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How moderate changes in Akt T-loop phosphorylation impact on tumorigenesis and insulin resistance

Authors :
Stephan Wullschleger
Kei Sakamoto
Lana Johnstone
Suzanne Duce
Stewart Fleming
Dario R. Alessi
Source :
Disease Models & Mechanisms, Vol 4, Iss 1, Pp 95-103 (2011)
Publication Year :
2011
Publisher :
The Company of Biologists, 2011.

Abstract

SUMMARY 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.

Subjects

Subjects :
Medicine
Pathology
RB1-214

Details

Language :
English
ISSN :
17548403 and 17548411
Volume :
4
Issue :
1
Database :
Directory of Open Access Journals
Journal :
Disease Models & Mechanisms
Publication Type :
Academic Journal
Accession number :
edsdoj.3fd6bdb610c34164b034f5802ee8f06e
Document Type :
article
Full Text :
https://doi.org/10.1242/dmm.005603