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Induction of Mesenchymal-Epithelial Transitions in Sarcoma Cells
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The ZEB1 transcription factor acts in a negative feedback loop with miR200 downstream of Ras and Rb1 to regulate Bmi1

Yongqing Liu1, Ester Sánchez-Tilló, Xiaoqin Lu

  • 1From the Molecular Targets Program, James Brown Cancer Center.

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|December 28, 2013
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Mutant Ras triggers tumor suppression in primary cells by repressing Bmi1, but promotes cancer progression in tumor cells. This occurs through the Rb1 pathway

Keywords:
CancerCancer BiologyCell SignalingEpithelial Mesenchymal TransitionSenescence

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Area of Science:

  • Oncology
  • Molecular Biology
  • Cellular Biology

Background:

  • Ras mutations drive cancer proliferation and apoptosis resistance.
  • In primary cells, mutant Ras induces oncogene-induced senescence, a tumor suppressor function.
  • The polycomb factor Bmi1 regulates cell cycle inhibitory cyclin-dependent kinase inhibitors (cdki).

Purpose of the Study:

  • To elucidate the opposing roles of Ras in primary versus cancer cells.
  • To investigate the mechanism by which Ras regulates Bmi1 expression.
  • To understand the role of the Rb1 pathway and ZEB1 in Ras-mediated cellular fate decisions.

Main Methods:

  • Analysis of Ras signaling in primary and cancer cells.
  • Investigation of the ZEB1-miR-200 feedback loop.
  • Assessment of Rb1 pathway status in relation to Ras-induced gene expression.

Main Results:

  • Mutant Ras represses Bmi1 in primary cells via Rb1-mediated ZEB1 repression, inducing senescence.
  • In cancer cells lacking Rb1 pathway activity, Ras induces ZEB1, leading to Bmi1 upregulation and tumor progression.
  • The ZEB1-miR-200 loop, regulated by Rb1 status, dictates the switch between senescence and tumor initiation downstream of Ras.

Conclusions:

  • Rb1 pathway status is critical in determining the cellular response to mutant Ras.
  • The ZEB1-miR-200-Bmi1 axis provides a novel mechanism for Ras to control senescence versus oncogenesis.
  • Targeting this pathway could offer new therapeutic strategies for Ras-driven cancers.