Tpl2 kinase signal transduction in inflammation and cancer

Vougioukalaki, Maria; Kanellis, Dimitris C.; Gkouskou, Kalliopi; Eliopoulos, Aristides G.

doi:10.1016/j.canlet.2011.02.004

Cited by 89 publications

(136 citation statements)

References 85 publications

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“…Because the overexpression of WT TPL2 did not exert similar oncogenic effects in vivo, it has been proposed that TPL2 is a proto-oncogene activated by Cterminal truncation (10). Nevertheless, activating mutations in TPL2 have not been described in humans (11). Although elevated levels of TPL2 have been reported in certain tumor types, a detailed comparative evaluation of TPL2 expression in human malignancy and normal tissue is missing, and its physiological role in carcinogenesis remains enigmatic.…”

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confidence: 99%

TPL2 kinase is a suppressor of lung carcinogenesis

Gkirtzimanaki

Gkouskou

Oleksiewicz

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Lung cancer is a heterogeneous disease at both clinical and molecular levels, posing conceptual and practical bottlenecks in defining key pathways affecting its initiation and progression. Molecules with a central role in lung carcinogenesis are likely to be targeted by multiple deregulated pathways and may have prognostic, predictive, and/or therapeutic value. Here, we report that Tumor Progression Locus 2 (TPL2), a kinase implicated in the regulation of innate and adaptive immune responses, fulfils a role as a suppressor of lung carcinogenesis and is subject to diverse genetic and epigenetic aberrations in lung cancer patients. We show that allelic imbalance at the TPL2 locus, up-regulation of microRNA-370, which targets TPL2 transcripts, and activated RAS (rat sarcoma) signaling may result in down-regulation of TPL2 expression. Low TPL2 levels correlate with reduced lung cancer patient survival and accelerated onset and multiplicity of urethane-induced lung tumors in mice. Mechanistically, TPL2 was found to antagonize oncogene-induced cell transformation and survival through a pathway involving p53 downstream of cJun N-terminal kinase (JNK) and be required for optimal p53 response to genotoxic stress. These results identify multiple oncogenic pathways leading to TPL2 deregulation and highlight its major tumor-suppressing function in the lung.

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confidence: 99%

TPL2 kinase is a suppressor of lung carcinogenesis

Gkirtzimanaki

Gkouskou

Oleksiewicz

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Progression and metastasis can be summarized in a series of steps starting with local invasion, followed by intravasation, survival in the circulation, extravasation, initiation of micrometastasis at a distant site, and vascularization of the new metastatic tumor (31). While overexpression of Tpl2 has been observed in different types of human tumors (12) and a recent article reported significant upregulation of Tpl2 in metastatic prostate cancer samples (32), there is little evidence about the role of the Tpl2 oncogene in RCC. Herein, we showed that Tpl2 promotes ccRCC tumorigenesis and metastasis in vitro and in vivo by regulating diverse steps including cell-cycle progression that leads to increased proliferation, anoikis resistance, clonogenicity, migration, and invasion.…”

Section: Discussionmentioning

confidence: 99%

“…Tumor Progression Locus 2 (Tpl2), which is known as MAP3 kinase 8 (MAP3K8), plays essential roles in tumor necrosis factor, interleukin-1 (IL-1), CD40, Toll-like receptor and G protein-coupled receptor-mediated MAPK and c-jun-NH 2 -kinase (JNK) pathways (12). Tpl2 has been reported to be overexpressed in various human tumors and to promote cell transformation, proliferation, migration, and invasion by the activation of extracellular signal-regulated kinase (ERK), Rac1, and focal adhesion kinase (FAK; refs.…”

Section: Introductionmentioning

confidence: 99%

“…Tpl2 has been reported to be overexpressed in various human tumors and to promote cell transformation, proliferation, migration, and invasion by the activation of extracellular signal-regulated kinase (ERK), Rac1, and focal adhesion kinase (FAK; refs. [12][13][14][15][16][17][18].…”

Section: Introductionmentioning

confidence: 99%

“…Tpl2 maybe a novel target for ccRCC as its mRNA levels are significantly elevated in ccRCC compared with normal kidneys (12), and elevated MKK or ERK activity has been detected in human RCC cases (19,20). However, little information exists about prognostic relevance and functional significance of Tpl2 in oncogenesis and metastatic conversion of ccRCC.…”

Section: Introductionmentioning

confidence: 99%

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Tpl2 Kinase Impacts Tumor Growth and Metastasis of Clear Cell Renal Cell Carcinoma

Lee

Joo

Lim

et al. 2013

Molecular Cancer Research

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Due to the innate high metastatic ability of renal cell carcinoma (RCC), many patients with RCC experience local or systemic relapses after surgical resection. A deeper understanding of the molecular pathogenesis underlying advanced RCC is essential for novel innovative therapeutics. Tumor progression locus 2 (Tpl2), upregulated in various tumor types, has been reported to be associated with oncogenesis and metastatic progression via activation of the MAPK signaling pathway. Herein, the relevance of Tpl2 in tumor growth and metastasis of RCC is explored. Inspection of The Cancer Genome Atlas (TCGA) indicated that Tpl2 overexpression was significantly related to the presence of metastases and poor outcome in clear cell RCC (ccRCC), which is the most aggressive subtype of RCC. Moreover, expression of Tpl2 and CXCR4 showed a positive correlation in ccRCC patients. Depletion of Tpl2 by RNAi or activity by a Tpl2 kinase inhibitor in human ccRCC cells remarkably suppressed MAPK pathways and impaired in vitro cell proliferation, clonogenicity, anoikis resistance, migration, and invasion capabilities. Similarly, orthotopic xenograft growth and lung metastasis were significantly inhibited by Tpl2 silencing. Furthermore, Tpl2 knockdown reduced CXCL12-directed chemotaxis and chemoinvasion accompanied with impaired downstream signaling, indicating potential involvement of Tpl2 in CXCR4-mediated metastasis. Taken together, these data indicate that Tpl2 kinase is associated with and contributes to disease progression of ccRCC.

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Tumor progression locus 2/Cot is required for activation of extracellular regulated kinase in liver injury and toll-like receptor–induced TIMP-1 gene transcription in hepatic stellate cells in mice

et al. 2013

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Toll‐like receptors (TLRs) function as key regulators of liver fibrosis and are able to modulate the fibrogenic actions of nonparenchymal liver cells. The fibrogenic signaling events downstream of TLRs on Kupffer cells (KCs) and hepatic stellate cells (HSCs) are poorly defined. Here, we describe the MAP3K tumor progression locus 2 (Tpl2) as being important for the activation of extracellular regulated kinase (ERK) signaling in KCs and HSCs responding to stimulation of TLR4 and TLR9. KCs lacking Tpl2 display defects with TLR induction of cytokines interleukin (IL)‐1β, IL‐10, and IL‐23. tpl2−/− HSCs were unable to increase expression of fibrogenic genes IL‐1β and tissue inhibitor of metalloproteinase 1 (TIMP‐1), with the latter being the result of defective stimulation of TIMP‐1 promoter activity by TLRs. To determine the in vivo relevance of Tpl2 signaling in liver fibrosis, we compared the fibrogenic responses of wild‐type (WT) and tpl2−/− mice in three distinct models of chronic liver injury. In the carbon tetrachloride and methionine‐choline–deficient diet models, we observed a significant reduction in fibrosis in mice lacking Tpl2, compared to WT controls. However, in the bile duct ligation model, there was no effect of tpl2 deletion, which may reflect a lesser role for HSCs in wounding response to biliary injury. Conclusion: We conclude that Tpl2 is an important signal transducer for TLR activation of gene expression in KCs and HSCs by the ERK pathway and that suppression of its catalytic activity may be a route toward suppressing fibrosis caused by hepatocellular injuries. (HEPATOLOGY 2013)

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Tpl2 kinase signal transduction in inflammation and cancer

Cited by 89 publications

References 85 publications

TPL2 kinase is a suppressor of lung carcinogenesis

TPL2 kinase is a suppressor of lung carcinogenesis

Tpl2 Kinase Impacts Tumor Growth and Metastasis of Clear Cell Renal Cell Carcinoma

Tumor progression locus 2/Cot is required for activation of extracellular regulated kinase in liver injury and toll-like receptor–induced TIMP-1 gene transcription in hepatic stellate cells in mice

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