PMID- 25514788
OWN - NLM
STAT- MEDLINE
DCOM- 20160104
LR  - 20181113
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 9
IP  - 12
DP  - 2014
TI  - Novel role for NFAT3 in ERK-mediated regulation of CXCR4.
PG  - e115249
LID - 10.1371/journal.pone.0115249 [doi]
LID - e115249
AB  - The G-protein coupled chemokine (C-X-C motif) receptor CXCR4 is linked to cancer, 
      HIV, and WHIM (Warts, Hypogammaglobulinemia, Infections, and Myelokathexis) 
      syndrome. While CXCR4 is reported to be overexpressed in multiple human cancer 
      types and many hematological cancer cell lines, we have observed poor in vitro 
      cell surface expression of CXCR4 in many solid tumor cell lines. We explore 
      further the possible factors and pathways involved in regulating CXCR4 
      expression. Here, we showed that MEK-ERK signaling pathway and NFAT3 
      transcriptional factor plays a novel role in regulating CXCR4 expression. When 
      cultured as 3D spheroids, HeyA8 ovarian tumor cells showed a dramatic increase in 
      surface CXCR4 protein levels as well as mRNA transcripts. Furthermore, HeyA8 3D 
      spheroids showed a decrease in phospho-ERK levels when compared to adherent 
      cells. The treatment of adherent HeyA8 cells with an inhibitor of the MEK-ERK 
      pathway, U0126, resulted in a significant increase in surface CXCR4 expression. 
      Additional investigation using the PCR array assay comparing adherent to 3D 
      spheroid showed a wide range of transcription factors being up-regulated, most 
      notably a > 20 fold increase in NFAT3 transcription factor mRNA. Finally, 
      chromatin immunoprecipitation (ChIP) analysis showed that direct binding of NFAT3 
      on the CXCR4 promoter corresponds to increased CXCR4 expression in HeyA8 ovarian 
      cell line. Taken together, our results suggest that high phospho-ERK levels and 
      NFAT3 expression plays a novel role in regulating CXCR4 expression.
FAU - Huang, Keven
AU  - Huang K
AD  - Department of Oncology Research, MedImmune, Gaithersburg, Maryland, United States 
      of America.
FAU - Kiefer, Christine
AU  - Kiefer C
AD  - Department of Antibody Discovery and Protein Engineering, MedImmune, 
      Gaithersburg, Maryland, United States of America.
FAU - Kamal, Adeela
AU  - Kamal A
AD  - Department of Oncology Research, MedImmune, Gaithersburg, Maryland, United States 
      of America.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20141216
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Butadienes)
RN  - 0 (CXCR4 protein, human)
RN  - 0 (Chromones)
RN  - 0 (Morpholines)
RN  - 0 (NFATC Transcription Factors)
RN  - 0 (NFATC4 protein, human)
RN  - 0 (Nitriles)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Receptors, CXCR4)
RN  - 0 (U 0126)
RN  - 31M2U1DVID (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one)
RN  - 56092-81-0 (Ionomycin)
RN  - 83HN0GTJ6D (Cyclosporine)
RN  - WM0HAQ4WNM (Tacrolimus)
SB  - IM
MH  - Blotting, Western
MH  - Butadienes
MH  - Cell Line, Tumor
MH  - Chromatin Immunoprecipitation
MH  - Chromones
MH  - Cyclosporine/pharmacology
MH  - Flow Cytometry
MH  - Gene Expression Regulation, Neoplastic/genetics/*physiology
MH  - Gene Knockdown Techniques
MH  - Humans
MH  - Ionomycin
MH  - MAP Kinase Signaling System/*physiology
MH  - Morpholines
MH  - NFATC Transcription Factors/antagonists & inhibitors/*metabolism
MH  - Nitriles
MH  - RNA, Small Interfering/genetics
MH  - Real-Time Polymerase Chain Reaction
MH  - Receptors, CXCR4/*metabolism
MH  - Spheroids, Cellular
MH  - Tacrolimus
PMC - PMC4267837
COIS- Competing Interests: The authors have read the journal's policy and have the 
      following conflicts. The authors are employees of MedImmune. This does not alter 
      the authors' adherence to all the PLOS ONE policies on sharing data and 
      materials.
EDAT- 2014/12/17 06:00
MHDA- 2016/01/05 06:00
PMCR- 2014/12/16
CRDT- 2014/12/17 06:00
PHST- 2013/05/28 00:00 [received]
PHST- 2014/11/20 00:00 [accepted]
PHST- 2014/12/17 06:00 [entrez]
PHST- 2014/12/17 06:00 [pubmed]
PHST- 2016/01/05 06:00 [medline]
PHST- 2014/12/16 00:00 [pmc-release]
AID - PONE-D-13-21987 [pii]
AID - 10.1371/journal.pone.0115249 [doi]
PST - epublish
SO  - PLoS One. 2014 Dec 16;9(12):e115249. doi: 10.1371/journal.pone.0115249. 
      eCollection 2014.