Genetic evidence for the role of Erk activation in a lymphoproliferative disease of mice.
Germline mutation of the linker for activation of T cells (LAT) gene at the phospholipase C-gamma1 (PLC-gamma1)-binding site leads to a fatal lymphoproliferative disease in mice. The hyperactivated T cells that develop in these mice have defective T-cell antigen receptor (TCR)-induced calcium flux but enhanced mitogen-activated protein kinase (MAPK) activation. We used genetic analysis to investigate genes whose products might suppress MAPK activation and lymphoproliferative disease in LAT mutant mice. B-lymphocyte adaptor molecule of 32 kDa (Bam32) is a known mediator of MAPK activation in B cells. We recently reported that in CD4(+) T cells, Bam32 deficiency decreased MAPK activation and specifically extracellular-signal-regulated kinase (Erk) signaling, following TCR stimulation. By crossing the Bam32 null mutation onto the LAT knock-in background, we found that the Bam32 null mutation delayed the onset and decreased the severity of lymphoproliferative disease in LAT knock-in mice. The pulmonary lymphocyte infiltration seen in LAT knock-in mice was also markedly decreased in double-mutant mice. Additionally, Erk activation was diminished in LAT knock-in Bam32 knockout CD4(+) T cells. To more accurately determine the role of Erk in this delay of lymphoproliferative disease, we also bred a transgenic, hypersensitive Erk allele (the Erk2 sevenmaker mutant) onto the LAT knock-in Bam32 knockout double-mutant background. These triple transgenic mice demonstrated a role for Erk activation in lymphoproliferative disease caused by the LAT knock-in mutation.
Miyaji
Michihiko
M
Laboratory of Cellular and Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Kortum
Robert L
RL
Surana
Rishi
R
Li
Wenmei
W
Woolard
Kevin D
KD
Simpson
R Mark
RM
Samelson
Lawrence E
LE
Sommers
Connie L
CL
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D016516:CD4-CD8 Ratio; D002118:Calcium / Q000378:metabolism; D049109:Cell Proliferation; D004789:Enzyme Activation / Q000502:physiology; D004797:Enzyme-Linked Immunosorbent Assay; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry; D015847:Interleukin-4 / Q000097:blood; D008074:Lipoproteins / Q000235:genetics / Q000378:metabolism; D008214:Lymphocytes / Q000378:metabolism / Q000473:pathology; D008232:Lymphoproliferative Disorders / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013154:Spleen / Q000378:metabolism / Q000473:pathology; D013163:Splenomegaly / Q000235:genetics / Q000378:metabolism / Q000473:pathology
D048868:Adaptor Proteins, Signal Transducing; C403524:Dapp1 protein, mouse; C491734:Lat protein, mouse; D008074:Lipoproteins; D008565:Membrane Proteins; D010750:Phosphoproteins; D011948:Receptors, Antigen, T-Cell; D015847:Interleukin-4; D048049:Extracellular Signal-Regulated MAP Kinases; D002118:Calcium