Deregulated Activation of Oncoprotein Kinase Tpl2/Cot in HTLV-I-transformed T Cells

Babu, Geetha R.; Waterfield, Michael; Chang, Mikyoung; Wu, Xuefeng; Sun, Shao Cong

doi:10.1074/jbc.m512375200

Cited by 17 publications

(12 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Also, Cot kinase was found to be constitutively activated in several human T cell leukemia cell lines [42], and BCL11B was recently identified as a potential oncogene for ATL [43]. Thus, our data may also suggest an interesting functional link between enhanced expression of BCL11B and the NF-kB constitutive activation in the adult T cell leukemia/lymphoma cells.…”

Section: Discussionsupporting

confidence: 54%

BCL11B enhances TCR/CD28-triggered NF-κB activation through up-regulation of Cot kinase gene expression in T-lymphocytes

Cismasiu

Duque

Paskaleva

et al. 2008

Biochemical Journal

View full text Add to dashboard Cite

BCL11B is a transcriptional regulator with important role in T cell development and leukemogenesis. Recently we demonstrated that BCL11B controls expression from IL-2 promoter through direct binding to the US1 site. Here we provide evidence that BCL11B also participates in the activation of IL-2 gene expression by enhancing NF-kB activity in the context of TCR/CD28–triggered T cell activation. Enhanced NF-kB activation is not a consequence of BCL11B binding to the NF-kB response elements or association with the NF-kB-DNA complexes, but rather the result of higher translocation of NF-kB to the nucleus caused by enhanced degradation of the IkB. The enhanced IkB degradation in cells with increased levels of BCL11B was specific for T cells activated through TCR, but not through TNFα or UV, and was caused by higher activity of IkB kinase, as indicated by its higher phosphorylation. As BCL11B is a transcription factor we investigated whether expression of genes upstream of IkB kinase in the TCR/CD28 signaling pathway was affected by increased BCL11B expression, and found that Cot kinase mRNA levels were elevated. Cot kinase is known to promote enhanced IkB kinase activity which results in phosphorylation and degradation of the IkB inhibitors and activation of NF-kB. Implication of Cot kinase in BCL11B-mediated NF-kB activation in response TCR activation is supported by the fact that a Cot kinase dominant negative mutant or Cot kinase siRNA blocked BCL11B-mediated NF-kB activation. In support of our observations, we report that BCL11B enhances expression of several other NF-kB target genes, in addition to IL-2. In addition, we provide evidence that BCL11B associates with Cot kinase gene intron 2 to regulate its expression.

show abstract

Section: Discussionsupporting

confidence: 54%

BCL11B enhances TCR/CD28-triggered NF-κB activation through up-regulation of Cot kinase gene expression in T-lymphocytes

Cismasiu

Duque

Paskaleva

et al. 2008

Biochemical Journal

View full text Add to dashboard Cite

show abstract

“…IL-2 induction by TPL-2 has also been suggested to involve activation of NF-κB transcription factors via the related MAP3 kinase NIK [23,24]. Transfection experiments in Jurkat T cells indicate that TPL-2 may control NF-κB activity by modulating the transactivation potential of the RelA transcription factor [25,26]. In addition, overexpression experiments in COS-7 cells demonstrate that TPL-2, which is complexed with the NF-κB inhibitory protein NF-κB1 p105 [27] (see section 3), may regulate NF-κB activation by inducing p105 proteolysis, releasing associated Rel subunits for translocation into the nucleus [28].…”

Section: S125mentioning

confidence: 98%

Regulation and function of TPL-2, an IκB kinase-regulated MAP kinase kinase kinase

Gantke¹,

Sriskantharajah²,

Ley³

2010

Cell Res

138

158

View full text Add to dashboard Cite

The IκB kinase (IKK) complex plays a well-documented role in innate and adaptive immunity. This function has been widely attributed to its role as the central activator of the NF-κB family of transcription factors. However, another important consequence of IKK activation is the regulation of TPL-2, a MEK kinase that is required for activation of ERK-1/2 MAP kinases in myeloid cells following Toll-like receptor and TNF receptor stimulation. In unstimulated cells, TPL-2 is stoichiometrically complexed with the NF-κB inhibitory protein NF-κB1 p105, which blocks TPL-2 access to its substrate MEK, and the ubiquitin-binding protein ABIN-2 (A20-binding inhibitor of NF-κB 2), both of which are required to maintain TPL-2 protein stability. Following agonist stimulation, the IKK complex phosphorylates p105, triggering its K48-linked ubiquitination and degradation by the proteasome. This releases TPL-2 from p105-mediated inhibition, facilitating activation of MEK, in addition to modulating NF-κB activation by liberating associated Rel subunits for translocation into the nucleus. IKK-induced proteolysis of p105, therefore, can directly regulate both NF-κB and ERK MAP kinase activation via NF-κB1 p105. TPL-2 is critical for production of the proinflammatory cytokine TNF during inflammatory responses. Consequently, there has been considerable interest in the pharmaceutical industry to develop selective TPL-2 inhibitors as drugs for the treatment of TNF-dependent inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease. This review summarizes our current understanding of the regulation of TPL-2 signaling function, and also the complex positive and negative roles of TPL-2 in immune and inflammatory responses.

show abstract

“…Activated MAP3K8 induces the ERK1/2, JNK, NF-B, and p38MAPK pathways, and a study has shown that it is constitutively activated in HTLV-Itransformed human CD4ϩ T-cell lines. 59 The MAP3K8 gene therefore illustrates a gene deregulation (increased expression) detected in our patient cohort during chronic disease, which was further augmented in L-HES-associated T lymphoma and identified as a potential target of microRNAs shown to be downmodulated in the patients' cells.…”

Section: Discussionmentioning

confidence: 99%

Molecular profiling of CD3−CD4+ T cells from patients with the lymphocytic variant of hypereosinophilic syndrome reveals targeting of growth control pathways

Ravoet

Sibille

et al. 2009

Blood

View full text Add to dashboard Cite

Deregulated Activation of Oncoprotein Kinase Tpl2/Cot in HTLV-I-transformed T Cells

Cited by 17 publications

References 61 publications

BCL11B enhances TCR/CD28-triggered NF-κB activation through up-regulation of Cot kinase gene expression in T-lymphocytes

BCL11B enhances TCR/CD28-triggered NF-κB activation through up-regulation of Cot kinase gene expression in T-lymphocytes

Regulation and function of TPL-2, an IκB kinase-regulated MAP kinase kinase kinase

Molecular profiling of CD3−CD4+ T cells from patients with the lymphocytic variant of hypereosinophilic syndrome reveals targeting of growth control pathways

Contact Info

Product

Resources

About