PMID- 20682912
OWN - NLM
STAT- MEDLINE
DCOM- 20110315
LR  - 20250529
IS  - 1937-9145 (Electronic)
IS  - 1945-0877 (Linking)
VI  - 3
IP  - 133
DP  - 2010 Aug 3
TI  - HCMV-encoded chemokine receptor US28 mediates proliferative signaling through the 
      IL-6-STAT3 axis.
PG  - ra58
LID - 10.1126/scisignal.2001180 [doi]
AB  - US28 is a viral G protein (heterotrimeric guanosine triphosphate-binding 
      protein)-coupled receptor encoded by the human cytomegalovirus (HCMV). In 
      addition to binding and internalizing chemokines, US28 constitutively activates 
      signaling pathways linked to cell proliferation. Here, we show increased 
      concentrations of vascular endothelial growth factor and interleukin-6 (IL-6) in 
      supernatants of US28-expressing NIH 3T3 cells. Increased IL-6 was associated with 
      increased activation of the signal transducer and activator of transcription 3 
      (STAT3) through upstream activation of the Janus-activated kinase JAK1. We used 
      conditioned growth medium, IL-6-neutralizing antibodies, an inhibitor of the IL-6 
      receptor, and short hairpin RNA targeting IL-6 to show that US28 activates the 
      IL-6-JAK1-STAT3 signaling axis through activation of the transcription factor 
      nuclear factor kappaB and the consequent production of IL-6. Treatment of cells 
      with a specific inhibitor of STAT3 inhibited US28-dependent [(3)H]thymidine 
      incorporation and foci formation, suggesting a key role for STAT3 in the 
      US28-mediated proliferative phenotype. US28 also elicited STAT3 activation and 
      IL-6 secretion in HCMV-infected cells. Analyses of tumor specimens from 
      glioblastoma patients demonstrated colocalization of US28 and phosphorylated 
      STAT3 in the vascular niche of these tumors. Moreover, increased phospho-STAT3 
      abundance correlated with poor patient outcome. We propose that US28 induces 
      proliferation in HCMV-infected tumors by establishing a positive feedback loop 
      through activation of the IL-6-STAT3 signaling axis.
FAU - Slinger, Erik
AU  - Slinger E
AD  - Leiden/Amsterdam Center for Drug Research, Division of Medicinal Chemistry, 
      Faculty of Sciences, VU University Amsterdam, De Boelelaan 1083, 1081 HV 
      Amsterdam, The Netherlands.
FAU - Maussang, David
AU  - Maussang D
FAU - Schreiber, Andreas
AU  - Schreiber A
FAU - Siderius, Marco
AU  - Siderius M
FAU - Rahbar, Afsar
AU  - Rahbar A
FAU - Fraile-Ramos, Alberto
AU  - Fraile-Ramos A
FAU - Lira, Sergio A
AU  - Lira SA
FAU - Soderberg-Naucler, Cecilia
AU  - Soderberg-Naucler C
FAU - Smit, Martine J
AU  - Smit MJ
LA  - eng
GR  - MC_U122665002/MRC_/Medical Research Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20100803
PL  - United States
TA  - Sci Signal
JT  - Science signaling
JID - 101465400
RN  - 0 (Interleukin-6)
RN  - 0 (Receptors, Chemokine)
RN  - 0 (STAT3 Transcription Factor)
RN  - 0 (US28 receptor, Cytomegalovirus)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 0 (Viral Proteins)
RN  - EC 2.7.10.2 (Janus Kinase 1)
SB  - IM
MH  - Animals
MH  - Cell Proliferation/*drug effects
MH  - Feedback, Physiological
MH  - Humans
MH  - Interleukin-6/*metabolism
MH  - Janus Kinase 1/metabolism
MH  - Mice
MH  - NIH 3T3 Cells
MH  - Neoplasms/*etiology/virology
MH  - Receptors, Chemokine
MH  - STAT3 Transcription Factor/*metabolism
MH  - Signal Transduction/*drug effects
MH  - Vascular Endothelial Growth Factor A/metabolism
MH  - Viral Proteins/*pharmacology
EDAT- 2010/08/05 06:00
MHDA- 2011/03/16 06:00
CRDT- 2010/08/05 06:00
PHST- 2010/08/05 06:00 [entrez]
PHST- 2010/08/05 06:00 [pubmed]
PHST- 2011/03/16 06:00 [medline]
AID - 3/133/ra58 [pii]
AID - 10.1126/scisignal.2001180 [doi]
PST - epublish
SO  - Sci Signal. 2010 Aug 3;3(133):ra58. doi: 10.1126/scisignal.2001180.