Overexpression of the Tpl-2/Cot oncogene in human breast cancer

Sourvinos, George; Tsatsanis, Christos; Spandidos, Demetrios Α.

doi:10.1038/sj.onc.1202891

Cited by 89 publications

(77 citation statements)

References 36 publications

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“…Recent studies revealed that the Tpl2/Cot gene expression (mRNA level) is enhanced in breast cancer cells and large granular leukemia cells (60,61). The results presented in this report suggest the possibility that deregulation of Tpl2/Cot in cancer cells may also occur posttranslationally.…”

Section: Discussionmentioning

confidence: 49%

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

Babu

Waterfield

Chang

et al. 2006

Journal of Biological Chemistry

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Protein kinase Tpl2/Cot is encoded by a protooncogene that is cis-activated by retroviral insertion in murine T cell lymphomas. It has remained unclear whether this oncoprotein kinase is mutated or post-translationally activated in human cancer cells. We have shown here that Tpl2/Cot is constitutively activated in human leukemia cell lines transformed by the human T cell leukemia virus type I (HTLV-I). The kinase activity of Tpl2/Cot is normally suppressed through its physical interaction with an inhibitor, the NF-B1 precursor protein p105. Interestingly, a large pool of Tpl2/ Cot is liberated from p105 and exhibits constitutive kinase activity in HTLV-I-transformed T cells. In contrast to its labile property in normal cells, the pathologically activated Tpl2/Cot is remarkably stable. Further, whereas the physiological activation of Tpl2/Cot involves its long isoform, the HTLV-activated Tpl2/Cot is predominantly the short isoform. We have also shown that the HTLV-Iencoded Tax protein is able to activate Tpl2/Cot in transfected cells. Finally, Tpl2/Cot participates in the activation of NF-B by Tax. These findings indicate that deregulated activation of Tpl2/Cot may occur in human cancer cells.

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Section: Discussionmentioning

confidence: 49%

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

Babu

Waterfield

Chang

et al. 2006

Journal of Biological Chemistry

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“…However, analyses of other lung cancer cells suggested that this is a very rare event. Tpl2 overexpression may be important in oncogenesis, and has been reported both in breast tumors [13] and in a small panel of large granular lymphocyte proliferative disorders [14]. Thus, while somatic mutation of Tpl2 does not appear to be an important event in the development of human cancer, increased TPL-2 protein expression may sometimes contribute to oncogenesis or tumor progression.…”

Section: Discovery Of Tpl2 Oncogene and Initial Characterizationmentioning

confidence: 99%

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

Gantke¹,

Sriskantharajah²,

Ley³

2010

Cell Res

138

158

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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.

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“…Given the nature of its discovery, it is surprising that there have been few reports concerning the role of Tpl-2 in human tumors. In studies with small sample populations, Tpl-2 was found to be overexpressed without gene amplification in some large granular lymphocyte proliferative disorders (Christoforidou et al, 2004), whereas Sourvinos et al (1999) detected gene amplification and corresponding increased Tpl-2 expression in some human breast cancers.…”

Section: Raf Groupmentioning

confidence: 99%

Role of mitogen-activated protein kinase kinase kinases in signal integration

2007

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Mitogen-activated protein kinases (MAPKs) are members of a dynamic protein kinase network through which diverse stimuli regulate the spatio-temporal activities of complex biological systems. MAPKs regulate critical cellular functions required for homeostasis such as the expression of cytokines and proteases, cell cycle progression, cell adherence, motility and metabolism. MAPKs therefore influence cell proliferation, differentiation, survival, apoptosis and development. In vertebrates, five MAPK families are regulated by MAPK kinase kinase-MAPK kinase-MAPK (MKKK-MKK-MAPK) phosphorelay systems. There are at least 20 MKKKs that selectively phosphorylate and activate different combinations of the seven MKKs, resulting in a specific activation profile of members within the five MAPK families. MKKKs are differentially activated by upstream stimuli including cytokines, antigens, toxins and stress insults providing a mechanism to integrate the activation of different MAPKs with the cellular response to each stimulus. Thus, MKKKs can be considered as 'signaling hubs' that regulate the specificity of MAPK activation. In this review, we describe how the MKKK 'hub' function regulates the specificity of MAPK activation, highlighting MKKKs as targets for therapeutic intervention in cancer and other diseases.

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Overexpression of the Tpl-2/Cot oncogene in human breast cancer

Cited by 89 publications

References 36 publications

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

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

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

Role of mitogen-activated protein kinase kinase kinases in signal integration

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