PMID- 28464229
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20191120
IS  - 1471-4159 (Electronic)
IS  - 0022-3042 (Linking)
VI  - 142
IP  - 6
DP  - 2017 Sep
TI  - Functional characterization of the neuron-restrictive silencer element in the 
      human tryptophan hydroxylase 2 gene expression.
PG  - 827-840
LID - 10.1111/jnc.14060 [doi]
AB  - Tryptophan hydroxylase 2 (TPH2) is the key enzyme in the synthesis of neuronal 
      serotonin. Although previous studies suggest that TPH2 neuron-restrictive 
      silencer element (NRSE) functions as a negative regulator dependent on 
      neuron-restrictive silencer factor (NRSF) activity, the underlying mechanisms are 
      yet to be fully elucidated. Here, we show a detailed analysis of the 
      NRSE-mediated repression of the human TPH2 (hTPH2) promoter activity in RN46A 
      cells, a cell line derived from rat raphe neurons. Quantitative real-time RT-PCR 
      analysis revealed the expression of serotonergic marker genes (Mash1, Nkx2.2, 
      Gata2, Gata3, Lmx1b, Pet-1, 5-Htt, and Vmat2) and Nrsf gene in RN46A cells. Tph1 
      mRNA is the prevalent form expressed in RN46A cells; Tph2 mRNA is also expressed 
      but at a lower level. Electrophoretic mobility shift assays and reporter assays 
      showed that hTPH2 NRSE is necessary for the efficient DNA binding of NRSF and for 
      the NRSF-dependent repression of the hTPH2 promoter activity. The hTPH2 promoter 
      activity was increased by knockdown of NRSF, or over-expression of the engineered 
      NRSF (a dominant-negative mutant or a DNA-binding domain and activation domain 
      fusion protein). MS-275, a class I histone deacetylase (HDAC) inhibitor, was 
      found to be more potent than MC-1568, a class II HDAC inhibitor, in enhancing the 
      hTPH2 promoter activity. Furthermore, treatment with the ubiquitin-specific 
      protease 7 deubiquitinase inhibitors, P-22077 or HBX 41108, increased the hTPH2 
      promoter activity. Collectively, our data demonstrate that the hTPH2 
      NRSE-mediated promoter repression via NRSF involves class I HDACs and is 
      modulated by the ubiquitin-specific protease 7-mediated deubiquitination and 
      stabilization of NRSF.
CI  - (c) 2017 International Society for Neurochemistry.
FAU - Nawa, Yukino
AU  - Nawa Y
AD  - Institute of Radioisotope Research, St. Marianna University Graduate School of 
      Medicine, Kawasaki, Japan.
FAU - Kaneko, Hanae
AU  - Kaneko H
AD  - Institute of Radioisotope Research, St. Marianna University Graduate School of 
      Medicine, Kawasaki, Japan.
FAU - Oda, Masayuki
AU  - Oda M
AD  - Department of Pharmacogenomics, St. Marianna University Graduate School of 
      Medicine, Kawasaki, Japan.
FAU - Tsubonoya, Masaaki
AU  - Tsubonoya M
AD  - Institute of Radioisotope Research, St. Marianna University Graduate School of 
      Medicine, Kawasaki, Japan.
FAU - Hiroi, Tomoko
AU  - Hiroi T
AD  - Institute of Radioisotope Research, St. Marianna University Graduate School of 
      Medicine, Kawasaki, Japan.
FAU - Gentile, Maria Teresa
AU  - Gentile MT
AD  - Laboratory of Molecular and Cellular Pathology, Department of Environmental, 
      Biological and Pharmaceutical Sciences and Technologies, Second University of 
      Naples, Caserta, Italy.
FAU - Colucci-D'Amato, Luca
AU  - Colucci-D'Amato L
AD  - Laboratory of Molecular and Cellular Pathology, Department of Environmental, 
      Biological and Pharmaceutical Sciences and Technologies, Second University of 
      Naples, Caserta, Italy.
FAU - Takahashi, Ryoya
AU  - Takahashi R
AD  - Department of Biochemistry, Faculty of Pharmaceutical Sciences, Toho University, 
      Funabashi, Japan.
FAU - Matsui, Hiroaki
AU  - Matsui H
AUID- ORCID: 0000-0001-7077-7593
AD  - Institute of Radioisotope Research, St. Marianna University Graduate School of 
      Medicine, Kawasaki, Japan.
AD  - Department of Molecular and Behavioral Neuroscience, St. Marianna University 
      Graduate School of Medicine, Kawasaki, Japan.
LA  - eng
GR  - 24659548/Grant-in-Aid for Exploratory Research/
PT  - Journal Article
DEP - 20170613
PL  - England
TA  - J Neurochem
JT  - Journal of neurochemistry
JID - 2985190R
OTO - NOTNLM
OT  - NRSF
OT  - TPH2
OT  - gene expression
OT  - promoter
OT  - serotonergic neuron
OT  - transcriptional regulation
EDAT- 2017/05/04 06:00
MHDA- 2017/05/04 06:01
CRDT- 2017/05/03 06:00
PHST- 2016/10/17 00:00 [received]
PHST- 2017/04/20 00:00 [revised]
PHST- 2017/04/21 00:00 [accepted]
PHST- 2017/05/04 06:00 [pubmed]
PHST- 2017/05/04 06:01 [medline]
PHST- 2017/05/03 06:00 [entrez]
AID - 10.1111/jnc.14060 [doi]
PST - ppublish
SO  - J Neurochem. 2017 Sep;142(6):827-840. doi: 10.1111/jnc.14060. Epub 2017 Jun 13.