PMID- 30240752
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20210109
IS  - 2589-0042 (Electronic)
IS  - 2589-0042 (Linking)
VI  - 4
DP  - 2018 Jun 29
TI  - Aryl Hydrocarbon Receptor Promotes Liver Polyploidization and Inhibits PI3K, ERK, 
      and Wnt/beta-Catenin Signaling.
PG  - 44-63
LID - S2589-0042(18)30061-0 [pii]
LID - 10.1016/j.isci.2018.05.006 [doi]
AB  - Aryl hydrocarbon receptor (AhR) deficiency alters tissue homeostasis. However, 
      how AhR regulates organ maturation and differentiation remains mostly unknown. 
      Liver differentiation entails a polyploidization process fundamental for cell 
      growth, metabolism, and stress responses. Here, we report that AhR regulates 
      polyploidization during the preweaning-to-adult mouse liver maturation. 
      Preweaning AhR-null (AhR-/-) livers had smaller hepatocytes, hypercellularity, 
      altered cell cycle regulation, and enhanced proliferation. Those phenotypes 
      persisted in adult AhR-/- mice and correlated with compromised polyploidy, 
      predominance of diploid hepatocytes, and enlarged centrosomes. 
      Phosphatidylinositol-3-phosphate kinase (PI3K), extracellular signal-regulated 
      kinase (ERK), and Wnt/beta-catenin signaling remained upregulated from preweaning to 
      adult AhR-null liver, likely increasing mammalian target of rapamycin (mTOR) 
      activation. Metabolomics revealed the deregulation of mitochondrial oxidative 
      phosphorylation intermediates succinate and fumarate in AhR-/- liver. 
      Consistently, PI3K, ERK, and Wnt/beta-catenin inhibition partially rescued 
      polyploidy in AhR-/- mice. Thus, AhR may integrate survival, proliferation, and 
      metabolism for liver polyploidization. Since tumor cells tend to be polyploid, 
      AhR modulation could have therapeutic value in the liver.
CI  - Copyright (c) 2018 The Author(s). Published by Elsevier Inc. All rights reserved.
FAU - Moreno-Marin, Nuria
AU  - Moreno-Marin N
AD  - Departamento de Bioquimica y Biologia Molecular, Facultad de Ciencias, 
      Universidad de Extremadura, Badajoz, Badajoz 06071, Spain.
FAU - Merino, Jaime M
AU  - Merino JM
AD  - Departamento de Bioquimica y Biologia Molecular, Facultad de Ciencias, 
      Universidad de Extremadura, Badajoz, Badajoz 06071, Spain.
FAU - Alvarez-Barrientos, Alberto
AU  - Alvarez-Barrientos A
AD  - Servicio de Tecnicas Aplicadas a las Biociencias (STAB), Universidad de 
      Extremadura, Badajoz, Badajoz 06071, Spain.
FAU - Patel, Daxeshkumar P
AU  - Patel DP
AD  - Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, 
      National Institutes of Health, Bethesda, MD 20892, USA.
FAU - Takahashi, Shogo
AU  - Takahashi S
AD  - Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, 
      National Institutes of Health, Bethesda, MD 20892, USA.
FAU - Gonzalez-Sancho, Jose M
AU  - Gonzalez-Sancho JM
AD  - Instituto de Investigaciones Biomedicas "Alberto Sols", Consejo Superior de 
      Investigaciones Cientificas - Universidad Autonoma de Madrid, and CIBER de Cancer 
      (CIBERONC), Instituto de Salud Carlos III, Madrid 28029, Spain.
FAU - Gandolfo, Pablo
AU  - Gandolfo P
AD  - Cell Signaling Department, CABIMER-CSIC, Sevilla 41092, Spain.
FAU - Rios, Rosa M
AU  - Rios RM
AD  - Cell Signaling Department, CABIMER-CSIC, Sevilla 41092, Spain.
FAU - Munoz, Alberto
AU  - Munoz A
AD  - Instituto de Investigaciones Biomedicas "Alberto Sols", Consejo Superior de 
      Investigaciones Cientificas - Universidad Autonoma de Madrid, and CIBER de Cancer 
      (CIBERONC), Instituto de Salud Carlos III, Madrid 28029, Spain.
FAU - Gonzalez, Frank J
AU  - Gonzalez FJ
AD  - Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, 
      National Institutes of Health, Bethesda, MD 20892, USA.
FAU - Fernandez-Salguero, Pedro M
AU  - Fernandez-Salguero PM
AD  - Departamento de Bioquimica y Biologia Molecular, Facultad de Ciencias, 
      Universidad de Extremadura, Badajoz, Badajoz 06071, Spain. Electronic address: 
      pmfersal@unex.es.
LA  - eng
PT  - Journal Article
DEP - 20180515
PL  - United States
TA  - iScience
JT  - iScience
JID - 101724038
PMC - PMC6147018
OTO - NOTNLM
OT  - Cancer Systems Biology
OT  - Developmental Biology
OT  - Metabolomics
EDAT- 2018/09/22 06:00
MHDA- 2018/09/22 06:01
PMCR- 2018/05/15
CRDT- 2018/09/22 06:00
PHST- 2017/12/30 00:00 [received]
PHST- 2018/04/25 00:00 [revised]
PHST- 2018/05/09 00:00 [accepted]
PHST- 2018/09/22 06:00 [entrez]
PHST- 2018/09/22 06:00 [pubmed]
PHST- 2018/09/22 06:01 [medline]
PHST- 2018/05/15 00:00 [pmc-release]
AID - S2589-0042(18)30061-0 [pii]
AID - 10.1016/j.isci.2018.05.006 [doi]
PST - ppublish
SO  - iScience. 2018 Jun 29;4:44-63. doi: 10.1016/j.isci.2018.05.006. Epub 2018 May 15.