Downregulation of the PI3K/Akt survival pathway in cells with deregulated expression of c-Myc |
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Authors: | Kerstin Bellmann Julie Martel Dominic J P Poirier Mireille M Labrie Jacques Landry |
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Institution: | 1. Centre de recherche en cancérologie de l'Université Laval, L'H?tel-Dieu de Québec, 9, rue McMahon, Québec, Canada, G1R 2J6
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Abstract: | Oncogenic transformation leads to an increased sensitivity to apoptosis, a characteristic that is selectively lost during
tumor progression. The sensitization process affects the mitochondrial pathway of apoptosis through signaling events that
are poorly defined. We previously showed that a deregulated expression of c-Myc in cells treated with toxic agents caused
an enhanced activation of p38 that acts in a death-promoting pathway. Here, we show that deregulated expression of c-Myc causes
a severe reduction in the basal activity of Akt, which was further accelerated by serum deprivation. Furthermore, c-Myc expression
repressed the activation of Akt induced by the toxic agents doxorubicin, cisplatin and H2O2, and also by the physiological agonists PDGF and insulin. We determined that the activation of Akt was inhibited as a result
of the action of c-Myc upstream of phosphatidylinositol 3-kinase (PI3K) activation. c-Myc overexpression impaired the induced
association of the p85 subunit of PI3K with phosphotyrosine containing proteins, causing a reduction in the activation of
PI3K and recruitment of Akt to the membrane. Inhibiting Akt in addition to enhancing p38 further exacerbate the imbalance
between the death and survival signals and results in an enhanced sensitivity to apoptosis.
This study was supported by the Canadian Institutes of Health Research Grant MOP-37860 to J.L. and K.B. and the Canada Research
Chair in Stress Signal Transduction (to J.L.). |
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Keywords: | Akt/PKB p38 Phosphoinositide 3-kinase (PI3K) c-Myc |
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