International Mammalian Genome Society

The 14th International Mouse Genome Conference (2000)

B31. Tpl2 Knockout Mice are Defective in MAPK Activation by LPS and They are Resistant to LPS/D-Galactosamine-Induced Endotoxin Shock

Calin D. Dumitru1 *, Jeffrey D. Ceci2 4 *, Christos Tsatsanis1 5 *, Dimitris Kontoyiannis3 , Konstantinos Stamatakis1, Jun-Hsiang Lin1, Christos Patriotis6, Nancy A. Jenkins2, Neal G. Copeland2, George Kollias3 and Philip N. Tsichlis1
1Kimmel Cancer Center, Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA. 2Mouse Cancer Genetics Program, National Cancer Institute - FCRDC, Frederick, MD. 3Laboratory of Molecular Genetics, Hellenic Pasteur Institute, Athens, Greece. 4Department of Human Biological Chemistry and Genetics, University of Texas Medical Branch, Galveston, TX. 5Clinical Chemistry Laboratory University of Crete Medical School, 71409 Heraklion, Greece. 6Fox Chase Cancer Center, Philadelphia, PA 19111

* These authors contributed equally to this work.

The Tpl2 protooncogene encodes a serine-threonine protein kinase that is expressed primarily in hematopoietic cells. When overexpressed, TPL2 activates the MAPK and SAPK pathways, NFAT and NF-kB and is highly oncogenic. Here we show that despite these profound biological effects of the overexpressed TPL2 kinase, Tpl2 knockout mice appear normal. However, they produce low levels of TNF-alpha when exposed to lipopolysaccharide and they are resistant to LPS/D-Galactosamine induced endotoxin shock. The defect in the induction of TNF-alpha is posttranscriptional. LPS stimulation of peritoneal macrophages from these mice did not activate MEK1, ERK1 and ERK2 but activated JNK, p38MAPK and NF-kB. The block in ERK1 and ERK2 activation was causally linked to the defect in TNF-alpha induction by experiments showing that normal murine macrophages treated with the MEK inhibitor PD98059 exhibit a similar defect. Deletion of the AU-rich motif in the TNF-alpha mRNA minimized the effect of Tpl2 inactivation on the induction of TNF-alpha. Therefore, the LPS signals transduced via Tpl2 and the ERK pathway regulate the induction of TNF-alpha at least in part by targeting the AU-rich motif in the TNF-alpha mRNA.

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