Vivo-Morpholinos: Same oligos, from cultures to critters -


How moderate changes in Akt T-loop phosphorylation impact on tumorigenesis and insulin resistance
Stephan Wullschleger, Kei Sakamoto, Lana Johnstone, Suzanne Duce, Stewart Fleming, Dario R. Alessi


The Akt signalling pathway plays vital roles in controlling cellular responses to insulin as well as in proliferation and survival. Inhibition of Akt signalling leads to insulin resistance and type 2 diabetes, whereas hyperactivation of Akt promotes tumorigenesis. In this study, we investigate how modest changes in the activity of the Akt signalling pathway, to an extent that might be achieved by drug treatment, would impact on insulin resistance and tumorigenesis. Using insulin-resistant PDK1K465E/K465E PH domain knock-in mice, we found that introducing the PTEN+/− mutation to slightly stimulate Akt restored normal insulin sensitivity. Introducing the PDK1K465E/K465E PH domain knock-in mutation into cancer-prone PTEN+/− mice, lowered Akt activity only by about 50%, but led to a delay in tumour onset of ∼4 months in a broad range of tumours. This was also accompanied by slower growth of B cell follicular lymphomas, as monitored by magnetic resonance imaging. Our findings imply that signal transduction inhibitors that lead to a modest reduction in Akt activity would not only delay onset of tumours possessing elevated phosphoinositide 3-kinase pathway activity but would also reduce the growth rate of developed tumours.



    The authors declare no competing interests.


    S.W. and D.R.A. conceived of the project. All authors were involved in planning and analysing the experimental data. S.W. undertook most of the experimentation. K.S. helped with insulin studies, S.D. undertook the MRI analysis and S.F. and L.J. performed the immunohistochemistry and tumour classifications. S.W. and D.R.A. wrote manuscript. D.R.A. supervised the project.

  • Received February 22, 2010.
  • Accepted August 11, 2010.

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