PMID- 19949102
OWN - NLM
STAT- MEDLINE
DCOM- 20100108
LR  - 20211020
IS  - 1550-6606 (Electronic)
IS  - 0022-1767 (Print)
IS  - 0022-1767 (Linking)
VI  - 184
IP  - 1
DP  - 2010 Jan 1
TI  - ATP-binding cassette transporter G1 negatively regulates thymocyte and peripheral 
      lymphocyte proliferation.
PG  - 173-83
LID - 10.4049/jimmunol.0902372 [doi]
AB  - Cholesterol is a key component of cell membranes and is essential for cell growth 
      and proliferation. How the accumulation of cellular cholesterol affects 
      lymphocyte development and function is not well understood. We demonstrate that 
      ATP-binding cassette transporter G1 (ABCG1) regulates cholesterol homeostasis in 
      thymocytes and peripheral CD4 T cells. Our work is the first to describe a cell 
      type in Abcg1-deficient mice with such a robust change in cholesterol content and 
      the expression of cholesterol metabolism genes. Abcg1-deficient mice display 
      increased thymocyte cellularity and enhanced proliferation of thymocytes and 
      peripheral T lymphocytes in vivo. The absence of ABCG1 in CD4 T cells results in 
      hyperproliferation in vitro, but only when cells are stimulated through the TCR. 
      We hypothesize that cholesterol accumulation in Abcg1(-/-) T cells alters the 
      plasma membrane structure, resulting in enhanced TCR signaling for proliferation. 
      Supporting this idea, we demonstrate that B6 T cells pretreated with soluble 
      cholesterol have a significant increase in proliferation. Cholesterol 
      accumulation in Abcg1(-/-) CD4 T cells results in enhanced basal phosphorylation 
      levels of ZAP70 and ERK1/2. Furthermore, inhibition of ERK phosphorylation in 
      TCR-stimulated Abcg1(-/-) T cells rescues the hyperproliferative phenotype. We 
      describe a novel mechanism by which cholesterol can alter signaling from the 
      plasma membrane to affect downstream signaling pathways and proliferation. These 
      results implicate ABCG1 as an important negative regulator of lymphocyte 
      proliferation through the maintenance of cellular cholesterol homeostasis.
FAU - Armstrong, Allison J
AU  - Armstrong AJ
AD  - Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, 
      USA.
FAU - Gebre, Abraham K
AU  - Gebre AK
FAU - Parks, John S
AU  - Parks JS
FAU - Hedrick, Catherine C
AU  - Hedrick CC
LA  - eng
GR  - R01 HL094525/HL/NHLBI NIH HHS/United States
GR  - R01 HL085790-02/HL/NHLBI NIH HHS/United States
GR  - P01HL55798/HL/NHLBI NIH HHS/United States
GR  - P01 HL055798-13/HL/NHLBI NIH HHS/United States
GR  - P01 HL055798/HL/NHLBI NIH HHS/United States
GR  - P01 HL049373/HL/NHLBI NIH HHS/United States
GR  - P01 HL055798-140002/HL/NHLBI NIH HHS/United States
GR  - R01 HL085790/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20091130
PL  - United States
TA  - J Immunol
JT  - Journal of immunology (Baltimore, Md. : 1950)
JID - 2985117R
RN  - 0 (ABCG1 protein, mouse)
RN  - 0 (ATP Binding Cassette Transporter, Subfamily G, Member 1)
RN  - 0 (ATP-Binding Cassette Transporters)
RN  - 0 (Lipoproteins)
RN  - 97C5T2UQ7J (Cholesterol)
SB  - IM
MH  - ATP Binding Cassette Transporter, Subfamily G, Member 1
MH  - ATP-Binding Cassette Transporters/*metabolism
MH  - Animals
MH  - Blotting, Western
MH  - Cell Count
MH  - Cell Membrane/metabolism
MH  - *Cell Proliferation
MH  - Cholesterol/*metabolism
MH  - Flow Cytometry
MH  - Homeostasis/physiology
MH  - Lipoproteins/*metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Signal Transduction/*physiology
MH  - T-Lymphocyte Subsets/immunology/*metabolism
MH  - T-Lymphocytes/immunology/*metabolism
PMC - PMC3316475
MID - NIHMS188061
EDAT- 2009/12/02 06:00
MHDA- 2010/01/09 06:00
PMCR- 2012/03/30
CRDT- 2009/12/02 06:00
PHST- 2009/12/02 06:00 [entrez]
PHST- 2009/12/02 06:00 [pubmed]
PHST- 2010/01/09 06:00 [medline]
PHST- 2012/03/30 00:00 [pmc-release]
AID - jimmunol.0902372 [pii]
AID - 10.4049/jimmunol.0902372 [doi]
PST - ppublish
SO  - J Immunol. 2010 Jan 1;184(1):173-83. doi: 10.4049/jimmunol.0902372. Epub 2009 Nov 
      30.