Tribbles-Related Protein Family Members as Regulators or Substrates of the Ubiquitin-Proteasome System in Cancer Development

Sakai, Satoshi; Miyajima, Chiharu; Uchida, Chiharu; Itoh, Yoshio; Hayashi, Hidetoshi; Inoue, Yasumichi

doi:10.2174/1568009616666151112122645

Cited by 26 publications

(21 citation statements)

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“…TRIB3, a member of the mammalian pseudokinase tribbles family, plays a pivotal role in the unfolded protein response (UPR) 5 and is an important stress-related gene involved in multiple biological processes 29. In the present study, we showed that TRIB3 expression was significantly higher in RCC tissues than in normal paracancerous tissues.…”

Section: Discussionmentioning

confidence: 51%

TRIB3 Promotes the Proliferation and Invasion of Renal Cell Carcinoma Cells via Activating MAPK Signaling Pathway

Hong

Zhou

et al. 2019

Int. J. Biol. Sci.

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Tribbles pseudokinase 3 (TRIB3) is a member of the mammalian pseudokinase tribbles family and is involved in multiple biological processes. However, the role of TRIB3 in renal cell carcinoma (RCC) remains unclear. In this study, we aimed to elucidate the biological functions of TRIB3 in RCC and explore its underlying mechanisms. TRIB3 expression and its correlation with clinicopathological features was evaluated in 123 patients with RCC. A series of cytological experiments were performed to clarify the biological functions of TRIB3, and potential molecular regulatory mechanisms were explored using transcriptome sequencing. TRIB3 expression was significantly elevated in RCC tissues compared to that in paracancerous tissues, and high expression of TRIB3 was correlated with both advanced tumor stage and unfavorable prognosis. TRIB3 knockdown markedly inhibited RCC cell proliferation, migration and invasion. Furthermore, overexpression of TRIB3 promoted RCC cell proliferation, migration, invasion and xenograft tumor growth. Notably, TRIB3 expression was modulated by hypoxia-inducible factor-1α (HIF-1α), which enhanced cell viability and invasiveness via targeting the MAPK signaling pathway. This study reveals the potential oncogenic role of TRIB3 in RCC pathogenesis and illustrates the mechanisms underlying TRIB3-mediated tumor progression, providing new insight into the development of TRIB3 as a tumor biomarker and therapeutic target.

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Section: Discussionmentioning

confidence: 51%

TRIB3 Promotes the Proliferation and Invasion of Renal Cell Carcinoma Cells via Activating MAPK Signaling Pathway

Hong

Zhou

et al. 2019

Int. J. Biol. Sci.

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“…As a member of the tribble family, tribbles homolog 2 (TRIB2) is a mitosis blocker that regulates embryo and germ cell development [18]. It has been reported that, as a scaffold protein [19], TRIB2 plays a critical role in various biological processes as well as in pathological conditions, especially in tumor development [20,21]. For instance, the overexpression of TRIB2 may accelerate the acute myeloid leukemia (AML) through activating C/EBPα pathway [22]; in liver cancer, TRIB2 promoted cell proliferation and transformation via improving the stabilization of YAP through the E3 ubiquitin ligase βTrCP [23].…”

Section: Discussionmentioning

confidence: 99%

miR-509-5p Inhibits the Proliferation and Invasion of Osteosarcoma by Targeting TRIB2

Guo

Peng

et al. 2019

BioMed Research International

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Osteosarcoma (OS) is one of the most common malignant bone tumors in adolescents with a poor prognosis. Though miR-509-5p has been reported as a tumor suppressor in several human cancers, the role of miR-509-5p in OS remains unclear. In this study, our result of real-time PCR (RT-PCR) showed that the expression of miR-509-5p was significantly decreased in OS tissues and cell lines. Overexpression of miR-509-5p significantly suppressed cell proliferation and invasion in OS cell lines. Moreover, we identified tribbles homolog 2 (TRIB2) as the direct target of miR-509-5p. Knockdown of TRIB2 could inhibit the malignant capacity of OS cells. At last, we reported that TRIB2 could inhibit the bioactivity of the tumor suppressor gene p21 via blocking its transcriptional activity. Collectively, our study revealed that miR-509-5p functions as a tumor suppressor by targeting TRIB2 in OS and thus could affect the activity of p21, suggesting that miR-509-5p is a novel preventive intervention for OS patients.

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“…Trib3, Trib2 and Trib1 can each also bind the ubiquitin ligase COP1 [30]. Trib1 and Trib2 (but not Trib3) are myeloleukemogenic when overexpressed [31, 32] and act by promoting the ubiquitin-mediated degradation of the myeloid differentiation factor C/EBPα [32].…”

Section: Discussionmentioning

confidence: 99%

“…Trib1 and Trib2 (but not Trib3) are myeloleukemogenic when overexpressed [31, 32] and act by promoting the ubiquitin-mediated degradation of the myeloid differentiation factor C/EBPα [32]. In adipocytes, however, Trib3 can promote COP1-mediated ubiquitination and degradation of acetyl-coenzyme A carboxylase-1, and attenuate adipocyte differentiation [30, 33]. Whether Trib3 might additionally act as an important E3 ubiquitin ligase adaptor within EPCs during accelerated erythropoiesis is therefore meaningful to consider, with such actions perhaps contributing to Trib3’s presently observed effects on erythrocyte integrity, and ROS.…”

Section: Discussionmentioning

confidence: 99%

Governing roles for Trib3 pseudokinase during stress erythropoiesis

Dev

Asch

Jachimowicz

et al. 2017

Experimental Hematology

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In response to anemia, the heightened production of erythropoietin (EPO) can sharply promote erythroid progenitor cell (EPC) formation. Specific mediators of such EPO- accelerated erythropoiesis, however, are not well understood. Presently, we first report that the expression of Trib3 in adult bone marrow EPCs in vivo is nominal at steady state, but strongly activated upon EPO challenge. In a knockout mouse model, Trib3 disruption modestly increased steady-state erythrocyte numbers, and decreased mean corpuscular volume. Following 5-fluorouracil myeloablation, however, rebound RBC production and hemoglobin levels were substantially (and selectively) compromised in Trib3−/− mice vs Trib3+/+ congenic controls. Erythrocytes from 5-fluorouracil treated Trib3−/− mice additionally were more prone to lysis, and exhibited elevated peroxide-induced reactive oxygen species. Ex vivo, the development of CD71posTer119pos erythroblasts from Trib3−/− bone marrow progenitors was attenuated, and this was associated with heightened EPO-dependent Erk1/2 activation and moderately increased Akt activation. For developmentally staged EPCs, gene profiling provided further initial insight into candidate mediators of EPO-induced Trib3 gene expression, including Cebp-beta, Atf4, Egr-1, and Nab1. Overall, Trib3 is indicated to act as a novel EPC-intrinsic governor of stress erythropoiesis.

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Tribbles-Related Protein Family Members as Regulators or Substrates of the Ubiquitin-Proteasome System in Cancer Development

Cited by 26 publications

References 0 publications

TRIB3 Promotes the Proliferation and Invasion of Renal Cell Carcinoma Cells via Activating MAPK Signaling Pathway

TRIB3 Promotes the Proliferation and Invasion of Renal Cell Carcinoma Cells via Activating MAPK Signaling Pathway

miR-509-5p Inhibits the Proliferation and Invasion of Osteosarcoma by Targeting TRIB2

Governing roles for Trib3 pseudokinase during stress erythropoiesis

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