Protein Precursors / Q000096:biosynthesis*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D011994:Recombinant Proteins / Q000096:biosynthesis; D013947:Thymosin / Q000031:analogs & derivatives* / Q000096:biosynthesis; D050656:Transcription Factor AP-2; D014157:Transcription Factors / Q000096:biosynthesis / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D050976:Basic-Leucine Zipper Transcription Factors; D017931:DNA Primers; D004268:DNA-Binding Proteins; C499330:MAX protein, human; C067850:Myc associated factor X; D011498:Protein Precursors; D016271:Proto-Oncogene Proteins c-myc; D011994:Recombinant Proteins; D050656:Transcription Factor AP-2; D014157:Transcription Factors; C040782:prothymosin alpha; C068422:Max protein, mouse; D013947:Thymosin; D004247:DNA; D009955:Ornithine Decarboxylase