The proto-oncogene encoding the Tpl-2 kinase was identified as a common target of proviral integration in MoMuLV-induced rat T cell lymphomas. Proviral integration in Tpl-2 occurs during tumor progression in 22.5% of the tested thymonas, and the mRNA transcribed from the rearranged Tpl-2 locus encodes a C-terminally truncated protein. Recent studies using Tpl-2 transgenic mice confirmed that Tpl-2 is a highly oncogenic kinase whose oncogenic potential is induced by C-terminal truncation. Additional studies on the role of Tpl-2 in signal transduction showed that Tpl-2 is a mediator of TNFalpha signaling. Moreover, they showed that Tpl-2 interacts with the guanine nucleotide exchange factor Vav and activates the MAPK and JNK pathway as well as NF-kB. Through its effects on these signaling pathways Tpl-2 activates several promoters including its own promoter, the CMV major immediate early promoter, and the promoter of IL-2. Regarding the IL-2 promoter, it was shown that its activation was mediated by MAPK and JNK dependent signals as well as calcium/calmodulin dependent signals. Based on this information, experiments were designed to address the role of Tpl-2 in TNFalpha signaling, as well as in IL-2 expression and in the biology of neoplastic progression. The long term objective of this project is to use the Tpl-2 protoncogene as a probe to explore the biology of the immune system and the pathobiology of neoplasia with emphasis on tumor progression and metastasis.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Pathology B Study Section (PTHB)
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Shen, Grace L
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Thomas Jefferson University
Schools of Medicine
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Eliopoulos, Aristides G; Das, Santasabuj; Tsichlis, Philip N (2006) The tyrosine kinase Syk regulates TPL2 activation signals. J Biol Chem 281:1371-80
Cho, Jeonghee; Tsichlis, Philip N (2005) Phosphorylation at Thr-290 regulates Tpl2 binding to NF-kappaB1/p105 and Tpl2 activation and degradation by lipopolysaccharide. Proc Natl Acad Sci U S A 102:2350-5
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Eliopoulos, Aristides G; Dumitru, Calin D; Wang, Chun-Chi et al. (2002) Induction of COX-2 by LPS in macrophages is regulated by Tpl2-dependent CREB activation signals. EMBO J 21:4831-40
Kontoyiannis, Dimitris; Boulougouris, George; Manoloukos, Menelaos et al. (2002) Genetic dissection of the cellular pathways and signaling mechanisms in modeled tumor necrosis factor-induced Crohn's-like inflammatory bowel disease. J Exp Med 196:1563-74
Eliopoulos, Aristides G; Davies, Clare; Blake, Sarah S M et al. (2002) The oncogenic protein kinase Tpl-2/Cot contributes to Epstein-Barr virus-encoded latent infection membrane protein 1-induced NF-kappaB signaling downstream of TRAF2. J Virol 76:4567-79
Chan, T O; Tsichlis, P N (2001) PDK2: a complex tail in one Akt. Sci STKE 2001:pe1
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