Induction of ornithine decarboxylase by IL-3 is mediated by sequential c-Myc-independent and c-Myc-dependent pathways (original) (raw)

Oncogene volume 15, pages 1219–1232 (1997)Cite this article

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.

This is a preview of subscription content, access via your institution

Access options

Subscribe to this journal

Receive 50 print issues and online access

$259.00 per year

only $5.18 per issue

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Additional access options:

Similar content being viewed by others

Author information

Authors and Affiliations

  1. Department of Biochemistry, St Jude Children's Research Hospital, Memphis, 38105, Tenessee, USA
    Graham Packham & John L Cleveland
  2. Ludwig Institute for Cancer Research, Imperial College School of Medicine at St Mary's, London, W2 1PG, UK
    Graham Packham
  3. Department of Medical Microbiology, Virology and Cell Biology, Imperial College School of Medicine at St Mary's, London, W2 1PG, UK
    Graham Packham
  4. Department of Biochemistry, University of Tennessee, Memphis, 38163, Tennessee, USA
    John L Cleveland

Authors

  1. Graham Packham
    You can also search for this author inPubMed Google Scholar
  2. John L Cleveland
    You can also search for this author inPubMed Google Scholar

Rights and permissions

About this article

Cite this article

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

Download citation

Keywords

This article is cited by