[BIO Colloquium] Novel Role of AMP-activated Protein Kinase under Genotoxic Stress
  • Joo Hun Ha, Ph.D.(Kyung Hee University)
  • SLS Colloquia / Apr 15th 04:00pm / AMRB 113
Abstract
AMP-activated protein kinase (AMPK) plays a central role in the regulation of energy homeostasis. Once activated under various metabolic stress conditions, AMPK regulates a multitude of metabolic pathways to protect cells from ATP-depleting stresses. It is now considered a significant pharmacological target for the treatment of metabolic disorders such as obesity and type 2 diabetes. In contrast to the well-established role of AMPK in metabolic regulation, there is no consensus on its role or the underlying mechanism under genotoxic stress. Here, we report the differential roles of AMPKα subunits under genotoxic stresses such as doxorubicin. Doxorubicin robustly induced AMPKα2 expression, whereas it slightly reduced the level of AMPKα1 in MEFs. Our data demonstrate that AMPKα1 harbors survival properties, whereas AMPKα2 significantly contributes to cell death. In response to doxorubicin, the transcription level of AMPK alpha2 subunit was induced by a transcription factor E2F1, leading to cell apoptosis. We also observed a positive feedback regulation between AMPK and E2F1; AMPK stabilizes E2F1 and enhances its transcriptional activity by directly phosphorylating E2F1. This signal loop appears to be non-carcinoma specific because AMPKα2 was not induced by doxorubicin in five different tested cancer cell lines. These results suggest that AMPKα2 may serve as a novel target for alleviating the cytotoxicity of doxorubicin.