Identification of downstream-initiated c-Myc proteins which are dominant-negative inhibitors of transactivation by full-length c-Myc proteins.

Spotts GD, Patel SV, Xiao Q, Hann SR
Mol Cell Biol. 1997 17 (3): 1459-68

PMID: 9032273 · PMCID: PMC231871 · DOI:10.1128/mcb.17.3.1459

The c-myc gene has been implicated in multiple cellular processes including proliferation, differentiation, and apoptosis. In addition to the full-length c-Myc 1 and 2 proteins, we have found that human, murine, and avian cells express smaller c-Myc proteins arising from translational initiation at conserved downstream AUG codons. These c-Myc short (c-Myc S) proteins lack most of the N-terminal transactivation domain but retain the C-terminal protein dimerization and DNA binding domains. As with full-length c-Myc proteins, the c-Myc S proteins appear to be localized to the nucleus, are relatively unstable, and are phosphorylated. Significant levels of c-Myc S, often approaching the levels of full-length c-Myc, are transiently observed during the rapid growth phase of several different types of cells. Optimization of the upstream initiation codons resulted in greatly reduced synthesis of the c-Myc S proteins, suggesting that a "leaky scanning" mechanism leads to the translation of these proteins. In some hematopoietic tumor cell lines having altered c-myc genes, the c-Myc S proteins are constitutively expressed at levels equivalent to that of full-length c-Myc. As predicted, the c-Myc S proteins are unable to activate transcription and inhibited transactivation by full-length c-Myc proteins, suggesting a dominant-negative inhibitory function. While these transcriptional inhibitors would not be expected to function as full-length c-Myc, the occurrence of tumors which express constitutive high levels of c-Myc S and their transient synthesis during rapid cell growth suggest that these proteins do not interfere with the growth-promoting functions of full-length c-Myc.

MeSH Terms (17)

Animals Bursa of Fabricius Cell Division Cell Nucleus Chickens Codon, Initiator Humans Lymphoma Mice Molecular Weight Peptide Chain Initiation, Translational Phosphorylation Proto-Oncogene Proteins c-myc Recombinant Fusion Proteins Species Specificity Transcriptional Activation Tumor Cells, Cultured

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