title: BH3 mimetics reveal the network properties of autophagy-regulatory signaling cascades.
abstract: Beclin 1 usually interacts with several autophagy-inhibitory proteins including the anti-apoptotic proteins from the Bcl-2 family (Bcl-2, Bcl-XL and Mcl-1) and the inositol-1,4,5 trisphosphate (IP 3) receptor, which interacts with Beclin 1 indirectly, via Bcl-2. Beclin 1 possesses a BH3 domain that usually interacts with a hydrophobic cleft, the BH3 receptor domain, contained within Bcl-2 and its homologues. Dissociation of this interaction can be induced by phosphorylation or ubiquitination of the BH3 domain, by post-transcriptional modifications affecting the Bcl-2 protein, as well as by other BH3 domain-containing proteins that have a high affinity for Bcl-2 (or its homologues), and hence liberate Beclin 1 from its restraint. As a result, it has been thought that so-called BH3 mimetics, that is the pharmacological agents that occupy the hydrophobic cleft of Bcl-2, Bcl-XL and Mcl-1, would induce autophagy solely by disrupting the interaction between Beclin 1 and its inhibitors. Unexpectedly, we found that two distinct BH3 mimetics, ABT737 and HA14-1, also stimulate other pro-autophagic pathways and hence activate the nutrient sensors Sirtuin 1 and AMPK, inhibit mTOR, deplete cytoplasmic p53 and trigger the IKK kinase. All these additional activities are required for optimal autophagy induction by BH3 mimetics, pointing to the existence of a coordinated autophagy-regulatory network.
authors.affiliation: INSERM U848, Villejuif, France.
authors.forename: Shoaib Ahmad
authors.initials: SA
authors.lastname: Malik
authors.forename: Shensi
authors.initials: S
authors.lastname: Shen
authors.forename: Guillermo
authors.initials: G
authors.lastname: Mariño
authors.forename: Amena
authors.initials: A
authors.lastname: BenYounès
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Maiuri
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
mesh_terms: D000818:Animals; D001343:Autophagy; D006801:Humans; D008024:Ligands; D008954:Models, Biological; D017434:Protein Structure, Tertiary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction; D037761:Sirtuins / Q000037:antagonists & inhibitors / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D008024:Ligands; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D037761:Sirtuins