Mechanisms of transcriptional repression by the proto-oncogene c-Myc

Abstract

Several mechanisms of c-Myc-mediated transcriptional repression have been reported, but repression is best described when c-Myc interacts with the initiator element(Inr)-binding protein Miz-1.  c-Myc displaces co-activator proteins from binding Miz-1 and thereby represses transcription.  An alternative mechanism involves c-Myc binding Sp1 in a large inactive complex.  Mechanisms of c-Myc-mediated transcriptional repression have been examined and compared using the Nramp1 and NCAM genes.  Both genes have TATA box-deficient promoters, with NCAM, encoding a repertoire of adhesion molecules, and incorporates two Inr and one consensus Sp1 binding site.  Nramp1, encoding a macrophage-restricted divalent cation transporter, has a unique arrangement of a tandem duplication of  Inrs and one consensus Sp1 binding site.

Nramp1 is uniquely responsive to Miz-1-mediated transactivation and inhibition by RNAi directed against Miz-1, whereas, both promoters show a dependence on Sp1 for basal transcription.  A c-MycV394D mutant that prevents c-Myc-Miz-1 interaction, attenuates c-Myc’s ability to repress Nramp1 transcription.  The same mutation is silent with regard to attenuating NCAM repression.  These data indicate that Nramp1 is regulated specifically via Miz-1 and NCAM is subjected to Miz-1-independent regulation.  Data using a chromatin immunoprecipitation assay for Miz-1 are supportive of the functional data, as Miz-1 only is bound to the Nramp1 Inr.  Data are supportive of a mechanism by which c-Myc is recruited to the NCAM promoter through a conserved Sp1 site and repression is sensitive to TSA treatment suggesting active repression.  Nramp1 repression is TSA insensitive and repression is likely through a passive mechanism of co-activator displacement.  Both mechanisms proposed require intact Myc-Max heterodimers.

More information

Identifiers

Catalogue record

Export record

ASCII CitationAtomBibTeXData Cite XMLDublin CoreDublin CoreEP3 XMLEndNoteHTML CitationHTML CitationHTML ListJSONMETSMODSMPEG-21 DIDLOpenURL ContextObjectOpenURL ContextObject in SpanRDF+N-TriplesRDF+N3RDF+XMLRIOXX2 XMLReferReference ManagerSimple Metadata