title: Upregulation of human autophagy-initiation kinase ULK1 by tumor suppressor p53 contributes to DNA-damage-induced cell death.
abstract: In yeast, activation of ATG1/ATG13 kinase complex initiates autophagy. This mechanism of autophagy initiation is conserved, as unc-51-like kinase 1 (ULK1) and unc-51-like kinase 2 (ULK2) are two mammalian functional homologues of ATG1 and form similar complex with mammalian ATG13. Here, we report that both ULK1 and ULK2 are transcriptional targets of tumor suppressor p53. In response to DNA damage, ULK1 and ULK2 are upregulated by p53. The upregulation of ULK1 (ULK2)/ATG13 complex by p53 is necessary for the sustained autophagy activity induced by DNA damage. In this context, elevated autophagy contributes to subsequent cell death. These findings suggest that ULK1 and ULK2 may mediate part of tumor suppression activity in mammalian cells and contribute to the efficacy of genotoxic chemotherapeutic drugs.
authors.affiliation: Howard Hughes Medical Institute and Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
authors.forename: W
authors.initials: W
authors.lastname: Gao
authors.forename: Z
authors.initials: Z
authors.lastname: Shen
authors.forename: L
authors.initials: L
authors.lastname: Shang
authors.forename: X
authors.initials: X
authors.lastname: Wang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D001343:Autophagy / Q000235:genetics / Q000502:physiology*; D000071189:Autophagy-Related Protein-1 Homolog; D000071183:Autophagy-Related Proteins; D016923:Cell Death / Q000235:genetics / Q000502:physiology*; D004249:DNA Damage / Q000235:genetics / Q000502:physiology; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: C534291:ATG13 protein, human; D048868:Adaptor Proteins, Signal Transducing; D000071183:Autophagy-Related Proteins; D047908:Intracellular Signaling Peptides and Proteins; D016159:Tumor Suppressor Protein p53; D000071189:Autophagy-Related Protein-1 Homolog; D017346:Protein Serine-Threonine Kinases; C484754:ULK1 protein, human; C541703:Ulk2 protein, human