Developmental context determines latency of MYC-induced tumorigenesis

Shelly Beer, Anders Zetterberg, Rebecca A. Ihrie, Ryan A. McTaggart, Qiwei Yang, Nicole Bradon, Constadina Arvanitis, Laura D. Attardi, Sandy Feng, Boris Ruebner, Robert Cardiff, Dean W. Felsher

Research output: Contribution to journalArticle

103 Scopus citations

Abstract

One of the enigmas in tumor biology is that different types of cancers are prevalent in different age groups. One possible explanation is that the ability of a specific oncogene to cause tumorigenesis in a particular cell type depends on epigenetic parameters such as the developmental context. To address this hypothesis, we have used the tetracycline regulatory system to generate transgenic mice in which the expression of a c-MYC human transgene can be conditionally regulated in murine hepatocytes. MYC's ability to induce tumorigenesis was dependent upon developmental context. In embryonic and neonatal mice, MYC overexpression in the liver induced marked cell proliferation and immediate onset of neoplasia. In contrast, in adult mice MYC overexpression induced cell growth and DNA replication without mitotic cell division, and mice succumbed to neoplasia only after a prolonged latency. In adult hepatocytes, MYC activation failed to induce cell division, which was at least in part mediated through the activation of p53. Surprisingly, apoptosis is not a barrier to MYC inducing tumorigenesis. The ability of oncogenes to induce tumorigenesis may be generally restrained by developmentally specific mechanisms. Adult somatic cells have evolved mechanisms to prevent individual oncogenes from initiating cellular growth, DNA replication, and mitotic cellular division alone, thereby preventing any single genetic event from inducing tumorigenesis. Copyright:

Original languageEnglish (US)
JournalPLoS Biology
Volume2
Issue number11
DOIs
StatePublished - Nov 1 2004

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Agricultural and Biological Sciences(all)

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    Beer, S., Zetterberg, A., Ihrie, R. A., McTaggart, R. A., Yang, Q., Bradon, N., Arvanitis, C., Attardi, L. D., Feng, S., Ruebner, B., Cardiff, R., & Felsher, D. W. (2004). Developmental context determines latency of MYC-induced tumorigenesis. PLoS Biology, 2(11). https://doi.org/10.1371/journal.pbio.0020332