Hypermethylation of Ron proximal promoter associates with lack of full-length Ron and transcription of oncogenic short-Ron from an internal promoter

Angeloni, Debora; Danilkovitch‐Miagkova, Alla; Иванова, Т. А.; Брага, Э. А.; Zabarovsky, Eugene R.; Lerman, Michael I.

doi:10.1038/sj.onc.1210238

Cited by 43 publications

(49 citation statements)

References 28 publications

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“…However, the contribution of these variants to human tumorigenesis is unclear at present given that these studies had the potentially confounding concomitant overexpression of full length Ron. This is further supported by a recent study that suggests that the activity of SFRon may be affected by full length Ron expression [26]. Further studies are needed to clarify the clinical significance of Ron variants as causative factors in human tumorigenesis and as targets for therapeutic intervention.…”

Section: Variant Forms Of the Ron Receptormentioning

confidence: 61%

“…SF-Ron is generated from an alternative start site located in intron 10 of the Ron gene and generates a Ron protein containing only a small extracellular portion along with the transmembrane and intracellular domains. A recent report has shown that the expression of full length Ron and SF-Ron may be the result of variations in the methylation patterns within two distinct CpG islands in the Ron proximal promoter, wherein widespread hypermethylation associates with lack of full length Ron expression whereas hypermethylation of the distal island associates with transcriptional activity of SF-Ron [26]. In vivo, SF-Ron confers susceptibility to Friend virus-induced erythroleukemia and SF-Ron kinase activity is required for erythropoietin-independent expansion of erythroid progenitors in response to Friend virus [25,27].…”

Section: Variant Forms Of the Ron Receptormentioning

confidence: 99%

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Ron-receptor tyrosine kinase in tumorigenesis and metastasis

2007

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SummaryThe Ron receptor tyrosine kinase has been increasingly recognized for its tumorigenic potential in the last decade. Ron receptor activation leads to the activation of common receptor tyrosine kinase downstream signaling pathways, and most prominently in tumor models, activation of MAPK, PI3K and β-catenin. Numerous experimental models of mammalian tumorigenesis have demonstrated that increased Ron receptor activity correlates with increased tumorigenesis in a variety of organs of epithelial origin. The evidence for Ron as an oncogene in human tumor biology is growing. The Ron receptor is overexpressed and over-activated in a large number of human tumors, and overexpression of Ron correlates with a worse clinical outcome for patients in at least two human cancer states, namely breast and bladder cancer. Several experimental approaches have been taken to successfully block Ron activity and function, and given this convincing data, approaches to block Ron receptor activity in targeted human cancers should prove to be fruitful in the setting of future clinical research trials.

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Section: Variant Forms Of the Ron Receptormentioning

confidence: 61%

Section: Variant Forms Of the Ron Receptormentioning

confidence: 99%

Ron-receptor tyrosine kinase in tumorigenesis and metastasis

2007

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“…Activating mutations or amplification has not been observed thus far. On the other hand, splicing variants of RON with constitutive activity have been described both in cell lines and in cancer specimens, including colorectal and gastric cancers (14,27,28), suggesting that RON may play a key role in these cancers and may constitute an important target for intervention. It is presently unclear whether an antibody against RON would inhibit the constitutive activity of ROND160.…”

Section: Discussionmentioning

confidence: 99%

“…Instead, constitutively active RON variants generated by alternative splicing (ROND165, ROND160, and ROND155) or by methylation-dependent promoter usage [short form RON (sfRON)] have been identified (14,27,28). Cells expressing these RON proteins show greater scatter activity, focus formation, anchorage-independent growth, and tumor formation in nude mice compared with cells expressing wild-type RON (14,27,28). Among these RON variants, ROND160 is located at the plasma membrane, whereas ROND165 and ROND155 are retained in the cytoplasm.…”

Section: Introductionmentioning

confidence: 99%

Identification of a Novel Recepteur d'Origine Nantais/c-Met Small-Molecule Kinase Inhibitor with Antitumor Activity In vivo

Zhang¹,

Kaplan‐Lefko²,

Rex³

et al. 2008

Cancer Research

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Recepteur d'origine nantais (RON) is a receptor tyrosine kinase closely related to c-Met. Both receptors are involved in cell proliferation, migration, and invasion, and there is evidence that both are deregulated in cancer. Receptor overexpression has been most frequently described, but other mechanisms can lead to the oncogenic activation of RON and c-Met. They include activating mutations or gene amplification for c-Met and constitutively active splicing variants for RON. We identified a novel inhibitor of RON and c-Met, compound I, and characterized its in vitro and in vivo activities. Compound I selectively and potently inhibited the kinase activity of RON and c-Met with IC 50 s of 9 and 4 nmol/L, respectively. Compound I inhibited hepatocyte growth factormediated and macrophage-stimulating protein-mediated signaling and cell migration in a dose-dependent manner. Compound I was tested in vivo in xenograft models that either were dependent on c-Met or expressed a constitutively active form of . Compound I caused complete tumor growth inhibition in NIH3T3 TPR-Met and U-87 MG xenografts but showed only partial inhibition in HT-29 xenografts. The effect of compound I in HT-29 xenografts is consistent with the expression of the activating b-Raf V600E mutation, which activates the mitogen-activated protein kinase pathway downstream of RON. Importantly, tumor growth inhibition correlated with the inhibition of c-Met-dependent and RON-dependent signaling in tumors. Taken together, our results suggest that a small-molecule dual inhibitor of RON/c-Met has the potential to inhibit tumor growth and could therefore be useful for the treatment of patients with cancers where RON and/or c-Met are activated.

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“…Our results show that sf-Stk is critical to the transformation of fibroblasts that express SFFVgp55 and, by analogy, suggest that sf-Stk signals are critical to reaching a threshold to push erythroid cells into hyperplasia in SFFV disease. Inappropriate expression of the human homolog of sf-Stk, sf-RON, in human tumors (2,3) indicates that this key component of SFFV disease is a molecular endpoint of interest in human cancer as well. Furthermore, the transformed fibroblast system could be useful for screening anti-sf-Stk/RON therapeutic compounds.…”

Section: Discussionmentioning

confidence: 99%

The Tyrosine Kinase sf-Stk and Its Downstream Signals Are Required for Maintenance of Friend Spleen Focus-Forming Virus-Induced Fibroblast Transformation

Jelacic

Thompson

Hanson

et al. 2008

J Virol

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Infection of erythroid progenitor cells by Friend spleen focus-forming virus (SFFV) leads to acute erythroid hyperplasia and eventually to erythroleukemia in susceptible strains of mice. The viral envelope protein, SFFV gp55, forms a complex with the erythropoietin receptor (EpoR) and a short form of the receptor tyrosine kinase Stk (sf-Stk), activating both and inducing Epo-independent proliferation. Recently, we discovered that coexpression of SFFV gp55 and sf-Stk is sufficient to transform NIH 3T3 and primary fibroblasts. In the current study, we demonstrate that sf-Stk and its downstream effectors are critical to this transformation. Unlike SFFV-derived erythroleukemia cells, which depend on PU.1 expression for maintenance of the transformed phenotype, SFFV gp55-sf-Stk-transformed fibroblasts are negative for PU.1. Underscoring the importance of sf-Stk to fibroblast transformation, knockdown of sf-Stk abolished the ability of these cells to form anchorageindependent colonies. Like SFFV-infected erythroid cells, SFFV gp55-sf-Stk-transformed fibroblasts express high levels of phosphorylated MEK, ERK, phosphatidylinositol 3-kinase (PI3K), Gab1/2, Akt, Jun kinase (JNK), and STAT3, but unlike virus-infected erythroid cells they fail to express phosphorylated STATs 1 and 5, which may require involvement of the EpoR. In addition, the p38 mitogen-activated protein kinase (MAPK) stress response is suppressed in the transformed fibroblasts. Inhibition of either JNK or the PI3K pathway decreases both monolayer proliferation and anchorage-independent growth of the transformed fibroblasts as does the putative kinase inhibitor luteolin, but inhibition of p38 MAPK has no effect. Our results indicate that sf-Stk is a molecular endpoint of transformation that could be targeted directly or with agents against its downstream effectors.Friend spleen focus-forming virus (SFFV) is a replicationincompetent murine retrovirus that causes a rapid erythroblastosis when injected into mice with its related helper virus Friend MuLV (reviewed in reference 30). Friend SFFV has deletions in its env gene, which give rise to a unique glycoprotein, SFFV gp55. This unique glycoprotein confers pathogenicity on the virus; a vector encoding SFFV gp55 alone is sufficient to induce erythroblastosis in susceptible strains of mice. The Fv-2 gene encodes one of the key susceptibility factors for SFFV-induced erythroid disease (10, 26). Fv-2, which encodes the receptor tyrosine kinase Stk/RON, is unusual in that it has a second internal promoter, which allows for the transcription of two distinct gene products: full-length Stk and a short form, sf-Stk (8, 26). Full-length Stk is a typical receptor tyrosine kinase with an extracellular ligand binding domain, a transmembrane domain, and an intracellular kinase/ signaling domain. The short form lacks the extracellular ligand binding domain but retains the transmembrane domain and intracellular kinase/signaling domain. Susceptible strains of mice express both full-length Stk and sf-Stk, but resistant strain...

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Hypermethylation of Ron proximal promoter associates with lack of full-length Ron and transcription of oncogenic short-Ron from an internal promoter

Cited by 43 publications

References 28 publications

Ron-receptor tyrosine kinase in tumorigenesis and metastasis

Ron-receptor tyrosine kinase in tumorigenesis and metastasis

Identification of a Novel Recepteur d'Origine Nantais/c-Met Small-Molecule Kinase Inhibitor with Antitumor Activity In vivo

The Tyrosine Kinase sf-Stk and Its Downstream Signals Are Required for Maintenance of Friend Spleen Focus-Forming Virus-Induced Fibroblast Transformation

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