Abstract
The serine threonine kinase Akt1 has been implicated in the control of cellular metabolism, survival and growth. Herein, disruption of the ubiquitously expressed member of the Akt family of genes, Akt1, in the mouse, demonstrates a requirement for Akt1 in miRNA-mediated cellular apoptosis. The miR-17/20 cluster is known to inhibit breast cancer cellular proliferation through G1/S cell cycle arrest via binding to the cyclin D1 3'UTR. Here we show that miR-17/20 overexpression sensitizes cells to apoptosis induced by either Doxorubicin or UV irradiation in MCF-7 cells via Akt1. miR-17/20 mediates apoptosis via increased p53 expression which promotes Akt degradation. Akt1⁻/⁻ mammary epithelial cells which express Akt2 and Akt3 demonstrated increased apoptosis to DNA damaging agents. Akt1 deficiency abolished the miR-17/20-mediated apoptosis. These results demonstrated a novel pathway through which miR17/20 regulate p53 and Akt controlling breast cancer cell apoptosis.
Highlights
The cell survival oncoprotein Akt1, known as protein kinase B (PKB), is frequently hyperactivated in human cancers
Our previous studies demonstrated the suppression of cellular proliferation in human breast cancer cells by miR-17/20
In order to determine the potential role of miR17/20 in regulating breast cancer cell apoptosis, MCF-7 cells were transduced with a retrovirus encoding the miR17/20 cluster
Summary
The cell survival oncoprotein Akt, known as protein kinase B (PKB), is frequently hyperactivated in human cancers. Akt plays a central role in the ability of external signals to promote cell survival by preventing cytochrome c release from mitochondria [1,2,3] and maintaining mitochondrial membrane integrity by increasing hexokinase (HK) association with mitochondria [4]. In mammalian cells, activating growth factors and oncogenes stimulate Akt kinase activity to promote antiapoptotic signaling [4]. The pro-proliferative and prosurvival effects induced by Akt kinase are conducted through regulation of caspase 9, I B kinase , Bad, and induction of the GSK3/ cyclin D1 signaling pathways (reviewed in: [8, 9])
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