PMID- 29567474
OWN - NLM
STAT- MEDLINE
DCOM- 20180410
LR  - 20201209
IS  - 1090-2104 (Electronic)
IS  - 0006-291X (Linking)
VI  - 499
IP  - 1
DP  - 2018 Apr 30
TI  - Treacher Collins syndrome 3 (TCS3)-associated POLR1C mutants are localized in the 
      lysosome and inhibits chondrogenic differentiation.
PG  - 78-85
LID - S0006-291X(18)30632-6 [pii]
LID - 10.1016/j.bbrc.2018.03.136 [doi]
AB  - Treacher Collins syndrome (TCS) is a craniofacial developmental disorder whose 
      key feature is a combination of symptoms. For example, a patient could have 
      bilateral downward slanting of the palpebral fissures, colobomas of the lower 
      eyelids, hypoplasia of the facial bones, cleft palate, malformation of the 
      external ears, and atresia of the external auditory canals. TCS3 is caused by 
      mutations of the polr1c gene, which encodes RNA polymerase I and III subunit C 
      (POLR1C). There have been two known missense mutations (Arg279-to-Gln [R279Q] and 
      Arg279-to-Trp [R279W]) at the Arg-279 position. However, it remains to be 
      clarified whether or how both or each individual mutation affects the cellular 
      properties of POLR1C. Here we show that TCS3-associated missense mutations cause 
      aberrant intracellular localization of POLR1C, inhibiting chondrogenic 
      differentiation. The wild type POLR1C is normally localized in the nuclei. The 
      R279Q or R279W mutant is primarily found to be localized in the lysosome. 
      Expression of the R279Q or R279W mutant in mouse chondrogenic ATDC5 cells 
      decreases phosphorylation of 4E-BP1 and ribosomal S6 proteins, which belong to 
      the mammalian target of rapamycin (mTOR) signaling involved in critical roles in 
      the lysosome. Furthermore, expression of the R279Q or R279W mutant inhibits 
      chondrogenic differentiation in ATDC5 cells. Taken together, TCS3-associated 
      mutation leads to the localization of POLR1C into the lysosome and inhibits 
      chondrogenic differentiation, possibly explaining a portion of the pathological 
      molecular basis underlying Treacher Collins syndrome.
CI  - Copyright (c) 2018 Elsevier Inc. All rights reserved.
FAU - Matsumoto, Naoto
AU  - Matsumoto N
AD  - Laboratory of Molecular Neuroscience and Neurology, Tokyo University of Pharmacy 
      and Life Sciences, Hachioji, Tokyo 192-0392, Japan.
FAU - Kaneko, Minami
AU  - Kaneko M
AD  - Laboratory of Molecular Neuroscience and Neurology, Tokyo University of Pharmacy 
      and Life Sciences, Hachioji, Tokyo 192-0392, Japan.
FAU - Watanabe, Natsumi
AU  - Watanabe N
AD  - Laboratory of Molecular Neuroscience and Neurology, Tokyo University of Pharmacy 
      and Life Sciences, Hachioji, Tokyo 192-0392, Japan.
FAU - Itaoka, Misa
AU  - Itaoka M
AD  - Laboratory of Molecular Neuroscience and Neurology, Tokyo University of Pharmacy 
      and Life Sciences, Hachioji, Tokyo 192-0392, Japan.
FAU - Seki, Yoich
AU  - Seki Y
AD  - Laboratory of Molecular Neuroscience and Neurology, Tokyo University of Pharmacy 
      and Life Sciences, Hachioji, Tokyo 192-0392, Japan.
FAU - Morimoto, Takako
AU  - Morimoto T
AD  - Laboratory of Molecular Neuroscience and Neurology, Tokyo University of Pharmacy 
      and Life Sciences, Hachioji, Tokyo 192-0392, Japan.
FAU - Torii, Tomohiro
AU  - Torii T
AD  - Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.
FAU - Miyamoto, Yuki
AU  - Miyamoto Y
AD  - Laboratory of Molecular Neuroscience and Neurology, Tokyo University of Pharmacy 
      and Life Sciences, Hachioji, Tokyo 192-0392, Japan; Department of Pharmacology, 
      National Research Institute for Child Health and Development, Setagaya, Tokyo 
      157-8535, Japan.
FAU - Keiichi Homma
AU  - Keiichi Homma
AD  - Department of Life Science and Informatics, Maebashi Institute of Technology, 
      Maebashi, Gunma 371-0816, Japan.
FAU - Yamauchi, Junji
AU  - Yamauchi J
AD  - Laboratory of Molecular Neuroscience and Neurology, Tokyo University of Pharmacy 
      and Life Sciences, Hachioji, Tokyo 192-0392, Japan; Department of Pharmacology, 
      National Research Institute for Child Health and Development, Setagaya, Tokyo 
      157-8535, Japan. Electronic address: yamauchi@toyaku.ac.jp.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180321
PL  - United States
TA  - Biochem Biophys Res Commun
JT  - Biochemical and biophysical research communications
JID - 0372516
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (EIF4EBP1 protein, human)
RN  - 0 (Phosphoproteins)
RN  - 0 (Ribosomal Protein S6)
RN  - EC 2.7.7.6 (DNA-Directed RNA Polymerases)
RN  - EC 2.7.7.6 (POLR1C protein, human)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing/genetics/metabolism
MH  - Animals
MH  - COS Cells
MH  - Cell Cycle Proteins
MH  - Cell Nucleus/metabolism
MH  - Chlorocebus aethiops
MH  - Chondrocytes/*metabolism/pathology
MH  - Chondrogenesis/*genetics
MH  - DNA-Directed RNA Polymerases/*genetics/metabolism
MH  - Gene Expression Regulation
MH  - Humans
MH  - Lysosomes/metabolism
MH  - Mandibulofacial Dysostosis/*genetics/metabolism/pathology
MH  - Mice
MH  - Models, Biological
MH  - *Mutation
MH  - Phosphoproteins/genetics/metabolism
MH  - Phosphorylation
MH  - Ribosomal Protein S6/genetics/metabolism
MH  - Signal Transduction
MH  - Transgenes
OTO - NOTNLM
OT  - Differentiation
OT  - Lysosome
OT  - POLR1C
OT  - TSC3
EDAT- 2018/03/24 06:00
MHDA- 2018/04/11 06:00
CRDT- 2018/03/24 06:00
PHST- 2018/03/05 00:00 [received]
PHST- 2018/03/18 00:00 [accepted]
PHST- 2018/03/24 06:00 [pubmed]
PHST- 2018/04/11 06:00 [medline]
PHST- 2018/03/24 06:00 [entrez]
AID - S0006-291X(18)30632-6 [pii]
AID - 10.1016/j.bbrc.2018.03.136 [doi]
PST - ppublish
SO  - Biochem Biophys Res Commun. 2018 Apr 30;499(1):78-85. doi: 
      10.1016/j.bbrc.2018.03.136. Epub 2018 Mar 21.