Bif-1 haploinsufficiency promotes chromosomal instability and accelerates Myc-driven lymphomagenesis via suppression of mitophagy

Yoshinori Takahashi, Tsukasa Hori, Timothy Cooper, Jiangang (Jason) Liao, Neelam Desai, Jacob M. Serfass, Megan Marie Young, Sungman Park, Yayoi Izu, Hong-Gang Wang

Research output: Contribution to journalArticle

44 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1622-1632
Number of pages11
JournalBlood
Volume121
Issue number9
DOIs
StatePublished - Feb 28 2013

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Mitochondrial Degradation
Haploinsufficiency
Chromosomal Instability
Loss of Heterozygosity
Apoptosis
Tumors
Lymphoma
Mitochondria
Gene encoding
Autophagy
Transgenes
Oncogenes
Epigenomics
Caspase 3
Endoplasmic Reticulum
DNA Damage
Neoplasms
Proteins
Up-Regulation
Chemical activation

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Takahashi, Yoshinori ; Hori, Tsukasa ; Cooper, Timothy ; Liao, Jiangang (Jason) ; Desai, Neelam ; Serfass, Jacob M. ; Young, Megan Marie ; Park, Sungman ; Izu, Yayoi ; Wang, Hong-Gang. / Bif-1 haploinsufficiency promotes chromosomal instability and accelerates Myc-driven lymphomagenesis via suppression of mitophagy. In: Blood. 2013 ; Vol. 121, No. 9. pp. 1622-1632.
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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.",
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Bif-1 haploinsufficiency promotes chromosomal instability and accelerates Myc-driven lymphomagenesis via suppression of mitophagy. / Takahashi, Yoshinori; Hori, Tsukasa; Cooper, Timothy; Liao, Jiangang (Jason); Desai, Neelam; Serfass, Jacob M.; Young, Megan Marie; Park, Sungman; Izu, Yayoi; Wang, Hong-Gang.

In: Blood, Vol. 121, No. 9, 28.02.2013, p. 1622-1632.

Research output: Contribution to journalArticle

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T1 - Bif-1 haploinsufficiency promotes chromosomal instability and accelerates Myc-driven lymphomagenesis via suppression of mitophagy

AU - Takahashi, Yoshinori

AU - Hori, Tsukasa

AU - Cooper, Timothy

AU - Liao, Jiangang (Jason)

AU - Desai, Neelam

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AU - Izu, Yayoi

AU - Wang, Hong-Gang

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