PMID- 17027001
OWN - NLM
STAT- MEDLINE
DCOM- 20070220
LR  - 20220318
IS  - 0014-4835 (Print)
IS  - 0014-4835 (Linking)
VI  - 83
IP  - 6
DP  - 2006 Dec
TI  - Proteasome-dependent regulation of signal transduction in retinal pigment 
      epithelial cells.
PG  - 1472-81
AB  - As in many other types of cells, retinal pigment epithelial (RPE) cells have an 
      active ubiquitin-proteasome pathway (UPP). However, the function of the UPP in 
      RPE remains to be elucidated. The objective of this study is to determine the 
      role of the UPP in controlling the levels and activities of transcription factors 
      hypoxia-inducible factor (HIF) and NF-kappaB. We inhibited the UPP with 
      proteasome-specific inhibitors and determined the activation of HIF and NF-kappaB 
      as well as the expression and secretion of pro-angiogenic factors. HIF-1alpha was 
      not detectable in ARPE-19 cells under normal culture conditions. However, when 
      proteasome activity was inhibited, HIF-1alpha accumulated in RPE in a 
      time-dependent manner. Consistent with accumulation of HIF-1alpha in the cells, 
      levels of mRNA for vascular endothelial growth factor (VEGF) and angiopoietin-2 
      (Ang-2) in RPE were up to 7-fold higher upon inhibition of the proteasome. 
      Proteasome inhibition was also associated with a 2-fold increase in levels of 
      mRNA for angiopoietin-1 (Ang-1). ARPE-19 cells secrete significant levels of VEGF 
      under normal culture conditions. Inhibition of proteasome activity increased the 
      secretion of VEGF by 2-fold. In contrast to the increase in HIF activity, 
      NF-kappaB activation was reduced by proteasome inhibition. In addition, the 
      expression and secretion of monocyte chemoattractant protein-1 (MCP-1) by RPE 
      were substantially attenuated by the inhibition of proteasome activity. These 
      data demonstrate that the UPP plays an important role in modulating the 
      activities of HIF and NF-kappaB in the RPE. Consequences of an impairment of the 
      UPP include accumulation of HIF-1alpha and diminished NF-kappaB activation, which 
      lead to enhanced expression and secretion of pro-angiogenic factors and 
      attenuated expression of MCP-1. Taken together, these data predict that the 
      impairment of the UPP could lead to the development of AMD-related phenotypes.
FAU - Fernandes, Alexandre F
AU  - Fernandes AF
AD  - Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, 
      Boston, MA 02111, USA.
FAU - Guo, Weimin
AU  - Guo W
FAU - Zhang, Xinyu
AU  - Zhang X
FAU - Gallagher, Matthew
AU  - Gallagher M
FAU - Ivan, Mircea
AU  - Ivan M
FAU - Taylor, Allen
AU  - Taylor A
FAU - Pereira, Paulo
AU  - Pereira P
FAU - Shang, Fu
AU  - Shang F
LA  - eng
GR  - R01 EY013250/EY/NEI NIH HHS/United States
GR  - R01 EY011717-07/EY/NEI NIH HHS/United States
GR  - R01 EY011717/EY/NEI NIH HHS/United States
GR  - EY 11717/EY/NEI NIH HHS/United States
GR  - EY 13250/EY/NEI NIH HHS/United States
GR  - R01 EY011717-09/EY/NEI NIH HHS/United States
GR  - R01 EY011717-08/EY/NEI NIH HHS/United States
GR  - R29 EY011717/EY/NEI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20061005
PL  - England
TA  - Exp Eye Res
JT  - Experimental eye research
JID - 0370707
RN  - 0 (Angiogenesis Inducing Agents)
RN  - 0 (CCL2 protein, human)
RN  - 0 (Chemokine CCL2)
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (NF-kappa B)
RN  - 0 (Ubiquitin)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - EC 3.4.25.1 (Proteasome Endopeptidase Complex)
SB  - IM
MH  - Angiogenesis Inducing Agents/metabolism
MH  - Blotting, Western/methods
MH  - Cells, Cultured
MH  - Chemokine CCL2/metabolism
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
MH  - NF-kappa B/metabolism
MH  - Pigment Epithelium of Eye/cytology/*metabolism
MH  - Proteasome Endopeptidase Complex/*physiology
MH  - Retina/cytology/*metabolism
MH  - Signal Transduction/*physiology
MH  - Ubiquitin/physiology
MH  - Vascular Endothelial Growth Factor A/metabolism
PMC - PMC2039698
MID - NIHMS31857
EDAT- 2006/10/10 09:00
MHDA- 2007/02/21 09:00
PMCR- 2007/12/01
CRDT- 2006/10/10 09:00
PHST- 2006/03/21 00:00 [received]
PHST- 2006/07/05 00:00 [revised]
PHST- 2006/07/31 00:00 [accepted]
PHST- 2006/10/10 09:00 [pubmed]
PHST- 2007/02/21 09:00 [medline]
PHST- 2006/10/10 09:00 [entrez]
PHST- 2007/12/01 00:00 [pmc-release]
AID - S0014-4835(06)00343-5 [pii]
AID - 10.1016/j.exer.2006.07.024 [doi]
PST - ppublish
SO  - Exp Eye Res. 2006 Dec;83(6):1472-81. doi: 10.1016/j.exer.2006.07.024. Epub 2006 
      Oct 5.