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  • Mitophagy defects arising from BNip3 loss promote mammary tumor progression to metastasis
    Mitophagy defects arising from BNip3 loss promote mammary tumor progression to metastasis
    1. Aparajita H Chourasia1,2,
    2. Kristin Tracy1,2,
    3. Casey Frankenberger1,
    4. Michelle L Boland1,3,
    5. Marina N Sharifi1,2,
    6. Lauren E Drake1,4,
    7. Joseph R Sachleben5,
    8. John M Asara6,
    9. Jason W Locasale7,
    10. Gregory S Karczmar8 and
    11. Kay F Macleod*,1,2,3
    1. 1The Ben May Department for Cancer Research, The University of Chicago, Chicago, IL, USA
    2. 2The Committee on Cancer Biology, Chicago, IL, USA
    3. 3The Committee on Molecular Metabolism and Nutrition, Chicago, IL, USA
    4. 4The Committee on Molecular Pathogenesis & Molecular Medicine, Chicago, IL, USA
    5. 5Biomolecular NMR Facility, The University of Chicago, Chicago, IL, USA
    6. 6Division of Signal Transduction, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
    7. 7Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA
    8. 8Department of Radiology, The University of Chicago, Chicago, IL, USA
    1. *Corresponding author. Tel: +1 773 834 8309; Fax: +1 773 702 4476; E‐mail: kmacleod{at}uchicago.edu

    This study shows that BNip3 loss and the ensuing defects in mitophagy lead to ROS production, Hif transcriptional responses and mammary tumor progression. BNIP3 deletion is a prognostic marker of metastatic potential in triple negative breast cancer.

    Synopsis

    This study shows that BNip3 loss and the ensuing defects in mitophagy lead to ROS production, Hif transcriptional responses and mammary tumor progression. BNIP3 deletion is a prognostic marker of metastatic potential in triple negative breast cancer.

    • Elevated ROS production by dysfunctional mitochondria in BNip3 null tumors results in increased Hif‐1α levels and increased tumor progression to invasiveness.

    • This novel negative feedback loop between BNip3 and Hif‐1α limits the oncogenic activity of Hif‐1 in glycolysis and angiogenesis.

    • Defective mitochondria and aerobic glycolysis arising from loss of BNip3 is associated with increased dependence on autophagy for survival.

    • BNIP3 is focally deleted in triple negative breast cancer and, together with high HIF‐1α levels, strongly predicts progression to metastasis in TNBC patients.

    • BNip3
    • breast cancer
    • glycolysis
    • HIF‐1α
    • invasive carcinoma
    • mitophagy
    • ROS
    • Received May 29, 2015.
    • Revision received July 8, 2015.
    • Accepted July 9, 2015.
    Aparajita H Chourasia, Kristin Tracy, Casey Frankenberger, Michelle L Boland, Marina N Sharifi, Lauren E Drake, Joseph R Sachleben, John M Asara, Jason W Locasale, Gregory S Karczmar, Kay F Macleod
  • Mitochondrial metabolism in hematopoietic stem cells requires functional FOXO3
    Mitochondrial metabolism in hematopoietic stem cells requires functional FOXO3
    1. Pauline Rimmelé1,,
    2. Raymond Liang1,2,,
    3. Carolina L Bigarella1,,
    4. Fatih Kocabas3,
    5. Jingjing Xie3,
    6. Madhavika N Serasinghe4,
    7. Jerry Chipuk4,5,
    8. Hesham Sadek3,6,
    9. Cheng Cheng Zhang6 and
    10. Saghi Ghaffari*,1,2,5,7,8
    1. 1Department of Developmental & Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
    2. 2Developmental and Stem Cell Biology Multidisciplinary Training Area, Icahn School of Medicine at Mount Sinai, New York, NY, USA
    3. 3Division of Cardiology, UT Southwestern Medical Center, Dallas, TX, USA
    4. 4Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
    5. 5Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
    6. 6Department of Physiology, UT Southwestern Medical Center, Dallas, TX, USA
    7. 7Division of Hematology, Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
    8. 8Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
    1. *Corresponding author. Tel: +1 212 659 8271; Fax: +1 212 803 6740; E‐mail: saghi.ghaffari{at}mssm.edu
    1. These authors contributed equally to this work

    FOXO3 regulates oxidative stress in LT‐HSCs, which are highly sensitive to increased reactive oxygen species. However, while the impaired function of Foxo3−/− LT‐HSCs is associated with defective mitochondrial metabolism, it is not mediated by oxidative stress or mTOR signaling.

    Synopsis

    FOXO3 regulates oxidative stress in LT‐HSC, which are highly sensitive to increased reactive oxygen species. However, while the impaired function of Foxo3−/− LT‐HSC is associated with defective mitochondrial metabolism, it is not mediated by oxidative stress or mTOR signaling.

    • Mitochondrial metabolism is impaired in Foxo3−/− LT‐HSCs.

    • Defects in Foxo3−/− LT‐HSC activity in vivo or Foxo3−/− LT‐HSC mitochondrial function are not mediated by oxidative stress.

    • FOXO3
    • HSC
    • metabolism
    • mitochondria
    • ROS
    • Received October 9, 2014.
    • Revision received June 11, 2015.
    • Accepted June 15, 2015.
    Pauline Rimmelé, Raymond Liang, Carolina L Bigarella, Fatih Kocabas, Jingjing Xie, Madhavika N Serasinghe, Jerry Chipuk, Hesham Sadek, Cheng Cheng Zhang, Saghi Ghaffari
  • DGCR8 is essential for tumor progression following PTEN loss in the prostate
    DGCR8 is essential for tumor progression following PTEN loss in the prostate
    1. Cassandra D Belair*,1,2,3,
    2. Alireza Paikari1,2,
    3. Felix Moltzahn1,3,
    4. Archana Shenoy1,3,
    5. Christina Yau4,5,
    6. Marc Dall'Era3,
    7. Jeff Simko3,6,
    8. Christopher Benz4,5 and
    9. Robert Blelloch1,2,3,6
    1. 1The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California – San Francisco, San Francisco, CA, USA
    2. 2Center for Reproductive Sciences, University of California – San Francisco, San Francisco, CA, USA
    3. 3Department of Urology, University of California – San Francisco, San Francisco, CA, USA
    4. 4Department of Medicine, University of California – San Francisco, San Francisco, CA, USA
    5. 5Buck Institute for Research on Aging, Novato, CA, USA
    6. 6Department of Anatomic Pathology, University of California – San Francisco, San Francisco, CA, USA
    1. *Corresponding author. Tel: +1 415 476 2838; E‐mail: cassandra.belair{at}ucsf.edu

    This study uncovers an essential role for the microRNA biogenesis factor DGCR8 in prostate tumor progression following PTEN loss. The simultaneous deletion of Dgcr8 and Pten allows early progression to hyperplasia but not later progression to dysplasia.

    Synopsis

    This study uncovers an essential role for the microRNA biogenesis factor DGCR8 in prostate tumor progression following PTEN loss. The simultaneous deletion of Dgcr8 and Pten allows early progression to hyperplasia but not later progression to dysplasia.

    • DGCR8 loss prevents growth and progression of Pten null prostate tumors.

    • DGCR8 loss mainly inhibits expansion of the basal cell compartment of the Pten null epithelium.

    • Small RNA sequencing reveals numerous microRNA level changes associated with PTEN loss.

    • Increases in DGCR8 are associated with AKT activation in a large cohort of human patient samples.

    • DGCR8
    • microRNA
    • microRNA biogenesis
    • prostate cancer
    • PTEN
    • Received November 25, 2014.
    • Revision received June 24, 2015.
    • Accepted June 27, 2015.
    Cassandra D Belair, Alireza Paikari, Felix Moltzahn, Archana Shenoy, Christina Yau, Marc Dall'Era, Jeff Simko, Christopher Benz, Robert Blelloch
  • BRHIS1 suppresses rice innate immunity through binding to monoubiquitinated H2A and H2B variants
    BRHIS1 suppresses rice innate immunity through binding to monoubiquitinated H2A and H2B variants
    1. Xiaoyu Li1,2,
    2. Yanxiang Jiang1,2,
    3. Zhicheng Ji1,2,
    4. Yaoguang Liu*,1,2 and
    5. Qunyu Zhang*,1,2
    1. 1State Key Laboratory for Conservation and Utilization of Subtropical Agro‐bioresources, College of Life Sciences, South China Agricultural University, Guangzhou, China
    2. 2Key Laboratory of Plant Functional Genomics and Biotechnology of Guangdong Provincial Higher Education Institutions, College of Life Sciences, South China Agricultural University, Guangzhou, China
    1. * Corresponding author. Tel: +86 20 85281908; Fax: +86 20 85280200; E‐mail: ygliu{at}scau.edu.cn

      Corresponding author. Tel: +86 20 85288395; Fax: +86 20 85282180; E‐mail: zqy{at}scau.edu.cn

    The plant chromatin remodeler BRHIS1 represses the poised promoters of disease defense genes by binding monoubiquitinated histone variants. Repression is counteracted by BRHIS1 down‐regulation upon infection.

    Synopsis

    The plant chromatin remodeler BRHIS1 is recruited to the promoters of genes implicated in disease defense through interactions with monoubiquitinated histone variants. This induces the repression of these poised promoters, which is relieved by BRHIS1 down‐regulation upon infection.

    • Under normal growth conditions, some disease defense‐related gene loci are poised for expression by the deposition of monoubiquitinated histone variants H2A.Xa/H2A.Xb/H2A.3 and H2B.7 on their promoter regions.

    • In rice seedlings, BRHIS1 binds monoubiquitinated H2A.Xa/H2A.Xb/H2A.3 and H2B.7 for the prevention of further histone monoubiquitination, thus suppressing disease defense‐related gene expression.

    • Upon pathogen attack, the down‐regulation of BRHIS1 and the coincident up‐regulation of H2A.Xa and H2B.7 displace BRHIS1 binding, leading to gene activation and the prompt initiation of immune responses.

    • chromatin remodeling
    • disease defense
    • histone H2A and H2B monoubiquitination
    • priming
    • SNF2
    • Received December 15, 2014.
    • Revision received June 22, 2015.
    • Accepted June 22, 2015.
    Xiaoyu Li, Yanxiang Jiang, Zhicheng Ji, Yaoguang Liu, Qunyu Zhang
  • Lip sync conferences
    Lip sync conferences
    1. Frank Gannon, Director and CEO (frank.gannon{at}qimrberghofer.edu.au)1
    1. 1QIMR Berghofer Medical Research Institute, Herston, Qld, Australia

    The trend for scientific meetings to feature ageing stars who repeat their old hits, or up‐and‐comers too afraid to present their latest data, is a hindrance to communication. What could be done to restore meetings as venues to discuss new science?

    Frank Gannon
  • Squaring excellence and equalityThe focus on funding excellent science and promoting mobility is causing poorer countries and regions to haemorrhage talent to their science‐rich neighbours
    Squaring excellence and equality

    The focus on funding excellent science and promoting mobility is causing poorer countries and regions to haemorrhage talent to their science‐rich neighbours

    1. Philip Hunter, Freelance journalist (ph{at}philiphunter.com)1
    1. 1 London, UK

    EU and US research funding agencies are struggling to reconcile their mission to support high‐quality research with trying to help underperforming regions and underrepresented minorities catch up with traditional centres of research.

    Philip Hunter
  • Blinded by the lightAnonymization should be used in peer review to prevent bias, not protect referees
    Blinded by the light

    Anonymization should be used in peer review to prevent bias, not protect referees

    1. David M Shaw, Senior Research Fellow (david.shaw{at}unibas.ch)1
    1. 1 Institute for Biomedical Ethics University of Basel, Basel, Switzerland

    What are the pros and cons of different peer review blinding systems? Should only author identities be anonymized? Is blinding authors to the identities of reviewers unethical?

    David M Shaw