P13K/PTEN/Akt (PKB), Signaling and genesis of cancer

点击翻译按钮获取中文摘要

DESCRIPTION (PROVIDED BY APPLICANT): The PI 3-kinase/PTEN/Akt(PKB) signaling pathway has been recently emerged as one of the most frequently abrogated pathway in human cancer. Both PI 3-kinase and its downstream effector, the serine/threonine kinase Akt, posses oncogenic activity whereas PTEN that negates their activities is a tumor suppressor. PTEN is frequently inactivated by deletion or mutations in human cancer and heterozygous deletion of PTEN in mice induces diverse types of tumors. Thus far, the tumorigenic consequence of PTEN inactivation has been mostly attributed to elevation of Akt activity. Our long-term goal is to understand how does constitutive activation of Akt contribute to genesis of cancer at both cellular and organism levels. We have previously demonstrated that Akt promotes cell survival and blocks apoptosis induced by a variety of apoptotic stimuli and also induces protein synthesis. While these and other known activities of Akt may contribute to its oncogenic potential they may not be sufficient for Akt to exert its oncogenic function. In this proposal we intend to investigate a new activity of Akt as a regulator of DNA damage-induced G2/M checkpoint. We discovered this activity by showing that cells expressing activated Akt are resistant to exposure to 6-thioguanine (6-TG) and bypass the G2/M arrest induced by gamma-irradiation and 6-TO. This activity of Akt, which is independent of its anti-apoptotic activity and independent of p53, may be a critical determinant of its oncogenic function. We propose that the anti-apoptotic activity of Akt in conjunction with its ability to bypass G2/M checkpoint can lead to continuos cellular proliferation despite disruption of genome integrity. We will also determine the requirement of Akt for PTEN+/- induced tumorigenesis in mice by crossing PTEN+/- mice to Akt null mice. We have already disrupted the akt-1 gene in mice and crossed these mice with PTEN +/- mice to generate PTEN+/-/Aktl-/- mice. The requirement of Akt for the genesis of cancer in other mice models will be also determined. Finally, because of the frequent activation of Akt in prostate cancer we will focus on studying its role in prostate cancer by targeting activated Akt and dominant negative Akt to the mouse prostate. The studies presented in this proposal will have strong implications on determination of effective cancer therapy because many current therapy strategies rely on the induction of DNA mismatch repair, and G2/M checkpoint that lead to apoptosis.