Autorepression of c-myc requires both initiator and E2F-binding site elements and cooperation with the p107 gene product
Myc proteins are transcriptional activators, but also repress transcription through initiator (Inr) elements. Repression requires the conserved Myc Box II, but the cis -acting element(s) required for c- myc autorepression have eluded definition. Since the gene has a candidate Inr at the P2 promoter,...
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Veröffentlicht in: | Oncogene 2004-02, Vol.23 (5), p.1088-1097 |
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Sprache: | eng |
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Zusammenfassung: | Myc proteins are transcriptional activators, but also repress transcription through initiator (Inr) elements. Repression requires the conserved Myc Box II, but the
cis
-acting element(s) required for c-
myc
autorepression have eluded definition. Since the gene has a candidate Inr at the P2 promoter, we tested whether Myc autorepression operates through the Inr/BoxII mechanism. Overexpression of c-Myc but not a Box II deletion mutation represses both c-
myc
P2 reporter genes and endogenous c-
myc
, as does Mxi1 expression. Only 45 nucleotides surrounding the P2 start suffice to mediate autorepression, but Myc and Mxi1 also downregulate P2 Inr mutations, suggesting other core promoter sequence requirements for autorepression. We tested the importance of conserved E2F sites, based on known Myc interaction with the pRb-related p107 and on the transrepressive effects of Rb family proteins. Myc, Mxi1, and p107 repress c-
myc
somewhat less well in the absence of E2F binding sites, while an E2F+Inr double mutation is not repressed at all by these gene products. Further, Myc repression at the c-
myc
P2 core promoter is augmented by p107, but not by pRb or p130, nor by p107 lacking the conserved pocket domain. Our data suggest that Myc autorepression requires both the c-
myc
Inr and E2F sites in
cis,
as well as p107 in
trans
. Consistent with this, we found that retrovirally transduced c-Myc cannot downregulate endogenous c-
myc
in p107-null fibroblasts, and show evidence that both Myc and p107 are present in a complex assembled at the c-
myc
P2 core promoter. |
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ISSN: | 0950-9232 1476-5594 |
DOI: | 10.1038/sj.onc.1207225 |