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PMID: 8972190 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

The Myc negative autoregulation mechanism requires Myc-Max association and involves the c-myc P2 minimal promoter.

Molecular and cellular biology ·Vol. 17 ·No. 1 ·1997-01-00 ·Pages 100-14

Facchini LM, Chen S, Marhin WW, Lear JN, Penn LZ

Abstract

Increasing evidence supports an important biological role for Myc in the downregulation of specific gene transcription. Recent studies suggest that c-Myc may suppress promoter activity through proteins of the basal transcription machinery. We have previously reported that Myc protein, in combination with additional cellular factors, suppresses transcription initiation from the c-myc promoter. To characterize the cis components of this Myc negative autoregulation pathway, fragments of the human c-myc promoter were inserted upstream of luciferase reporter genes and assayed for responsiveness to inducible MycER activation in Rat-1 fibroblasts. We found four- to fivefold suppression of a c-myc P2 minimal promoter fragment upon induction of wild-type MycER protein activity, while induction of a mutant MycER protein lacking amino acids 106 to 143 required for Myc autosuppression failed to elicit this response. This assay is physiologically significant, as it reflects Myc autosuppression of the endogenous c-myc gene with regard to kinetics, dose dependency, cell type specificity, and c-Myc functional domains. Analysis of mutations within the P2 minimal promoter indicated that the cis components of Myc autosuppression could not be ascribed to any known protein-binding motifs. In addition, to address the trans factors required for Myc negative autoregulation, we expressed MycEG and MaxEG leucine zipper dimerization mutants in Rat-1 cells and found that Myc-Max heterodimerization is obligatory for Myc autosuppression. Two models for the Myc autosuppression mechanism are discussed.

MeSH Terms
3T3 Cells Animals Basic Helix-Loop-Helix Leucine Zipper Transcription Factors Basic-Leucine Zipper Transcription Factors Cell Line DNA-Binding Proteins/metabolism Dimerization Estradiol/pharmacology Estrogen Antagonists/pharmacology Gene Expression Regulation/drug effects Genes, Reporter/genetics Genes, myc/genetics Homeostasis/genetics Humans Luciferases/genetics Mice Promoter Regions, Genetic/genetics Proto-Oncogene Proteins c-myc/genetics,metabolism Rats Receptors, Estrogen/genetics Recombinant Fusion Proteins Tamoxifen/analogs & derivatives,pharmacology Transcription Factors Transcription, Genetic/physiology
Chemicals
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors Basic-Leucine Zipper Transcription Factors DNA-Binding Proteins Estrogen Antagonists MAX protein, human Max protein, rat Myc associated factor X Proto-Oncogene Proteins c-myc Receptors, Estrogen Recombinant Fusion Proteins Transcription Factors Tamoxifen Max protein, mouse afimoxifene Estradiol Luciferases
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Facchini L M
Department of Microbiology, University of Toronto, Ontario, Canada.
Chen S
Marhin W W
Lear J N
Penn L Z
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.17.1.100
Published
1997-01-00
Pages
100-14
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC231734
Subset
IM
External Links
PubMed source DOI: 10.1128/MCB.17.1.100 PMC Full Text View journal details
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