Genetic evidence for the role of Erk activation in a lymphoproliferative disease of mice

Michihiko Miyaji, Robert L. Kortum, Rishi Surana, Wenmei Li, Kevin D Woolard, R. Mark Simpson, Lawrence E. Samelson, Connie L. Sommers

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Germline mutation of the linker for activation of T cells (LAT) gene at the phospholipase C-γ1 (PLC-γ1)-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.

Original languageEnglish (US)
Pages (from-to)14502-14507
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number34
DOIs
StatePublished - Aug 25 2009
Externally publishedYes

Fingerprint

Extracellular Signal-Regulated MAP Kinases
T-Lymphocytes
B-Lymphocytes
Mitogen-Activated Protein Kinases
T-Cell Antigen Receptor
Mutation
Germ-Line Mutation
Type C Phospholipases
Transgenic Mice
Genes
Alleles
Binding Sites
Lymphocytes
Calcium
Lung

Keywords

  • Bam32
  • LAT
  • Lymphoproliferation
  • T cells

ASJC Scopus subject areas

  • General

Cite this

Genetic evidence for the role of Erk activation in a lymphoproliferative disease of mice. / Miyaji, Michihiko; Kortum, Robert L.; Surana, Rishi; Li, Wenmei; Woolard, Kevin D; Simpson, R. Mark; Samelson, Lawrence E.; Sommers, Connie L.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 106, No. 34, 25.08.2009, p. 14502-14507.

Research output: Contribution to journalArticle

Miyaji, Michihiko ; Kortum, Robert L. ; Surana, Rishi ; Li, Wenmei ; Woolard, Kevin D ; Simpson, R. Mark ; Samelson, Lawrence E. ; Sommers, Connie L. / Genetic evidence for the role of Erk activation in a lymphoproliferative disease of mice. In: Proceedings of the National Academy of Sciences of the United States of America. 2009 ; Vol. 106, No. 34. pp. 14502-14507.
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