PMID- 22505606
OWN - NLM
STAT- MEDLINE
DCOM- 20130325
LR  - 20220129
IS  - 1477-9137 (Electronic)
IS  - 0021-9533 (Linking)
VI  - 125
IP  - Pt 14
DP  - 2012 Jul 15
TI  - ARNT controls the expression of epidermal differentiation genes through HDAC- and 
      EGFR-dependent pathways.
PG  - 3320-32
LID - 10.1242/jcs.095125 [doi]
AB  - Previously we showed that spatial and developmental modulation of ARNT (HIF1beta) 
      expression in mouse epidermis is essential for maintenance of keratinocyte 
      differentiation, proper formation of the barrier and normal desquamation. Here, 
      using lentiviral suppression or induction of ARNT in TERT-immortalized (N-TERT) 
      and HaCaT cells we assessed the nature and mechanisms of ARNT involvement in 
      control of differentiation in human epidermal keratinocytes. ARNT depletion did 
      not affect the levels of basal keratins K5 and K14, but significantly induced 
      expression of several key differentiation markers (an effect abolished by EGF 
      supplementation). Furthermore, ARNT deficiency resulted in the downregulation of 
      amphiregulin (AREG) - the most highly expressed EGFR ligand in human 
      keratinocytes - whereas upregulation of ARNT showed the opposite. In 
      ARNT-deficient monolayer cultures and 3D epidermal equivalents, the 
      downregulation of AREG was concurrent with a decline of EGFR and ERK1/2 
      phosphorylation. TSA, a potent suppressor of HDAC activity, abolished the effects 
      of ARNT deficiency, implying a role for HDACs in ARNT-dependent modulation of the 
      AREG-EGFR pathway and downstream epidermal genes. Total HDAC activity was 
      significantly increased in ARNT-depleted cells and decreased with ARNT 
      overexpression. ARNT-dependent shifts in HDAC activity were specifically 
      attributed to significant changes in the levels of HDAC1, HDAC2 and HDAC3 
      proteins (but not mRNA) in both monolayer and 3D cultures. Collectively, our 
      results suggest that ARNT controls AREG expression and the downstream EGFR-ERK 
      pathway in keratinocytes, at least in part, by modulating HDAC activity. This 
      novel regulatory pathway targeting advanced stages of epidermal differentiation 
      might have important implications for skin pathology such as psoriasis, atopic 
      dermatitis and cancer.
FAU - Robertson, E Douglas
AU  - Robertson ED
AD  - Centre for Oncology and Molecular Medicine, Division of Medical Sciences, College 
      of Medicine, Dentistry and Nursing, Ninewells Hospital, University of Dundee, UK.
FAU - Weir, Lynda
AU  - Weir L
FAU - Romanowska, Malgorzata
AU  - Romanowska M
FAU - Leigh, Irene M
AU  - Leigh IM
FAU - Panteleyev, Andrey A
AU  - Panteleyev AA
LA  - eng
GR  - 13044/CRUK_/Cancer Research UK/United Kingdom
GR  - C5314/A6695/CRUK_/Cancer Research UK/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120414
PL  - England
TA  - J Cell Sci
JT  - Journal of cell science
JID - 0052457
RN  - 0 (ARNT protein, human)
RN  - 138391-32-9 (Aryl Hydrocarbon Receptor Nuclear Translocator)
RN  - 68238-35-7 (Keratins)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3)
RN  - EC 3.5.1.98 (Histone Deacetylases)
SB  - IM
MH  - Animals
MH  - Aryl Hydrocarbon Receptor Nuclear 
      Translocator/biosynthesis/deficiency/genetics/*metabolism
MH  - Cell Differentiation/genetics
MH  - Cell Line
MH  - Cells, Cultured
MH  - Epidermal Cells
MH  - ErbB Receptors/genetics/*metabolism
MH  - Gene Expression
MH  - *Gene Expression Regulation
MH  - Histone Deacetylases/*metabolism
MH  - Humans
MH  - Keratinocytes/*cytology/*metabolism
MH  - Keratins/metabolism
MH  - Mice
MH  - Mitogen-Activated Protein Kinase 1/metabolism
MH  - Mitogen-Activated Protein Kinase 3/metabolism
MH  - Phosphorylation
MH  - Signal Transduction
EDAT- 2012/04/17 06:00
MHDA- 2013/03/26 06:00
CRDT- 2012/04/17 06:00
PHST- 2012/04/17 06:00 [entrez]
PHST- 2012/04/17 06:00 [pubmed]
PHST- 2013/03/26 06:00 [medline]
AID - jcs.095125 [pii]
AID - 10.1242/jcs.095125 [doi]
PST - ppublish
SO  - J Cell Sci. 2012 Jul 15;125(Pt 14):3320-32. doi: 10.1242/jcs.095125. Epub 2012 
      Apr 14.