Human TRIB2 is a repressor of FOXO that contributes to the malignant phenotype of melanoma cells

Zanella, Fabian; Renner, Oliver; García, Beatriz; Callejas, Sergio; Dopazo, Ana; Peregrina, Sandra; Carnero, Amancio; Link, Wolfgang

doi:10.1038/onc.2010.58

Cited by 85 publications

(86 citation statements)

References 29 publications

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“…We previously reported that the anti-apoptotic function of CD166 is via enhancement of both expression and activity of oncoprotein, YAP (7). The degradation of YAP can be protected by TRIB2 (21)(22), a protein that is also capable of inhibiting and reducing nuclear FOXO proteins (23). Thus, we consider that CD166 plays a similar role to that of TRIB2.…”

Section: Discussionmentioning

confidence: 89%

CD166 plays a pro-carcinogenic role in liver cancer cells via inhibition of FOXO proteins through AKT

Wang

et al. 2014

Oncology Reports

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Abstract. Cluster of differentiation 166 (CD166) is a cell surface membrane protein, which is regarded as a valuable prognostic marker in several types of epithelial tumors. We previously reported that CD166 exerts its pro-carcinogenic role by enhancing YAP function in liver cancer cells. However, YAP cannot completely rescue the increased anti-carcinogenic effects by gene silencing of CD166, whose downstream effectors require further investigation. Here, we found that knockdown of CD166 inhibits phosphorylation of anti-carcinogenic FOXO proteins. Overexpression of CD166 led, not only to a faster protein degradation rate, but also a more accumulated ubiquitination of FOXO compared to the control. Moreover, overexpression of CD166 facilitated FOXO protein localization from the nuclear fraction to the cytosolic fraction, suggesting that CD166 modulates FOXO protein stability through alteration of their subcellular localization. In addition, simultaneous overexpression of CD166 partially reversed the evoked anti-carcinogenic effects by overexpression of FOXO both in vitro and in vivo. Furthermore, CD166 knockdown-induced anti-carcinogenic effects and dephosphorylation of FOXO proteins were rescued by overexpression of AKT. In liver cancer tissues, we also observed that higher expression levels of CD166, phospho-AKT, total AKT and phospho-FOXO were correlated with lower expression levels of total FOXO, suggesting that the upregulation of CD166 leads to the activation of AKT, which in turn facilitates phosphorylation and degradation of FOXO. Taken together, our data demonstrate that AKT is an inter-mediator between the upstream regulator, CD166, and downstream effector, FOXO, in liver cancer cells. Disrupting the relationship between CD166 and the AKT/FOXO axis may serve as a novel therapeutic target for liver cancer patients. IntroductionCluster of differentiation 166 (CD166) is a cell surface member of the immunoglobulin superfamily (1), which is overexpressed and regarded as a valuable prognostic marker of disease progression and poor survival in several types of epithelial tumors (2-4). Gene silencing of CD166 decreases the concentration of Bcl-2 and increases the level of apoptosis (PARP, active caspase-7) (5). We previously reported that the activation of anti-apoptotic canonical NF-κB signaling greatly induces CD166 expression in liver cancer cells after serum deprivation (6), suggesting its important roles in regulating apoptosis. Most recently, we revealed that CD166 can exert its anti-apoptotic role by enhancing YAP function, demonstrating that CD166 is an upstream regulator of YAP (7). However, overexpression of YAP cannot completely rescue the increased anti-carcinogenic effects evoked by knockdown of CD166 (7). Thus, the downstream regulation of the CD166 pro-carcinogenic function needs to be further explored.The forkhead box transcription factor superfamily consists of 19 subclasses of FOX genes, FOXA-FOXS (8). The FOX transcription factors that belong to the other (O) subfamily (FOXO) include four memb...

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Section: Discussionmentioning

confidence: 89%

CD166 plays a pro-carcinogenic role in liver cancer cells via inhibition of FOXO proteins through AKT

Wang

et al. 2014

Oncology Reports

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“…It is worth noting that it has been reported that TRIB3-null animals show upregulation of TRIB1 and TRIB2 in at least some tissues. 39 As TRIB2 is associated with induction of acute myelogenous leukemia 40,41 and TRIB1 with other malignancies, 42,43 changes in the levels of the other Tribbles isoforms may also contribute to the phenotype observed in Trib3 À / À animals.…”

Section: Discussionmentioning

confidence: 99%

Loss of Tribbles pseudokinase-3 promotes Akt-driven tumorigenesis via FOXO inactivation

et al. 2014

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Tribbles pseudokinase-3 (TRIB3) has been proposed to act as an inhibitor of AKT although the precise molecular basis of this activity and whether the loss of TRIB3 contributes to cancer initiation and progression remain to be clarified. In this study, by using a wide array of in vitro and in vivo approaches, including a Trib3 knockout mouse, we demonstrate that TRIB3 has a tumorsuppressing role. We also find that the mechanism by which TRIB3 loss enhances tumorigenesis relies on the dysregulation of the phosphorylation of AKT by the mTORC2 complex, which leads to an enhanced phosphorylation of AKT on Ser473 and the subsequent hyperphosphorylation and inactivation of the transcription factor FOXO3. These observations support the notion that loss of TRIB3 is associated with a more aggressive phenotype in various types of tumors by enhancing the activity of the mTORC2/AKT/FOXO axis. Pseudokinases constitute a group of proteins that have a kinase-like domain that lacks at least one of the conserved catalytic residues. 1,2 Different studies have shown that some pseudokinases can exhibit low levels of kinase activity, while others have critical roles as activators of their specific targets. 1,2 Moreover, aberrant regulation of pseudokinases has been implicated in the etiology and progression of a variety of diseases, including cancer. 3 The Tribbles family of pseudokinases was first described in Drosophila as a negative regulator of cell division in early embryogenesis. [4][5][6][7] There are three mammalian Tribbles isoforms (Trib1, Trib2 and Trib3), homologs to the Drosophila tribbles proteins, and they all share a highly conserved central kinase-like domain, which lacks catalytic residues, and a 'tribbles specific' C-terminal domain, which has been proposed to participate in the binding to different Tribbles partners. 8 Tribbles pseudokinase-3 (TRIB3; also named TRB3, NIPK and SKIP3) has been proposed to interact with several proteins, including the transcription factors activating transcription factor 4 (ATF-4) and CHOP 9 as well as with several MAPKs. 10 TRIB3 has also been shown to interact and inhibit AKT, 11 which has been suggested to suppress insulin signaling. 11,12 In addition, administration of different anticancer agents promotes cancer cell death via TRIB3 upregulation and the subsequent inhibition of Akt. [13][14][15][16][17][18][19] However, the precise molecular basis of the regulation of Akt by TRIB3 and whether loss of this pseudokinase may contribute to cancer initiation and progression remains to be clarified.In this study, we investigated the effect of the genetic inactivation of TRIB3 in several cellular and animal models of cancer. Our findings indicate that genetic inhibition of TRIB3 enhances tumorigenesis and that this effect is due -at least primarily -to a selective inactivation of the transcription factor FOXO by the mammalian target of rapamycin complex 2 (mTORC2)/AKT axis. ResultsGenetic inhibition of TRIB3 facilitates oncogene transformation and enhances the tumorigenicity of cancer c...

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“…While Trib2 directs turnover of C/EBPa in these tumor cells, C/EBPa mutants do not result in AML, making it likely that Trib2 has more targets (Keeshan et al, 2006). In melanomas, Trib2 facilitates growth and survival by down-regulating FOXO activity (Zanella et al, 2010). Trib levels are increased in lung cancers (Grandinetti et al, 2011), breast cancers (Wennemers et al, 2011a,b), B-cell chronic lymphocytic leukemia (B-CLL Johansson et al, 2010), and cancers of the esophagus and colon (Miyoshi et al, 2009).…”

Section: Tribs As Oncogenesmentioning

confidence: 99%

Developmental roles of tribbles protein family members

Dobens

Bouyain

2012

Developmental Dynamics

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The gene tribbles (trbl), identified 12 years ago in genetic screens for mutations that control both cell division and cell migration during embryonic Drosophila development, is the founding member of the Tribbles (Trib) family of kinase-like proteins that have diverse roles in cell signaling, tissue homeostasis, and cancer. Trib proteins share three motifs: (1) a divergent kinase region (Trib domain) with undetermined catalytic activity, (2) a COP1 site used to direct key target proteins to the proteosome for degradation, and (3) a MEK1 site that binds and modulates MAPKK kinase activity. The notion that Tribs act as scaffolding proteins to balance signaling levels in multiple pathways retains an attractive simplicity, but given recent data showing that divergent kinases act by means of novel catalytic mechanisms, the enzymatic activity of Tribs remains untested. Here, we focus on the role of Tribs during development. Developmental analysis of Drosophila trbl phenotypes reveals tissue-specific, sometimes contradictory roles. In mammals, multiple Trib isoforms exhibit overlapping and tissue-specific functions. Recent data indicate the mechanism of Trib activity is conserved and requires the Trib domain. Finally, we discuss the connections between Tribs in disease and cancer that have implications for their normal roles during organogenesis.

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Human TRIB2 is a repressor of FOXO that contributes to the malignant phenotype of melanoma cells

Cited by 85 publications

References 29 publications

CD166 plays a pro-carcinogenic role in liver cancer cells via inhibition of FOXO proteins through AKT

CD166 plays a pro-carcinogenic role in liver cancer cells via inhibition of FOXO proteins through AKT

Loss of Tribbles pseudokinase-3 promotes Akt-driven tumorigenesis via FOXO inactivation

Developmental roles of tribbles protein family members

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