Modeling the effect of the RB tumor suppressor on disease progression: Dependence on oncogene network and cellular context

J. L. Dean, A. K. McClendon, K. R. Stengel, E. S. Knudsen

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

The retinoblastoma tumor suppressor, RB, is a key regulator of cellular proliferation that is functionally inactivated at high frequency in human cancer. Although RB has been extensively studied with regard to tumor etiology, loss of tumor-suppressor function often occurs relatively late in tumor progression. Therefore, inactivation of RB could have a profound impact on the behavior of tumors driven by discrete oncogenes. Here, collaboration between Ras or c-Myc deregulation and RB functional state was investigated in a model of conditional genetic deletion to decipher the effects related to disease progression. These studies showed that RB loss had a robust impact on mitogen dependence, anchorage dependence and overall survival, which was significantly modified by oncogene activation. Specifically, RB deficiency predisposed c-Myc-expressing cells to cell death and reduced overall tumorigenic proliferation. In contrast, RB deficiency exacerbated the tumorigenic behavior of Ras-transformed cells in both the model system and human tumor cell lines. As these tumors exhibited highly aggressive behavior, the possibility of exploiting the intrinsic sensitivity to cell death with RB loss was evaluated. Particularly, although Ras-transformed, RB-deficient cells bypassed the G1-checkpoint elicited by pharmacological activation of the p53 pathway, they were also highly sensitized to cell death. Altogether, these data suggest that the impact of RB deletion is dependent on the oncogene milieu, and can directly contribute to transformed phenotypes and response to therapeutic intervention.

Original languageEnglish (US)
Pages (from-to)68-80
Number of pages13
JournalOncogene
Volume29
Issue number1
DOIs
StatePublished - Jan 1 2010

Keywords

  • C-Myc
  • Cell cycle checkpoints
  • Chemotherapeutics
  • Ras
  • Retinoblastoma tumor suppressor (RB)

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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