PMID- 26802239
OWN - NLM
STAT- MEDLINE
DCOM- 20160609
LR  - 20181202
IS  - 1523-1747 (Electronic)
IS  - 0022-202X (Print)
IS  - 0022-202X (Linking)
VI  - 136
IP  - 2
DP  - 2016 Feb
TI  - Membrane-Tethered Intracellular Domain of Amphiregulin Promotes Keratinocyte 
      Proliferation.
PG  - 444-452
LID - S0022-202X(15)00062-7 [pii]
LID - 10.1016/j.jid.2015.10.061 [doi]
AB  - The epidermal growth factor receptor (EGFR) and its ligands are essential 
      regulators of epithelial biology, which are often amplified in cancer cells. We 
      have previously shown that shRNA-mediated silencing of one of these ligands, 
      amphiregulin (AREG), results in keratinocyte growth arrest that cannot be rescued 
      by soluble extracellular EGFR ligands. To further explore the functional 
      importance of specific AREG domains, we stably transduced keratinocytes 
      expressing tetracycline-inducible AREG-targeted shRNA with lentiviruses 
      expressing silencing-proof, membrane-tethered AREG cytoplasmic and extracellular 
      domains (AREG-CTD and AREG-ECD), as well as full-length AREG precursor (proAREG). 
      Here we show that growth arrest of AREG-silenced keratinocytes occurs in G2/M and 
      is significantly restored by proAREG and AREG-CTD but not by AREG-ECD. Moreover, 
      the AREG-CTD was sufficient to normalize cell cycle distribution profiles and 
      expression of mitosis-related genes. Our findings uncover an important role of 
      the AREG-CTD in regulating cell division, which may be relevant to tumor 
      resistance to EGFR-directed therapies.
CI  - Copyright (c) 2015 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Stoll, Stefan W
AU  - Stoll SW
AD  - Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA. 
      Electronic address: sstoll@umich.edu.
FAU - Stuart, Philip E
AU  - Stuart PE
AD  - Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.
FAU - Lambert, Sylviane
AU  - Lambert S
AD  - Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.
FAU - Gandarillas, Alberto
AU  - Gandarillas A
AD  - Cell Cycle, Stem Cells and Cancer Lab, Instituto de Investigacion Marques de 
      Valdecilla (IDIVAL), Santander, Spain.
FAU - Rittie, Laure
AU  - Rittie L
AD  - Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.
FAU - Johnston, Andrew
AU  - Johnston A
AD  - Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.
FAU - Elder, James T
AU  - Elder JT
AD  - Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA; Ann 
      Arbor Veterans Affairs Health System, Ann Arbor, Michigan, USA.
LA  - eng
GR  - R03 AR049420/AR/NIAMS NIH HHS/United States
GR  - K01 AR050462/AR/NIAMS NIH HHS/United States
GR  - K01 AR064765/AR/NIAMS NIH HHS/United States
GR  - R01 AR 052889/AR/NIAMS NIH HHS/United States
GR  - R01 AR052889/AR/NIAMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Invest Dermatol
JT  - The Journal of investigative dermatology
JID - 0426720
RN  - 0 (Amphiregulin)
RN  - 0 (Areg protein, mouse)
RN  - 0 (EGF Family of Proteins)
RN  - 0 (RNA, Messenger)
RN  - 0 (RNA, Small Interfering)
RN  - EC 2.7.10.1 (ErbB Receptors)
SB  - IM
MH  - Amphiregulin/genetics
MH  - Animals
MH  - Blotting, Western
MH  - Cell Proliferation/*genetics
MH  - Cells, Cultured
MH  - EGF Family of Proteins/*genetics
MH  - Enzyme-Linked Immunosorbent Assay
MH  - ErbB Receptors/metabolism
MH  - Flow Cytometry
MH  - Fluorescent Antibody Technique
MH  - *Gene Expression Regulation
MH  - *Gene Silencing
MH  - Humans
MH  - Keratinocytes/*cytology
MH  - Mice
MH  - Mice, Knockout
MH  - RNA, Messenger/metabolism
MH  - RNA, Small Interfering/genetics
MH  - Real-Time Polymerase Chain Reaction/methods
MH  - Signal Transduction/genetics
PMC - PMC4788462
MID - NIHMS758544
COIS- Conflict of Interest The authors state no conflict of interest.
EDAT- 2016/01/24 06:00
MHDA- 2016/06/10 06:00
PMCR- 2016/08/01
CRDT- 2016/01/24 06:00
PHST- 2015/02/11 00:00 [received]
PHST- 2015/09/16 00:00 [revised]
PHST- 2015/10/09 00:00 [accepted]
PHST- 2016/01/24 06:00 [entrez]
PHST- 2016/01/24 06:00 [pubmed]
PHST- 2016/06/10 06:00 [medline]
PHST- 2016/08/01 00:00 [pmc-release]
AID - S0022-202X(15)00062-7 [pii]
AID - 10.1016/j.jid.2015.10.061 [doi]
PST - ppublish
SO  - J Invest Dermatol. 2016 Feb;136(2):444-452. doi: 10.1016/j.jid.2015.10.061.