Characterization of a Phosphoprotein whose mRNA is Regulated by the Mitogenic Pathways in Dog Thyroid Cells

Wilkin, Fraçoise; Suarez-Huerta, Nathalie; Robaye, Bernard; Peetermans, J; Libert, Frédérick; Dumont, Jacques Emile; Maenhaut, Carine

doi:10.1111/j.1432-1033.1997.t01-1-00660.x

Cited by 60 publications

(47 citation statements)

References 38 publications

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“…The trbl gene sequence revealed a divergent kinase structure similar to a previously identified cDNA (C5FW, subsequently renamed Trib2) induced by mitogens in dog thyroid cells (Wilkin et al, 1996;Wilkin et al, 1997), indicating that this family of genes is conserved throughout the metazoan lineage. Because fly genes are named after their phenotype, the overproliferating mesodermal cells seen in trbl mutant embryos resembles, as it were, ''Tribbles,'' the fictional small, furry, and fecund animals who vexed the crew of the Enterprise in the classic ''Trouble with Tribbles'' episode from the original Star Trek television series.…”

Section: Introductionmentioning

confidence: 65%

“…All three mouse Trib isoforms-Trib1/ C8FW/SKIP1, Trib2/C5FW/SKIP2/ SINK and Trib3/NIPK/SKIP3 (Wilkin et al, 1996(Wilkin et al, , 1997Mayumi-Matsuda et al, 1999)-are reported dispensable for development Yamamoto et al, 2007;Takasato et al, 2008). Trib3 knock-in lacZ expression occurs in the liver and adipose tissues, however, the mutant show neither liver defects, nor a change in the phosphorylation state of Akt .…”

Section: Tribs In Vertebrate Development Mouse Knockouts: Do Overlappmentioning

confidence: 99%

“…When the corresponding mutation was made in the catalytic loop of the Trib domain of Trib3, its function was abrogated (Naiki et al, 2007). Because kinases typically autophosphorylate, it is notable that Trib2 and Drosophila Trbl are phosphoproteins (Wilkin et al, 1997;Bodenmiller et al, 2008). Thus, it will be important to ascertain if they remain autophosphorylated when the catalytic loop of kinase domain is mutated.…”

Section: Perspectivesmentioning

confidence: 99%

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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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Section: Introductionmentioning

confidence: 65%

Section: Tribs In Vertebrate Development Mouse Knockouts: Do Overlappmentioning

confidence: 99%

Section: Perspectivesmentioning

confidence: 99%

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Developmental roles of tribbles protein family members

Dobens

Bouyain

2012

Developmental Dynamics

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“…In dog thyroid cells, the levels of C5FW protein have been shown to increase upon stimulation with thyrotropin or epidermal growth factor (Wilkin et al, 1997). Expression of neuronal cell death inducible putative kinase (NIPK) is induced when rat neuronal PC6-3 cells are deprived of NGF (MayumiMatsuda et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

SKIP3, a novel Drosophila tribbles ortholog, is overexpressed in human tumors and is regulated by hypoxia

2003

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Regions of hypoxia are a hallmark of solid tumors. Tumor cells modulate the regulation of specific genes allowing adaptation and survival in the harsh hypoxic environment. We have identified SKIP3, a novel human kinase-like gene, which is overexpressed in multiple human tumors and is regulated by hypoxia. SKIP3 is an ortholog of the Drosophila tribbles, rat NIPK, dog C5FW, and human C8FW genes. Drosophila tribbles is involved in slowing cell-cycle progression during Drosophila development, but little is known regarding the function or tissue distribution of the vertebrate orthologs. We show that the normal tissue expression of SKIP3 is confined to human liver, while multiple primary human lung, colon, and breast tumors express high levels of SKIP3 transcript. Endogenous SKIP3 protein accumulates within 48 h under hypoxic growth conditions in HT-29 and PC-3 cells, with upregulation of the SKIP3 mRNA transcript by 72 h. We identified activating transcription factor 4 (ATF4) as a SKIP3-binding partner using the yeast-two-hybrid assay. Coexpression of SKIP3 and ATF4 showed that SKIP3 is associated with the proteolysis of ATF4, which can be blocked using a proteosome inhibitor. These results indicate that SKIP3 may be an important participant in tumor cell growth.

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“…This molecule contains a serine/threonine kinase catalytic domain but lacks an ATP binding site or one of the conserved catalytic motifs essential for kinase activity. [1][2][3] TRB3 has also been shown to be involved in multiple cellular processes such as glucose/lipid metabolism, muscle/adipocyte differentiation, and stress response by interacting with various functional proteins. 1,[3][4][5][6][7][8][9][10] Three mammalian Tribbles homologues, TRB1, TRB2, and TRB3 are crucial modulators of tumorigenesis.…”

Section: Abstract Tribbles Related Protein 3 (Trb3); Transgenic Mousmentioning

confidence: 99%

A Novel Transgenic Mouse Model Carrying Human Tribbles Related Protein 3 (TRB3) Gene and Its Site Specific Phenotype

Sakai

Fukamachi

Futakuchi

et al. 2014

Biological & Pharmaceutical Bulletin

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Tribbles related protein 3 (TRB3) pseudokinase plays a crucial role in cell proliferation, migration and morphogenesis during development. In our recent study, an introduction of human TRB3 gene into mouse mammary tumor cells caused an increase of proliferation of tumor cells and their nuclear size. In the current study, to examine whether this gene causes de novo morphological changes in a specific organ site we have developed a novel variation of the transgenic mouse model that conditionally expresses human TRB3 (hTRB3) gene using Cre-recombinase (Cre)/loxP recombination system. By injecting hTRB3 transgene construct into pronuclei of mouse embryo, we eventually obtained four hTRB3 mice. The gene expression was controlled by infection of adenovirus-expressing Cre via the tail vein of hTRB3 mouse. In Cre-mediated hTRB3 mouse, expression of the hTRB3 protein was detected in the cytoplasm of hepatocytes in the liver. Expression of this protein was also seen in lymphocytes in the spleen, glomerular endothelial cells, and epithelial cells of collecting duct of the kidney. In hepatocytes of the hTRB3 mouse, nuclear size was significantly greater than that of the wild type mouse, indicating that hTRB3 can play a role at least in part in hepatic morphogenesis. The present animal model may provide a system for evaluation of de novo morphological changes induced by a specific transgene in a specific organ site.Key words Tribbles related protein 3 (TRB3); transgenic mouse; Cre-recombinase (Cre)/loxP Tribbles related protein 3 (TRB3) is one of the mammalian homologues of Drosophila Tribbles. This molecule contains a serine/threonine kinase catalytic domain but lacks an ATP binding site or one of the conserved catalytic motifs essential for kinase activity.1-3) TRB3 has also been shown to be involved in multiple cellular processes such as glucose/lipid metabolism, muscle/adipocyte differentiation, and stress response by interacting with various functional proteins. 1,[3][4][5][6][7][8][9][10] Three mammalian Tribbles homologues, TRB1, TRB2, and TRB3 are crucial modulators of tumorigenesis.3,11-13) TRB1 and TRB2 induce acute myelogenous leukemia by inhibiting CCAAT/enhancer binding protein α (C/EBPα) function. 12)TRB3 is highly expressed in a wide range of human carcinoma cell lines and in several types of human carcinoma. 3,13)We have recently demonstrated that TRB3 promotes proliferation and induces polyploidy of mouse mammary tumor cells.14) This finding was likely to indicate TRB3's response to morphological function. In the current study, by utilizing the recombinant adenovirus expressing Cre-recombinase (Cre) system we examined whether human TRB3 gene causes de novo morphological changes in a specific organ site. MATERIALS AND METHODS Generation of Human TRB3 Transgenic MouseWe ligated flag-tagged full length human TRB3 (hTRB3) cDNA 7) into KpnI and SwaI restriction sites of pCALNL5 vector (DNA Bank, RIKEN Bio Resource Center, Ibaraki, Japan), [15][16][17] and this construct was termed pCALNL-flag-hTRB3. The pCALNL-fl...

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Characterization of a Phosphoprotein whose mRNA is Regulated by the Mitogenic Pathways in Dog Thyroid Cells

Cited by 60 publications

References 38 publications

Developmental roles of tribbles protein family members

Developmental roles of tribbles protein family members

SKIP3, a novel Drosophila tribbles ortholog, is overexpressed in human tumors and is regulated by hypoxia

A Novel Transgenic Mouse Model Carrying Human Tribbles Related Protein 3 (TRB3) Gene and Its Site Specific Phenotype

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