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

21 Scopus citations

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

Keywords

  • Bam32
  • LAT
  • Lymphoproliferation
  • T cells

ASJC Scopus subject areas

  • General

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