Thirty-eight-negative kinase 1 (TNK1) facilitates TNFα-induced apoptosis by blocking NF-κB activation

Azoitei, Ninel; Brey, Andreas; Busch, Tobias; Fulda, Simone; Adler, Guido; Seufferlein, Thomas

doi:10.1038/sj.onc.1210476

Cited by 32 publications

(34 citation statements)

References 27 publications

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“…Therefore, we propose that epigenetic silencing of the Tnk1/ Kos1 promoter by hypermethylation may be a mechanism that accounts for Tnk1/Kos1 inactivation (30)(31)(32). In support of this possibility in human cancer, expression of Tnk1 is reported to be down-regulated/silenced in human leukemia and prostate cancer-derived cell lines, indicating a potential role for the loss of Tnk1/Kos1 activity in human cancer (1,2,33). It will now be important to determine the Tnk1 promoter methylation status in these cell lines.…”

Section: That Develop In the Tnk1mentioning

confidence: 86%

“…Whereas the 47-kDa Kos1 is ubiquitously expressed in mouse tissues, as well as human fetal blood and leukemia cell lines, the predicted 72-kDa Tnk1 can be detected in human fetal blood, but not in mouse cells, by Western blotting (3,33). A point mutation in Tnk1/Kos1 that inactivates the catalytic activity has been shown to abolish its growth inhibitory properties, indicating that the tyrosine kinase activity is required for Tnk1/Kos1 function (2,3). Interestingly, in support of this notion, a point mutation in the catalytic domain of Tnk1 (R339K) has recently been identified in a human lung adenocarcinoma that may potentially affect its tyrosine kinase activity (34).…”

Section: Discussionmentioning

confidence: 99%

“…Tnk1/Kos1 expression is developmentally regulated in mouse embryos, as well as in differentiating embryonic stem cells in vitro (3). Forced expression of Tnk1/Kos1 in various cell lines inhibits cell growth by a mechanism requiring its intrinsic tyrosine kinase activity (2,3). Importantly, auto-tyrosine phosphorylation of Tnk1/Kos1 results in the suppression of Ras activity.…”

Section: Introductionmentioning

confidence: 99%

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Tnk1/Kos1 Knockout Mice Develop Spontaneous Tumors

Hoare

Reinhard³

et al. 2008

Cancer Research

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Tnk1/Kos1 is a non-receptor protein tyrosine kinase implicated in negatively regulating cell growth in a mechanism requiring its intrinsic catalytic activity. Tnk1/Kos1 null mice were created by homologous recombination by deleting the catalytic domain. Both Tnk1 +/À and Tnk1 À/À mice develop spontaneous tumors, including lymphomas and carcinomas, at high rates [27% (14 of 52) and 43% (12 of 28), respectively]. Tnk1/Kos1 expression is silenced in tumors that develop in Tnk1 +/À mice but not in adjacent uninvolved tissue, and silencing occurs in association with Tnk1 promoter hypermethylation. Tissues and murine embryonic fibroblasts derived from Tnk1/Kos1-null mice exhibit proportionally higher levels of basal and epidermal growth factor-stimulated Ras activation that results from increased Ras-guanine exchange factor (GEF) activity. Mechanistically, Tnk1/Kos1 can directly tyrosine phosphorylate growth factor receptor binding protein 2 (Grb2), which promotes disruption of the Grb2-Sos1 complex that mediates growth factor-induced Ras activation, providing dynamic regulation of Ras GEF activity with suppression of Ras. Thus, Tnk1/Kos1 is a tumor suppressor that functions to down-regulate Ras activity.

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Section: That Develop In the Tnk1mentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Tnk1/Kos1 Knockout Mice Develop Spontaneous Tumors

Hoare

Reinhard³

et al. 2008

Cancer Research

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“…Figgins et al however, found no association between rs1554948 and LOAD [90]. In 2007, Azoitei et al reported that TNK1 acts as a molecular switch in TNF pathway and blocks p65-induced NF-B reporter gene activation [91] and induces apoptosis by blocking TNF -induced NF-B transactivation. It is notworthy that according to AlzGene, TNF gene is also one of potential candidate genes for AD.…”

Section: Tnk1mentioning

confidence: 99%

Genetic and Blood Biomarkers of Alzheimer`s Disease

Momeni¹,

Ferrari²

2010

TONMEDJ

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Alzheimer's disease (AD) is the most prevalent form of dementia. AD is highly heritable, with a complex pattern. Although clinical diagnosis is based on accurate and well defined diagnostic criteria (NINCDS-ADRDA), the definite diagnosis relies on the postmortem pathological findings. The need for measures for the early detection of AD, as well as the need to distinguish between AD and other forms of dementia, has put great emphasis on the discovery of biomarkers for Alzheimer's disease. In clinical practice, there is need for non-invasive, accurate methods for the early detection and differential diagnosis of AD. The successful identification and development of the biomarkers, depends completely on the understanding of pathology, genetic and molecular mechanisms involved in the disease. As blood is a circulating dynamic tissue and transcription reflects the ongoing changes in the system, it makes the transcriptional profiling of the blood cells, potentially, the most sensitive source for transcriptional biomarkers. A systematic comparison of the genetic and proteomic blood biomarkers in patients and healthy controls can reveal additional potential candidates for AD. In the first part of this review, we would like to discuss the most recent genetic findings and their possible involvement in the pathogenesis of AD. In the second part, we review the blood biomarkers which can be derived from peripheral blood mononuclear cells (PBMC), serum, and plasma. We discus three main category of bio-molecules, namely DNA, RNA (miRNA and mRNA), and protein as well as their possible role in the hypothetical mechanisms involved in pathogenesis of AD. A dynamic interaction between the genetic findings through the whole genome association studies and biomarkers discovery can advance our knowledge of AD pathogenesis beyond the scope of each field independently.

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“…16 The signaling pathways induced by TNK1 remain largely unknown, although it was recently suggested that activation of TNK1 enables TNFα-induced apoptosis by selectively inhibiting TNFα-induced activation of NF-κB. 17 Apart from this function, TNK1 was also shown to play a negative regulatory role in the Ras-Raf1-MAPK pathway. 18 The identification of TNK1 in our retroviral insertion screen indicates that activation of TNK1 can play a dominant role in oncogenic transformation, and suggests that TNK1 is also capable of stimulating proliferation and survival pathways.…”

confidence: 99%

Identification of protein tyrosine kinases with oncogenic potential using a retroviral insertion mutagenesis screen

Lierman¹,

Miegroet²,

Beullens³

et al. 2009

Haematologica

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Protein tyrosine kinases form a large family of signaling proteins implicated in both normal and malignant cell signaling. The aim of this study was to identify protein tyrosine kinases that can transform hematopoietic cells to growth factor independent proliferation when constitutively activated by homodimerization. We used a modified retroviral insertion mutagenesis screen with a retroviral vector containing the homodimerization domain of ETV6 followed by an artificial splice donor site. Integration of this retroviral vector within a gene of the host genome would generate a fusion transcript containing the dimerization domain and part of the disrupted gene. Using this strategy with the IL3 dependent Ba/F3 cell line, we identified 8 different protein tyrosine kinases (Abl1, Fgfr1, Hck, Jak2, Lck, Mertk, Mst1r, Tnk1) that transformed the cells. These results characterize HCK, MERTK, MST1R and TNK1 as potential oncogenes and describe a method to identify gain-of-function fusion genes using a retroviral insertion screen.

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Thirty-eight-negative kinase 1 (TNK1) facilitates TNFα-induced apoptosis by blocking NF-κB activation

Cited by 32 publications

References 27 publications

Tnk1/Kos1 Knockout Mice Develop Spontaneous Tumors

Tnk1/Kos1 Knockout Mice Develop Spontaneous Tumors

Genetic and Blood Biomarkers of Alzheimer`s Disease

Identification of protein tyrosine kinases with oncogenic potential using a retroviral insertion mutagenesis screen

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