title: Sh3glb1/Bif-1 and mitophagy: acquisition of apoptosis resistance during Myc-driven lymphomagenesis.
abstract: Evasion of apoptosis, which enables cells to survive and proliferate under metabolic stress, is one of the hallmarks of cancer. We have recently reported that SH3GLB1/Bif-1 functions as a haploinsufficient tumor suppressor to prevent the acquisition of apoptosis resistance and malignant transformation during Myc-driven lymphomagenesis. SH3GLB1 is a membrane curvature-inducing protein that interacts with BECN1 though UVRAG and regulates the post-Golgi trafficking of membrane-integrated ATG9A for autophagy. At the premalignant stage, allelic loss of Sh3glb1 enhances Myc-induced chromosomal instability and results in the upregulation of anti-apoptotic proteins, including MCL1 and BCL2L1. Notably, we found that Sh3glb1 haploinsufficiency increases mitochondrial mass in overproliferated prelymphomatous Eμ-Myc cells. Moreover, loss of Sh3glb1 suppresses autophagy-dependent mitochondrial clearance (mitophagy) in PARK2/Parkin-expressing mouse embryonic fibroblasts (MEFs) treated with the mitochondrial uncoupler CCCP. Interestingly, PARK2-expressing Sh3glb1-deficient cells accumulate ER-associated immature autophagosome-like structures after treatment with CCCP. Taken together, we propose a model of mitophagy in which SH3GLB1 together with the class III phosphatidylinositol 3-kinase complex II (PIK3C3CII) (PIK3R4-PIK3C3-BECN1-UVRAG) regulates the trafficking of ATG9A-containing Golgi-derived membranes (A9(+)GDMs) to damaged mitochondria for autophagosome formation to counteract oncogene-driven tumorigenesis.
authors.affiliation: Department of Pharmacology; Penn State Hershey Cancer Institute; Penn State College of Medicine; Hershey, PA USA.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Megan M
authors.initials: MM
authors.lastname: Young
authors.forename: Jacob M
authors.initials: JM
authors.lastname: Serfass
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Hori
authors.forename: Hong-Gang
authors.initials: HG
authors.lastname: Wang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D006801:Humans; D008223:Lymphoma / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D063306:Mitophagy; D008954:Models, Biological; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016271:Proto-Oncogene Proteins c-myc
keywords: DNA damage; MCL1; MYC; SH3GLB1/Bif-1; apoptosis; autophagy; chromosome instability; lymphoma; malignant transformation; mitophagy