PMID- 20428186
OWN - NLM
STAT- MEDLINE
DCOM- 20100805
LR  - 20211020
IS  - 1523-1747 (Electronic)
IS  - 0022-202X (Print)
IS  - 0022-202X (Linking)
VI  - 130
IP  - 8
DP  - 2010 Aug
TI  - Amphiregulin carboxy-terminal domain is required for autocrine keratinocyte 
      growth.
PG  - 2031-40
LID - 10.1038/jid.2010.98 [doi]
AB  - The EGFR ligand amphiregulin (AREG) has been implicated as an important autocrine 
      growth factor in several epithelial malignancies and in psoriasis, a 
      hyperproliferative skin disorder. To characterize the mechanisms by which AREG 
      regulates autocrine epithelial cell growth, we transduced human keratinocytes 
      (KCs) with lentiviral constructs expressing tetracycline (TET)-inducible small 
      hairpin RNA (shRNA). TET-induced expression of AREG shRNA markedly reduced 
      autocrine extracellular signal-regulated kinase phosphorylation, strongly 
      inhibited autocrine KC growth with an efficiency similar to metalloproteinase and 
      EGFR inhibitors, and induced several markers of KC differentiation, including 
      keratins 1 and 10. Addition of various concentrations of exogenous EGFR ligands 
      to KC cultures reversed the growth inhibition in response to AREG-blocking 
      antibodies but not to shRNA-mediated AREG knockdown. Lentivirus-mediated 
      expression of the full-length AREG transmembrane (TM) precursor, but not of the 
      AREG extracellular domain, markedly reversed the shRNA-mediated growth inhibition 
      and morphological changes, and strongly reduced the induction of multiple markers 
      of KC differentiation. Taken together, our data show that autocrine human KC 
      growth is highly dependent on the AREG TM precursor protein and strongly suggest 
      a previously unreported function of the metalloproteinase-processed carboxy 
      (C)-terminal domain of AREG.
FAU - Stoll, Stefan W
AU  - Stoll SW
AD  - Department of Dermatology, University of Michigan, Ann Arbor, Michigan 48109, 
      USA. sstoll@umich.edu
FAU - Johnson, Jessica L
AU  - Johnson JL
FAU - Li, Yong
AU  - Li Y
FAU - Rittie, Laure
AU  - Rittie L
FAU - Elder, James T
AU  - Elder JT
LA  - eng
GR  - R03 AR049420/AR/NIAMS NIH HHS/United States
GR  - R01 AR052889-04/AR/NIAMS NIH HHS/United States
GR  - K01 AR050462-04/AR/NIAMS NIH HHS/United States
GR  - R03 AR049420-03/AR/NIAMS NIH HHS/United States
GR  - K01 AR050462/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, U.S. Gov't, Non-P.H.S.
DEP - 20100429
PL  - United States
TA  - J Invest Dermatol
JT  - The Journal of investigative dermatology
JID - 0426720
RN  - 0 (AREG protein, human)
RN  - 0 (Amphiregulin)
RN  - 0 (EGF Family of Proteins)
RN  - 0 (Glycoproteins)
RN  - 0 (Intercellular Signaling Peptides and Proteins)
RN  - 0 (Ligands)
RN  - 0 (Protein Precursors)
RN  - 0 (RNA, Small Interfering)
RN  - EC 2.7.10.1 (ErbB Receptors)
SB  - IM
CIN - J Invest Dermatol. 2010 Aug;130(8):1966-8. PMID: 20631750
MH  - Amphiregulin
MH  - Autocrine Communication/*physiology
MH  - Cell Differentiation/physiology
MH  - Cell Division/physiology
MH  - Cell Line
MH  - EGF Family of Proteins
MH  - ErbB Receptors/metabolism
MH  - Glycoproteins/*chemistry/genetics/*metabolism
MH  - Humans
MH  - Intercellular Signaling Peptides and Proteins/*chemistry/genetics/*metabolism
MH  - Keratinocytes/*cytology/*metabolism
MH  - Lentivirus/genetics
MH  - Ligands
MH  - Phosphorylation/physiology
MH  - Protein Precursors/metabolism
MH  - Protein Structure, Tertiary
MH  - RNA, Small Interfering
MH  - Signal Transduction/physiology
MH  - Transduction, Genetic
PMC - PMC3072808
MID - NIHMS190448
EDAT- 2010/04/30 06:00
MHDA- 2010/08/06 06:00
PMCR- 2011/04/08
CRDT- 2010/04/30 06:00
PHST- 2010/04/30 06:00 [entrez]
PHST- 2010/04/30 06:00 [pubmed]
PHST- 2010/08/06 06:00 [medline]
PHST- 2011/04/08 00:00 [pmc-release]
AID - S0022-202X(15)34943-5 [pii]
AID - 10.1038/jid.2010.98 [doi]
PST - ppublish
SO  - J Invest Dermatol. 2010 Aug;130(8):2031-40. doi: 10.1038/jid.2010.98. Epub 2010 
      Apr 29.