title: AMPK couples p73 with p53 in cell fate decision.
abstract: The p53 family of proteins has an important role in determining cell fate in response to different types of stress, such as DNA damage, hypoxia, or oncogenic stress. In recent years, p53 has also been shown to respond to metabolic stress, and to be induced by the AMP-activated protein kinase (AMPK), a central cellular energy sensor. A bioinformatic analysis revealed three putative AMPK phopshorylation sites in p73, a p53 tumor suppressor paralog. In vitro and in vivo assays confirmed that AMPK phosphorylates p73 on a novel residue, S426. Following specific pharmacologic stimulation of AMPK in cells, p73 protein half-life was prolonged leading to p73 accumulation in the nucleus. We show that p73 escaped the E3 ligase Itch resulting in reduced p73 ubiquitination and proteasomal degradation. Furthermore, chronic activation of AMPK led to apoptosis that was p73 dependent, but only in p53-expressing cells. Surprisingly, we found that p73 was required for p53 stabilization and accumulation under AMPK activation, but was dispensable under DNA damage. Our findings couple p73 with p53 in determining cell fate under AMPK-induced metabolic stress.
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Y
authors.initials: Y
authors.lastname: Adamovich
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: J
authors.initials: J
authors.lastname: Adler
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: V
authors.initials: V
authors.lastname: Meltser
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: N
authors.identifier: 0000000315693818
authors.initials: N
authors.lastname: Reuven
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Y
authors.initials: Y
authors.lastname: Shaul
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D002454:Cell Differentiation; D019070:Cell Lineage; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism*; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D055372:AMP-Activated Protein Kinases