Tribbles-1 and -2 are tumour suppressors, down-regulated in human acute myeloid leukaemia

Gilby, Daniel C; Sung, Hye Youn; Winship, Peter R.; Goodeve, Anne; Reilly, John T.; Kiss-Tóth, Endre

doi:10.1016/j.imlet.2009.12.007

Cited by 45 publications

(42 citation statements)

References 45 publications

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“…The failure of the dCOP and dNs mutants to function in any of our multiple assays of Trib2 differentiation and transformation further highlights the importance of the Trib2 KD and COP1-binding site. Although data from our group and others show that Trib2 can induce apoptosis in cell lines, 34 Trib2 clearly functions as an oncogene in myeloid transformation, as demonstrated in both our colony and BMT assays, by inducing gain-offunction activities, such as C/EBP-␣ degradation. This illustrates a limitation of cell-line assays, where the effects of Tribbles on survival and differentiation may obscure its transforming effects.…”

Section: Discussioncontrasting

confidence: 39%

Transformation by Tribbles homolog 2 (Trib2) requires both the Trib2 kinase domain and COP1 binding

Keeshan

Bailis

Dedhia

et al. 2010

Blood

108

149

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Tribbles homolog 2 (Trib2) is a pseudokinase that induces acute myelogenous leukemia (AML) in mice and is highly expressed in a subset of human AML. Trib2 has 3 distinct regions, a proline-rich N-terminus, a serine/threonine kinase homology domain, and a C-terminal constitutive photomorphogenesis 1 (COP1)-binding domain. We performed a structure-function analysis of Trib2 using in vitro and in vivo assays. The N-terminus was not required for IntroductionTribbles (Trib) pseudokinases have recently emerged as important contributors to dysregulated signaling in malignant hematopoiesis. All 3 mammalian Trib homologs, Trib1, Trib2, and Trib3 (collectively termed "Trib1-3"), are associated with human malignancies. [1][2][3] Trib1 and Trib2 function as oncogenes in acute myelogenous leukemia (AML) and cooperate with homeobox gene 9 (HoxA9) to accelerate the onset of AML in murine AML models. 2,4 In particular, Trib2 is highly expressed in a specific subset of human AMLs that are associated with impaired CCAAT/ enhancer-binding protein-alpha (C/EBP-␣) function. 2 These AMLs express both myeloid and T-cell markers, and some contain activating Notch1 mutations. 5 As Trib2 is a direct transcriptional target of oncogenic Notch1, we hypothesize that the oncogenic Notch1 mutations are activating Trib2 expression in some of these tumors. 5 These biphenotypic AMLs respond poorly to current therapies, suggesting that new therapeutic strategies are needed. 6 Trib proteins interact with various signaling molecules and transcription factors, including activating transcription factor 4 (ATF4), 7 p65, 8 C-terminal interacting protein (CtIP), 9 mitogenactivated protein kinase kinase (MAPKK), 10 protein kinase B (AKT), 11 and constitutive morphogenesis 1 (COP1). 12 We recently demonstrated that Trib2 binds to and facilitates the degradation of C/EBP-␣, and proposed that this process is a key feature of Trib2-induced AML. 2 Trib2 (also termed c5Fw, TRB-2, GS3955, TRB2, and AW319517) has 3 clearly distinguishable regions, including an N-terminal portion, a central serine/threonine kinase-like domain (KD), and a C-terminal region that contains a COP1-binding site. The Trib2 N-terminus is the most divergent region of mammalian Trib proteins and is characterized by a high serine and proline content. The C-terminus contains a DQxVPx motif that is shared by Trib1-3 and binds the E3 ligase, COP1. 12 Trib2 belongs to the pseudokinase family because it contains a central region that shares considerable homology with serine/ threonine kinases, but has deviations in the catalytic loop that are likely to eliminate catalytic activity. 13 Canonical kinases have an N-terminal lobe that binds adenosine triphosphate (ATP), a central hinge region, and a C-terminal lobe that binds substrates. 14 The N-terminal lobe contains an invariant lysine residue critical for ATP binding that is conserved in Trib2, but the highly conserved sequence, HRDLKPEN, in the C-terminal subdomain, which is critical for phosphate transfer in active kinases, is altered to LRD...

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Section: Discussioncontrasting

confidence: 39%

Transformation by Tribbles homolog 2 (Trib2) requires both the Trib2 kinase domain and COP1 binding

Keeshan

Bailis

Dedhia

et al. 2010

Blood

108

149

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“…Gilby et al (2010) showed that TRIB1 enhanced apoptosis of leukemic cell line through suppression of JNK-Bcl-2 pathway. Yokoyama et al (2010) showed that TRIB1 suppressed apoptosis through enhancement of Erk phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

TRIB1 downregulates hepatic lipogenesis and glycogenesis via multiple molecular interactions

Ishizuka¹,

Nakayama²,

Ogawa³

et al. 2014

Journal of Molecular Endocrinology

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Mammalian tribbles homolog 1 (TRIB1) regulates hepatic lipogenesis and is genetically associated with plasma triglyceride (TG) levels and cholesterol, but the molecular mechanisms remain obscure. We explored these mechanisms in mouse livers transfected with a TRIB1 overexpression, a shRNA template or a control (LacZ) adenovirus vector. The overexpression of TRIB1 reduced, whereas induction of the shRNA template increased, plasma glucose, TG, and cholesterol and simultaneously hepatic TG and glycogen levels. The involvement of TRIB1 in hepatic lipid accumulation was supported by the findings of a human SNP association study. A TRIB1 SNP, rs6982502, was identified in an enhancer sequence, modulated enhancer activity in reporter gene assays, and was significantly (PZ9.39!10 K7 ) associated with ultrasonographically diagnosed nonalcoholic fatty liver disease in a population of 5570 individuals. Transcriptome analyses of mouse livers revealed significant modulation of the gene sets involved in glycogenolysis and lipogenesis. Enforced TRIB1 expression abolished CCAAT/enhancer binding protein A (CEBPA), CEBPB, and MLXIPL proteins, whereas knockdown increased the protein level. Levels of TRIB1 expression simultaneously affected MKK4 (MAP2K4), MEK1 (MAP2K1), and ERK1/2 (MAPK1/3) protein levels and the phosphorylation of JNK, but not of ERK1/2. Pull-down and mammalian two-hybrid analyses revealed novel molecular interaction between TRIB1 and a hepatic lipogenic master regulator, MLXIPL. Co-expression of TRIB1 and CEBPA or MLXIPL reduced their protein levels and proteasome inhibitors attenuated the reduction. These data suggested that the modulation of TRIB1 expression affects hepatic lipogenesis and glycogenesis through multiple molecular interactions.

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“…The ability of Tribs to promote AML noted above was contradicted by microarrays showing that Trib1 and Trib2 are down-regulated in these tumors and both effectively inhibit Jnk-mediated growth (Gilby et al, 2010). Thus, their role as either oncogene or tumor suppressor of AML remains unresolved.…”

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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Tribbles-1 and -2 are tumour suppressors, down-regulated in human acute myeloid leukaemia

Cited by 45 publications

References 45 publications

Transformation by Tribbles homolog 2 (Trib2) requires both the Trib2 kinase domain and COP1 binding

Transformation by Tribbles homolog 2 (Trib2) requires both the Trib2 kinase domain and COP1 binding

TRIB1 downregulates hepatic lipogenesis and glycogenesis via multiple molecular interactions

Developmental roles of tribbles protein family members

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