PMID- 26234682
OWN - NLM
STAT- MEDLINE
DCOM- 20160915
LR  - 20240325
IS  - 1476-5594 (Electronic)
IS  - 0950-9232 (Print)
IS  - 0950-9232 (Linking)
VI  - 35
IP  - 16
DP  - 2016 Apr 21
TI  - The EGF receptor ligand amphiregulin controls cell division via FoxM1.
PG  - 2075-86
LID - 10.1038/onc.2015.269 [doi]
AB  - Epidermal growth factor receptor (EGFR) is central to epithelial cell physiology, 
      and deregulated EGFR signaling has an important role in a variety of human 
      carcinomas. Here we show that silencing of the EGF-related factor amphiregulin 
      (AREG) markedly inhibits the expansion of human keratinocytes through mitotic 
      failure and accumulation of cells with ⩾ 4n DNA content. RNA-sequencing-based 
      transcriptome analysis revealed that tetracycline-mediated AREG silencing 
      significantly altered the expression of 2331 genes, 623 of which were not 
      normalized by treatment with EGF. Interestingly, genes irreversibly upregulated 
      by suppression of AREG overlapped with genes involved in keratinocyte 
      differentiation. Moreover, a significant proportion of the irreversibly 
      downregulated genes featured upstream binding sites recognized by forkhead box 
      protein M1 (FoxM1), a key transcription factor in the control of mitosis that is 
      widely dysregulated in cancer. The downregulation of FoxM1 and its target genes 
      preceded mitotic arrest. Constitutive expression of FoxM1 in AREG knockdown cells 
      normalized cell proliferation, reduced the number of cells with ⩾ 4n DNA content 
      and rescued expression of FoxM1 target genes. These results demonstrate that AREG 
      controls G2/M progression and cytokinesis in keratinocytes via activation of a 
      FoxM1-dependent transcriptional program, suggesting new avenues for treatment of 
      epithelial cancer.
FAU - Stoll, S W
AU  - Stoll SW
AD  - Department of Dermatology, University of Michigan, Ann Arbor, MI, USA.
FAU - Stuart, P E
AU  - Stuart PE
AD  - Department of Dermatology, University of Michigan, Ann Arbor, MI, USA.
FAU - Swindell, W R
AU  - Swindell WR
AD  - Department of Dermatology, University of Michigan, Ann Arbor, MI, USA.
FAU - Tsoi, L C
AU  - Tsoi LC
AD  - Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
FAU - Li, B
AU  - Li B
AD  - Department of Molecular Physiology and Biophysics, Vanderbilt University, 
      Nashville, TN, USA.
FAU - Gandarillas, A
AU  - Gandarillas A
AD  - Cell Cycle, Stem Cell Fate and Cancer Laboratory, Fundacion Instituto de 
      Investigacion Marques de Valdecilla (IDIVAL), Santander, Spain.
FAU - Lambert, S
AU  - Lambert S
AD  - Department of Dermatology, University of Michigan, Ann Arbor, MI, USA.
FAU - Johnston, A
AU  - Johnston A
AD  - Department of Dermatology, University of Michigan, Ann Arbor, MI, USA.
FAU - Nair, R P
AU  - Nair RP
AD  - Department of Dermatology, University of Michigan, Ann Arbor, MI, USA.
FAU - Elder, J T
AU  - Elder JT
AD  - Department of Dermatology, University of Michigan, Ann Arbor, MI, USA.
AD  - Ann Arbor Veterans Affairs Health System, Ann Arbor, MI, USA.
LA  - eng
GR  - K01 AR050462/AR/NIAMS NIH HHS/United States
GR  - R01 AR052889/AR/NIAMS NIH HHS/United States
GR  - R03 AR049420/AR/NIAMS NIH HHS/United States
GR  - K01 AR064754/AR/NIAMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20150803
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (AREG protein, human)
RN  - 0 (Amphiregulin)
RN  - 0 (EGF Family of Proteins)
RN  - 0 (FOXM1 protein, human)
RN  - 0 (Forkhead Box Protein M1)
RN  - 0 (Forkhead Transcription Factors)
RN  - 0 (Ligands)
RN  - EC 2.7.10.1 (ErbB Receptors)
SB  - IM
MH  - Amphiregulin
MH  - Cell Division/*physiology
MH  - Cells, Cultured
MH  - EGF Family of Proteins/genetics/metabolism/*physiology
MH  - ErbB Receptors/*metabolism
MH  - Forkhead Box Protein M1
MH  - Forkhead Transcription Factors/*physiology
MH  - G2 Phase
MH  - Gene Silencing
MH  - Humans
MH  - Keratinocytes/metabolism
MH  - Ligands
PMC - PMC4788585
MID - NIHMS757765
COIS- CONFLICT OF INTEREST The authors state no conflict of interest.
EDAT- 2015/08/04 06:00
MHDA- 2016/09/16 06:00
PMCR- 2016/10/21
CRDT- 2015/08/04 06:00
PHST- 2014/12/13 00:00 [received]
PHST- 2015/06/04 00:00 [revised]
PHST- 2015/06/13 00:00 [accepted]
PHST- 2015/08/04 06:00 [entrez]
PHST- 2015/08/04 06:00 [pubmed]
PHST- 2016/09/16 06:00 [medline]
PHST- 2016/10/21 00:00 [pmc-release]
AID - onc2015269 [pii]
AID - 10.1038/onc.2015.269 [doi]
PST - ppublish
SO  - Oncogene. 2016 Apr 21;35(16):2075-86. doi: 10.1038/onc.2015.269. Epub 2015 Aug 3.