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Sef downregulation by Ras causes MEK1/2 to become aberrantly nuclear localized leading to polyploidy and neoplastic

Stéphanie Duhamel1, Josée Hébert, Louis Gaboury

  • 1Program of Molecular Biology, Institut de Recherche en Immunologie et Cancérologie, Université de Montréal, Montreal, Quebec, Canada.

Cancer Research
|February 3, 2012
PubMed

Insights

Ras activation drives cancer by causing abnormal nuclear localization of MEK1/2, a key signaling molecule. Downregulation of Sef, a spatial regulator, enables this process, leading to uncontrolled cell growth and tumor formation.

Area of Science:

  • Cell Biology
  • Oncology
  • Molecular Biology

Background:

  • Subcellular trafficking of oncogenic signal pathway components is vital for neoplastic transformation.
  • Spatial control of these trafficking processes remains poorly understood.

Purpose of the Study:

  • To investigate how Ras activation leads to aberrant nuclear localization of phosphorylated mitogen-activated protein kinase (MAPK) kinase (MEK) MEK1/2.
  • To determine the role of this aberrant localization in neoplastic transformation and tumorigenesis.

Main Methods:

  • Examined the localization of phosphorylated MEK1/2 in primary colorectal tumors and human colon cancer cells.
  • Utilized oncogenic Ras activation in intestinal epithelial cells to study MEK1/2 and extracellular signal-regulated kinase (ERK) 1/2 nuclear accumulation.
  • Investigated the effect of enforced nuclear MEK1 localization in epithelial cells and fibroblasts.
  • Assessed the role of the spatial regulator Sef in Ras-induced MEK1/2 nuclear accumulation and its impact on tumorigenesis.

Main Results:

  • Phosphorylated MEK1/2 was found to be aberrantly localized in the nucleus of colorectal tumors and colon cancer cells.
  • Oncogenic Ras activation induced nuclear accumulation of phosphorylated MEK1/2 and ERK1/2 in intestinal epithelial cells.
  • Enforced nuclear MEK1 localization promoted ERK1/2 hyperactivation, driving cell proliferation, polyploidy, and tumorigenesis.
  • Ras-induced nuclear MEK1/2 accumulation depended on Sef downregulation; Sef reexpression reversed these effects.

Conclusions:

  • Ras-induced downregulation of Sef is an early oncogenic event.
  • This downregulation sustains nuclear ERK1/2 signaling, contributing to genetic instability and tumor progression.

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