Antiapoptotic roles of protein kinase B isoforms

Abstract

Protein Kinase B (PKB), also known as Akt, was discovered in 1991 as the mammalian homologue of the viral oncogene product, v-akt. Subsequently, overexpression or constitutive activation of PKBα, PKBβ and PKBγ has been demonstrated in a number of cancers. The idea that inhibition of PKB in cancer cells may restore the sensitivity of cells to chemotherapeutic drugs has fuelled the search for specific inhibitors of PKB.

The aim was to manipulate PKB levels by overexpression or antisense technology to determine whether PKB regulates apoptosis. To test whether various PKB isoforms have the potential to regulate apoptosis in cells PKB levels were first modulated by overexpression. For this the activation of caspase-3 by staurosporine, an established induced or apoptosis, was employed. Overexpression of PKBα or PKBγ protected staurosporine-treated PC12 cells against the activation of caspase-3.  To rigorously establish that these results were not non-specific effects of overexpression, antisense knockout of endogeneou PKB was then used to remove individual or combinations of PKB isoforms from cells. The combined depletion of greater than 95% PKBα, PKBβ and PKBγ from 3T3-L1 adipocytes sensitised cells to staurosporine-induced caspase-3 activation. Depletion of over 95% PKBα and PKBβ, or 95% of PKBγ alone, was not sufficient to sensitise 3T3-L1 adipocytes to the activation of caspase-3 induced by staurosporine. As staurosporine inhibited the activation of PKB, this effect requires PKB proteins and clearly indicates crucial roles of PKB in interacting with other proteins.

In conclusion these results show that endogenous PKB plays a critical role in regulating apoptosis as measured by caspase-3 activation.  This antiapoptotic potential makes PKB an attractive drug target in cancer treatment.

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