Chronic activation of protein kinase Bβ/Akt2 leads to multinucleation and cell fusion in human epithelial kidney cells:: events associated with tumorigenesis

Most cancers arise from the stepwise accumulation of genetic changes. There is also evidence for defects in the machinery and checkpoints for maintenance of normal diploid chromosome complements, resulting in genetic instability that helps fuel the accumulation of mutations that contribute to the development of cancer. The protooncogene protein kinase B (PKB/Akt), and its regulators including phosphatidylinositol 3' kinase and PTEN, has been shown to play critical roles in the regulation of multiple cellular functions such as transcription, cell survival, cell cycle progression, angiogenesis and cell motility - all of which are important to the malignant process. Here, we report the use of a membrane targeted PKB beta, the activation of which is under the control of a 4-hydroxy-Tamoxifen-responsive estrogen-receptor (ER) ligand binding domain. Induction of PKB beta-ER activity in human kidney epithelial cells (HEK293) resulted in changes in cellular growth, size, and in the appearance of aneuploid cells. Over time, in a PKB beta-dependent manner, cells also underwent extensive multinucleation caused due to a combination of both endomitosis and cell fusion. These findings suggest that chronic activation of PKB beta may contribute to genetic instability and autophagy, properties commonly found in tumor cells.