title: Bif-1 haploinsufficiency promotes chromosomal instability and accelerates Myc-driven lymphomagenesis via suppression of mitophagy.
abstract: Malignant transformation by oncogenes requires additional genetic/epigenetic changes to overcome enhanced susceptibility to apoptosis. In the present study, we report that Bif-1 (Sh3glb1), a gene encoding a membrane curvature–driving endophilin protein, is a haploinsufficient tumor suppressor that plays a key role in the prevention of chromosomal instability and suppresses the acquisition of apoptosis resistance during Myc-driven lymphomagenesis. Although a large portion of Bif-1–deficient mice harboring an Eμ-Myc transgene displayed embryonic lethality, allelic loss of Bif-1 dramatically accelerated the onset of Myc-induced lymphoma. At the premalignant stage, hemizygous deletion of Bif-1 resulted in an increase in mitochondrial mass, accumulation of DNA damage, and up-regulation of the antiapoptotic protein Mcl-1. Consistently, allelic loss of Bif-1 suppressed the activation of caspase-3 in Myc-induced lymphoma cells. Moreover, we found that Bif-1 is indispensable for the autophagy-dependent clearance of damaged mitochondria (mitophagy), because loss of Bif-1 resulted in the accumulation of endoplasmic reticulum–associated immature autophagosomes and suppressed the maturation of autophagosomes. The results of the present study indicate that Bif-1 haploinsufficiency attenuates mitophagy and results in the promotion of chromosomal instability, which enables tumor cells to efficiently bypass the oncogenic/metabolic pressures for apoptosis. .
authors.affiliation: Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Hori
authors.forename: Timothy K
authors.initials: TK
authors.lastname: Cooper
authors.forename: Jason
authors.initials: J
authors.lastname: Liao
authors.forename: Neelam
authors.initials: N
authors.lastname: Desai
authors.forename: Jacob M
authors.initials: JM
authors.lastname: Serfass
authors.forename: Megan M
authors.initials: MM
authors.lastname: Young
authors.forename: Sungman
authors.initials: S
authors.lastname: Park
authors.forename: Yayoi
authors.initials: Y
authors.lastname: Izu
authors.forename: Hong-Gang
authors.initials: HG
authors.lastname: Wang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000502:physiology; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002478:Cells, Cultured; D043171:Chromosomal Instability / Q000235:genetics*; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D016259:Genes, myc / Q000502:physiology*; D057895:Haploinsufficiency / Q000502:physiology*; D008223:Lymphoma / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D063306:Mitophagy / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C486100:Sh3glb1 protein, mouse