Wellcome Trust PhD Programme for Clinicians at the University of Dundee: Defining the role of the LKB1-AMPK signalling pathway in cancer and DNA damage. (360G-Wellcome-090668_Z_09_A)

AMP-activated protein kinase (AMPK) detects changes in AMP: ATP ratio and functions as an energy sensor in cells. Activation of AMPK leads to activation of catabolic processes and inhibition of anabolic processes. In addition to its metabolic effects, AMPK also causes a G1 phase cell cycle arrest. LKB1, a tumour suppressor, is the main upstream kinase that activates AMPK. AMPK also has several downstream targets such as TSC2 and Raptor (mTOR complex) that are implicated in tumourigenesis. Recent evidence suggests that many tumour cells may have down-regulated AMPK signalling. For example, some tumour cells have lost LKB1 expression. The aims of the PhD are to look at the mechanisms underlying loss of AMPK signalling in tumour cells. We will particularly examine the role of the C- terminal tail of LKB1 and the effect of its phosphorylation on AMPK activation. It has been reported that ionising radiation induces ataxia- telangectasia mutated (ATM) kinasemediated phosphorylation of LKB1 at Thr-366. We will look at the effect of this phosphorylation on AMPK activation, which may explain in part how ionising radiation affects cell fate. We will also study the role of DNA damaging chemotherapeutic agents (such as cisplatin and etoposide) on this pathway. We will also develop a mouse model, knocking out AMPK in T lymphocytes which lack one PTEN allele to see if loss of AMPK accelerates development of lymphomas.