Induction of ornithine decarboxylase by IL-3 is mediated by sequential c-Myc-independent and c-Myc-dependent pathways (original) (raw)
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- Published: 04 September 1997
Oncogene volume 15, pages 1219–1232 (1997)Cite this article
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Abstract
Enforced c-Myc expression promotes continuous, growth factor-independent, cell cycle progression and activates expression of the ornithine decarboxylase (ODC) gene and its promoter. c-Myc-responsiveness of murine ODC is mediated by two conserved c-Myc:Max E-boxes in ODC intron 1. c-Myc and ODC are both required for cell growth and their expression is sequentially induced in G0/G1 cells stimulated with mitogens, yet their expression is not modulated by the cell cycle in proliferating cells. Here we demonstrate that regulation of ODC and its promoter by Interleukin-3 (IL-3) in murine myeloid cells is mediated in part by c-Myc. c-Myc induced ODC through the same transcription start site as IL-3 and, in asynchronously growing cells, maximal activity of the ODC promoter required the intronic c-Myc binding sites. However, induction of ODC following IL-3 stimulation of quiescent cells is mediated by at least two pathways. The first phase of this response was independent of the intronic c-Myc:Max E-boxes and de novo protein synthesis. Sustained induction of the ODC promoter however required the c-Myc:Max binding sites and protein synthesis. Accumulation of c-Myc following stimulation of quiescent cells with IL-3 correlated with the delayed phase of the response. Consistent with a two pathway model of ODC regulation, inducible overexpression of dominant negative form of c-Myc (In373-Myc), which specifically inhibits the c-Myc-Max network, inhibited the delayed, but not immediate, induction of ODC promoter activity in response to IL-3. Dominant negative c-Myc protein also effectively suppressed induction of the endogenous ODC gene by IL-3. Therefore, c-Myc functions as a direct and required regulator of ODC. These results also suggest a model whereby c-Myc's role in regulating its targets may be to convert a transient, immediate-early, activation event into the persistent induction of gene expression.
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Authors and Affiliations
- Department of Biochemistry, St Jude Children's Research Hospital, Memphis, 38105, Tenessee, USA
Graham Packham & John L Cleveland - Ludwig Institute for Cancer Research, Imperial College School of Medicine at St Mary's, London, W2 1PG, UK
Graham Packham - Department of Medical Microbiology, Virology and Cell Biology, Imperial College School of Medicine at St Mary's, London, W2 1PG, UK
Graham Packham - Department of Biochemistry, University of Tennessee, Memphis, 38163, Tennessee, USA
John L Cleveland
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Packham, G., Cleveland, J. Induction of ornithine decarboxylase by IL-3 is mediated by sequential c-Myc-independent and c-Myc-dependent pathways.Oncogene 15, 1219–1232 (1997). https://doi.org/10.1038/sj.onc.1201273
- Received: 25 February 1997
- Accepted: 13 May 1997
- Issue Date: 04 September 1997
- DOI: https://doi.org/10.1038/sj.onc.1201273