Tribbles homolog 2 inactivates C/EBPα and causes acute myelogenous leukemia

Keeshan, Karen; He, Yiping; Wouters, Bas J.; Shestova, Olga; Xu, Lanwei; Sheng, Hong; Rodríguez, Carlos; Maillard, Ivan; Tobias, John W.; Valk, Peter J.M.; Carroll, Martin; Aster, Jon C.; Delwel, Ruud; Pear, Warren S.

doi:10.1016/j.ccr.2006.09.012

Cited by 221 publications

(275 citation statements)

References 51 publications

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“…In this study we identify the molecular mechanism involved in the dysregulation of C/EBPα expression via TRIB2 in AML. We and others (10,13,30) have previously demonstrated that TRIB2 overexpression induces AML and that it degrades C/EBPα p42. Here we provide novel insights on this process and show that the presence of C/EBPα p42 is required not only to initiate TRIB2 AML, but also for TRIB2 to cooperate with C/EBPα (p42 loss and increased p30) in driving AML disease.…”

Section: Discussionmentioning

confidence: 82%

“…In fact, TRIB2 leads to the degradation of C/EBPα p42 via E3 ligase COP1 binding whilst sparing p30 from degradation, resulting in disturbed granulopoiesis. This modulation of C/EBPα was found to be critical for the induction of AML in vivo (10,13). E2F1 cooperates with C/EBPα p30 to activate the Trib2 promoter in preleukaemic cells resulting in elevated TRIB2 expression.…”

Section: Introductionmentioning

confidence: 93%

“…TRIB2 is a potent oncogene capable of inducing fully penetrant AML in murine models, and can cooperate with other AML oncogenes to disrupt signaling pathways and transcription factors in AML disease (10)(11)(12)(13). TRIB2 expression was shown to be elevated in a cohort of AML patients with a mixed myeloid/lymphoid phenotype and a dysregulated CEBPA gene expression signature.…”

Section: Introductionmentioning

confidence: 99%

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The presence of C/EBPα and its degradation are both required for TRIB2-mediated leukaemia

et al. 2016

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C/EBPα (p42 and p30 isoforms) is commonly dysregulated in cancer via the action of oncogenes, and specifically in acute myeloid leukaemia (AML) by mutation. Elevated TRIB2 leads to the degradation of C/EBPα p42, leaving p30 intact in AML. Whether this relationship is a cooperative event in AML transformation is not known and the molecular mechanism involved remains elusive.Using mouse genetics our data reveal that in the complete absence of C/EBPα TRIB2 was unable to induce AML. Only in the presence of C/EBPα p42 and p30 were TRIB2 and p30 able to cooperate to decrease the latency of disease. We demonstrate the molecular mechanism involved in degradation of C/EBPα p42 requires site-specific direct interaction between TRIB2 and C/EBPα p42 for the K48-specific ubiquitin-dependent proteasomal degradation of C/EBPα p42. This interaction and ubiquitination is dependent on a critical C-terminal lysine residue on C/EBPα. We show effective targeting of this pathway pharmacologically using proteasome inhibitors in TRIB2 positive AML cells. Together, our data show that excess p30 cooperated with TRIB2 only in the presence of p42 to accelerate AML and the direct interaction and degradation of C/EBPα p42 is required for TRIB2-mediated AML.

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Section: Discussionmentioning

confidence: 82%

Section: Introductionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

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The presence of C/EBPα and its degradation are both required for TRIB2-mediated leukaemia

et al. 2016

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“…A mechanism for this was defined: Trbl binds to and promotes proteosome degradation of the fly C/EBP (CAAT enhancer binding protein) homolog encoded by the gene slow border cells (slbo), a key promoter of border cell migration. Subsequent work indicates that this interaction is highly conserved with Trib1 and Trib 2 in several mammalian tissues: (1) in acute myelogenous leukemia (AML) tumors, Trib1 accelerates degradation of C/EBPa; (2) upregulation of C/EBPb occurs in Trib1 knockout mice (Yamamoto et al, 2007;Keeshan et al, 2008); (3) overexpression of Trib2 reduces C/EBPa levels in a proteasome-dependent manner, resulting in myeloid differentiation (Keeshan et al, 2006); and (3) Trib2 (but not Trib3) increases degradation of C/EBPb, effectively suppressing differentiation of 3T3-L1 preadipocytes (Naiki et al, 2007).…”

Section: Developmental Dynamicsmentioning

confidence: 99%

“…Trib2 is up-regulated in acute myelogenous leukemia tumors (AML) and misexpression leads to growth advantages and transplantable tumors (Keeshan et al, 2006). 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).…”

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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The role of tribbles homolog 2 in vascular smooth muscle cell proliferation

Takaguri

Ishizaka

Maki

et al. 2023

Cell Biology International

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Tribbles homolog 2 (TRIB2) functions as an adapter protein that regulates signal transductions involved in a variety of cellular functions, including tumorigenesis. However, the role of TRIB2 in the proliferation of vascular smooth muscle cells (VSMCs) and the underlying expression mechanisms remain unclear. The present study investigated the role of TRIB2 in VSMC proliferation and revealed that TRIB2 expression increases following vascular injury and platelet‐derived growth factor (PDGF)‐BB‐stimulated VSMCs. We found that pretreatment with diphenyleneiodonium (a nicotinamide adenine dinucleotide phosphate oxidase inhibitor), U0126 (an inhibitor of mitogen‐activated protein kinase kinase 1 [MEK1]), or siRNA targeting the gene encoding early growth response 1 (EGR‐1) significantly inhibits PDGF‐BB‐induced TRIB2 expression in VSMCs. Furthermore, TRIB2 knockdown significantly inhibits PDGF‐BB‐induced proliferation of VSMCs but does not affect the phosphorylation of AKT. However, phosphorylation of ERK1 and expression of proliferating cell nuclear antibody are significantly suppressed in VSMCs by PDGF‐BB stimulation. Thus, PDGF‐BB‐induced TRIB2 expression is mediated by ROS/ERK/EGR‐1 pathways and plays a critical role in VSMC proliferation via modulation of ERK activity. We propose TRIB2 as a promising therapeutic target for the prevention of neointima formation and vascular disease.

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Tribbles homolog 2 inactivates C/EBPα and causes acute myelogenous leukemia

Cited by 221 publications

References 51 publications

The presence of C/EBPα and its degradation are both required for TRIB2-mediated leukaemia

The presence of C/EBPα and its degradation are both required for TRIB2-mediated leukaemia

Developmental roles of tribbles protein family members

The role of tribbles homolog 2 in vascular smooth muscle cell proliferation

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