DRO1, a Gene Down-regulated by Oncogenes, Mediates Growth Inhibition in Colon and Pancreatic Cancer Cells

Bommer, Guido T.; Jäger, Christoph; Dürr, E.; Baehs, Sebastian; Eichhorst, Sören T.; Brabletz, Thomas; Hu, Gang; Fröhlich, Thomas; Arnold, Georg J.; Kress, Dagmar C.; Göke, Burkhard; Fearon, Eric R.; Kolligs, Frank T.

doi:10.1074/jbc.m412593200

Cited by 51 publications

(93 citation statements)

References 59 publications

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“…Despite the strong prediction that Ccdc80 contains an N-terminal signal peptide sequence, published experiments had yielded contradictory results (23,25,47) prompting us to reexamine whether Ccdc80 is indeed a secreted protein. We found that human Ccdc80 ectopically expressed in HEK293T and, more importantly, endogenous Ccdc80 in 3T3-L1 adipocytes are secreted proteins.…”

Section: Discussionmentioning

confidence: 99%

“…1A). Although Ccdc80 is highly conserved between species, no close homologs are found in either human, mouse, or rat genomic sequences (22,23). Using real-time reverse transcription-PCR, we found that mouse Ccdc80 is highly expressed in white adipose tissue (WAT) with significantly lower mRNA levels in other tissues, including brown adipose tissue (BAT) (Fig.…”

Section: Identification Of Ccdc80 As a Gene Encoding A Potential Newmentioning

confidence: 99%

“…Ccdc80 has also been shown to be up-regulated in brown adipose tissue of mildly obese bombesin receptor subtype-3 (BRS-3 Ϫ/Ϫ ) mice (22) and to be down-regulated in cancer cell lines (23,24) and during the osteoblastic differentiation of bone marrow stromal cells (25). Ectopic expression of Ccdc80 inhibits growth properties of cancer cells in vitro, suggesting that Ccdc80 might be a candidate tumor suppressor gene (23). Here, we show that Ccdc80 is highly expressed in white adipose tissue and that its expression is regulated during adipocyte differentiation in vitro.…”

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confidence: 99%

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Bidirectional Modulation of Adipogenesis by the Secreted Protein Ccdc80/DRO1/URB

Tremblay¹,

Revett²,

Huard³

et al. 2009

Journal of Biological Chemistry

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Adipocyte-secreted proteins play important roles in metabolic regulation through autocrine, paracrine, and endocrine mechanisms. Using transcriptional profiling, we identified coiled-coil domain containing 80 (Ccdc80; also known as DRO1 and URB) as a novel secreted protein highly expressed in white adipose tissue. In 3T3-L1 cells Ccdc80 is expressed and secreted in a biphasic manner with high levels in postconfluent preadipocytes and terminally differentiated adipocytes. To determine whether Ccdc80 regulates adipocyte differentiation, Ccdc80 expression was manipulated using both knockdown and overexpression approaches. Small hairpin RNA-mediated silencing of Ccdc80 in 3T3-L1 cells inhibits adipocyte differentiation. This phenotype was partially reversed by treating the knockdown cells with Ccdc80-containing conditioned medium from differentiated 3T3-L1 cells. Molecular studies indicate that Ccdc80 is required for the full inhibition of T-cell factor-mediated transcriptional activity, down-regulation of Wnt/␤-catenin target genes during clonal expansion, and the subsequent induction of C/EBP␣ and peroxisome proliferator-activated receptor ␥. Surprisingly, overexpression of Ccdc80 in 3T3-L1 cells also inhibits adipocyte differentiation without affecting the repression of the Wnt/␤-catenin signaling pathway. Taken together, these data suggest that Ccdc80 plays dual roles in adipogenesis by mechanisms that involve at least in part down-regulation of Wnt/␤-catenin signaling and induction of C/EBP␣ and peroxisome proliferator-activated receptor ␥.The metabolic abnormalities associated with obesity underlie the development of insulin resistance and type 2 diabetes (1, 2). The emergence of white adipose tissue as an endocrine organ has refined our understanding of the mechanisms by which adipocytes can affect whole-body energy homeostasis (3). Adipose cells not only serve as lipid storage sites but can also secrete various autocrine, paracrine, and/or endocrine mediators referred to as adipocyte-secreted proteins or adipokines. These secreted proteins can have profound effects on energy balance and insulin sensitivity and are affected by hormonal changes, nutritional status, inflammatory mediators, and/or pharmacological treatments (4, 5). Understanding the full set of secreted proteins present in adipocytes and their regulation and activities might help reveal novel molecular links between obesity and metabolic disorders and potential therapeutic opportunities.Commitment of mesenchymal progenitor cells to the adipocyte lineage involves a complex transcriptional cascade that culminates in the induction of the basic leucine-region zipper proteins C/EBP␣, 2 C/EBP␤, and C/EBP␦, the Krüppel-like transcription factor KLF5, and the nuclear receptor PPAR␥ (6 -8). In the mouse 3T3-L1 cell line (9, 10) initiation of this cascade requires the stimulation of growth-arrested fibroblastlike cells with adipogenic inducers forcing the cells to re-enter the cell cycle allowing transcription of early adipogenic genes (11,12). This clona...

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Section: Discussionmentioning

confidence: 99%

Section: Identification Of Ccdc80 As a Gene Encoding A Potential Newmentioning

confidence: 99%

mentioning

confidence: 99%

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Bidirectional Modulation of Adipogenesis by the Secreted Protein Ccdc80/DRO1/URB

Tremblay¹,

Revett²,

Huard³

et al. 2009

Journal of Biological Chemistry

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“…Although our results showed negligible presence of high-molecular-weight forms of CCDC80 in human adipose tissue depots and a only small amount in control plasma, these species are consistently observed in cultured murine adipocytes (7) and in cells ectopically expressing CCDC80 (7,22). We therefore analyzed total CCDC80 protein in cultured human SGBS cells, in confluent preadipocytes, and in differentiating and mature adipocytes.…”

Section: Ccdc80 Expression In Human Sgbs Adipocytesmentioning

confidence: 99%

Adipose Tissue and Serum CCDC80 in Obesity and Its Association with Related Metabolic Disease

Osorio-Conles

Guitart

Moreno-Navarrete

et al. 2017

Mol Med

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“…In this study, we also included the RK3E cell line because it has been widely used to assess transformation ability of potential oncogenes. [27][28][29][30][31][32][33] Cells transfected with BRAF V600E were grown in 96-well plates at a density of 3000 cells per well. As controls, the empty vector and BRAF WT vector were also transfected into the cells.…”

Section: Cell Growth Assaymentioning

confidence: 99%

Mutant BRAF Induces DNA Strand Breaks, Activates DNA Damage Response Pathway, and Up-Regulates Glucose Transporter-1 in Nontransformed Epithelial Cells

Sheu

Guan

Tsai

et al. 2012

The American Journal of Pathology

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Although the oncogenic functions of activating BRAF mutations have been clearly demonstrated in human cancer, their roles in nontransformed epithelial cells remain largely unclear. Investigating the cellular response to the expression of mutant BRAF in nontransformed epithelial cells is fundamental to the understanding of the roles of BRAF in cancer pathogenesis. In this study, we used two nontransformed cyst108 and RK3E epithelial cell lines as models in which to compare the phenotypes of cells expressing BRAF WT and BRAF V600E . We found that transfection of the BRAF V600E , but not the BRAF WT , expression vector suppressed cellular proliferation and induced apoptosis in both cell types. BRAF V600E generated reactive oxygen species, induced DNA double-strand breaks, and caused subsequent DNA damage response as evidenced by an increased number of pCHK2 and ␥H2AX nuclear foci as well as the up-regulation of pCHK2, p53, and p21. Because BRAF and KRAS (alias Ki-ras) mutations have been correlated with GLUT1 up-regulation, which encodes glucose transporter-1, we demonstrated here that expression of BRAF V600E , but not BRAF WT , was sufficient to up-regulate GLUT1. Taken together, our findings provide new insights into mutant BRAF-induced oncogenic stress that is manifested by DNA damage and growth arrest by activating the pCHK2-p53-p21 pathway in nontransformed cells, while it also confers tumor-promoting phenotypes such as the up-regulation of GLUT1 that contributes to enhanced glucose metabolism that characterizes tumor cells.

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DRO1, a Gene Down-regulated by Oncogenes, Mediates Growth Inhibition in Colon and Pancreatic Cancer Cells

Cited by 51 publications

References 59 publications

Bidirectional Modulation of Adipogenesis by the Secreted Protein Ccdc80/DRO1/URB

Bidirectional Modulation of Adipogenesis by the Secreted Protein Ccdc80/DRO1/URB

Adipose Tissue and Serum CCDC80 in Obesity and Its Association with Related Metabolic Disease

Mutant BRAF Induces DNA Strand Breaks, Activates DNA Damage Response Pathway, and Up-Regulates Glucose Transporter-1 in Nontransformed Epithelial Cells

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