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Kinetic mechanisms for overexpression insensitivity and oncogene cooperation

Abstract:

Minor (5-10 fold) activation of mitogenic signalling cascades typically induces cell division upon extracellular stimulation and is sufficient to support tumourigenesis when permanently triggered by activating mutations. Surprisingly, even strong signalling protein overexpression usually does not trigger deregulated cell proliferation, suggesting that basal state signalling is insensitive to wildtype protein overexpression. Using kinetic modelling of the core Ras cycle, we show that basal RasGTP signalling can be insensitive to Ras overexpression and thus identify a possible tumour suppression mechanism. We further show how phenotypically silent overexpression events within signalling cascades cooperate to bring about carcinogenesis. Our analyses underscore the need for a systems level understanding of tumour formation.

19059249

Projects: HepatoSys

FEBS Lett.
FEBS Lett. 583(1): 93-6
4th Dec 2008

Stefan Legewie, Christine Sers, Hanspeter Herzel

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[Stefan Legewie]

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Views: 1785
  • Created: 11th Sep 2012 at 12:56
  • Last updated: 24th Oct 2013 at 16:22

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