Hepatocyte Nuclear Factor-4 Is Responsible for the Liver-specific Expression of the Gene Coding for Hepatocyte Growth Factor-like Protein

Waltz, Susan E.; Gould, Fiona K.; Air, Ellen L.; McDowell, Susan A.; Degen, Sandra J. Friezner

doi:10.1074/jbc.271.15.9024

Cited by 20 publications

(8 citation statements)

References 34 publications

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“…To determine whether SF-Ron contributes to this HGFL/Ronmediated morphological response, peritoneal macrophages isolated from wild-type mice and mice heterozygous (ϩ/FL) or homozygous (FL/FL) for the FL-Ron allele were analyzed for HGFL-induced morphological shape changes indicative of activation. Macrophages from wild-type mice had similar baseline levels of activated macrophages and in response to HGFL underwent morphological shape changes to a degree consistent with published analyses (data not shown) (2,18,27,28). Interestingly, both ϩ/FL and homozygous FL/FL macrophages responded to HGFL to the same degree as macrophages isolated from wild-type mice.…”

Section: Analysis Of Alternative Ron Receptor Mrna Expression In Fl-rsupporting

confidence: 84%

“…Peritoneal macrophages show dramatic morphological changes in response to HGFL in vitro (10,18,24,27,28,31,32). To determine whether SF-Ron contributes to this HGFL/Ronmediated morphological response, peritoneal macrophages isolated from wild-type mice and mice heterozygous (ϩ/FL) or homozygous (FL/FL) for the FL-Ron allele were analyzed for HGFL-induced morphological shape changes indicative of activation.…”

Section: Analysis Of Alternative Ron Receptor Mrna Expression In Fl-rmentioning

confidence: 99%

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Short-form Ron receptor is required for normal IFN-γ production in concanavalin A-induced acute liver injury

Wetzel

Leonis

Dent

et al. 2007

American Journal of Physiology-Gastrointestinal and Liver Physi

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Abrogation of Ron receptor tyrosine kinase function results in defects in macrophage activation and dysregulated acute inflammatory responses in vivo. Several naturally occurring constitutively active alternative forms of Ron have been identified, including from primary human tumors and tumor cell lines. One of these alternative forms, short-form (SF) Ron, is generated from an alternative start site in intron 10 of the Ron gene that eliminates most of the extracellular portion of the receptor and is overexpressed in several human cancers. To test the physiological significance of SF-Ron in vivo, mice were generated that solely express the full-length form of Ron (FL-Ron). Our results show that elimination of the capacity to express SF-Ron in vivo leads to augmented production of IFN-␥ from splenocytes following stimulation ex vivo with either concanavalin A or anti-CD3/T cell receptor monoclonal antibody. Moreover, in a concanavalin A-induced murine model of acute liver injury, FL-Ron mice have increased production of serum INF-␥ and serum alanine aminotransferase levels and worsened liver histology and overall survival compared with wild-type control mice. Taken together, these results suggest for the first time that SF-Ron impacts the progression of inflammatory immune responses in vivo and further support a role for the Ron receptor and its various forms in liver pathophysiology.receptor tyrosine kinases; regulation of cytokine production; animal models of liver injury RECEPTOR TYROSINE KINASES (RTK) play a critical role in multiple biological functions including immune system regulation. The Ron receptor is a member of a distinct family of multifunctional RTKs that also includes c-Met. Activation of Ron and Met results in pleiotropic biological responses, including a set of properties allowing cells to undergo "invasive growth" (4, 13, 33). In addition, Ron receptor activity is critical for proper modulation of inflammatory responses to toxic insults in vivo, including the necroinflammatory hepatic injury in an endotoxin-mediated murine model of acute liver failure (5,11,12,27).When mouse Ron (mRon) cDNA was cloned from hematopoietic stem cells, an alternative 1.9-kb short-form Ron (SF-Ron) transcript was identified in addition to the 4.8-kb full-length Ron (FL-Ron) mRNA transcript (9). SF-Ron is expressed in human lung, ovary, and tissues of the gastrointestinal tract and several human cancers and cancer cell lines; however, the tissue-specific expression of SF-Ron has not been fully characterized (1,7,9,22). The transcription start site for SF-Ron mRNA has been localized to intron 10 of the mRon gene (21, 30), and SF-Ron mRNA encodes a truncated Ron protein that possesses a truncated extracellular domain and the entire transmembrane and cytoplasmic tyrosine kinase domains. SF-Ron displays constitutive tyrosine kinase activity (1, 6), and overexpression of SF-Ron results in loss of an epithelial phenotype and aggressive cell behavior (1). Moreover, mouse strains that express SF-Ron transcript in adult bone ...

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Section: Analysis Of Alternative Ron Receptor Mrna Expression In Fl-rsupporting

confidence: 84%

Section: Analysis Of Alternative Ron Receptor Mrna Expression In Fl-rmentioning

confidence: 99%

Short-form Ron receptor is required for normal IFN-γ production in concanavalin A-induced acute liver injury

Wetzel

Leonis

Dent

et al. 2007

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Promoter analyses have suggested that the transcription factor hepatocyte nuclear factor-4 is important for the liver-specific expression of HGFL (Waltz et al, 1996). Specific elements in the first intron of HGFL have also been found to regulate liver-and kidney-specific expression (Wetzel et al, 2003).…”

Section: Ron Ligand Structure and Functionmentioning

confidence: 99%

Met‐Related Receptor Tyrosine Kinase Ron in Tumor Growth and Metastasis

Wagh

Peace

Waltz

2008

Advances in Cancer Research

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144

168

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The Ron receptor is a member of the Met family of cell surface receptor tyrosine kinases and is primarily expressed on epithelial cells and macrophages. The biological response of Ron is mediated by binding of its ligand, hepatocyte growth factor-like protein/macrophage stimulatingprotein (HGFL). HGFL is primarily synthesized and secreted from hepatocytes as an inactive precursor and is activated at the cell surface. Binding of HGFL to Ron activates Ron and leads to the induction of a variety of intracellular signaling cascades that leads to cellular growth, motility and invasion. Recent studies have documented Ron overexpression in a variety of human cancers including breast, colon, liver, pancreas, and bladder. Moreover, clinical studies have also shown that Ron overexpression is associated with both worse patient outcomes as well as metastasis. Forced overexpression of Ron in transgenic mice leads to tumorigenesis in both the lung and the mammary gland and is associated with metastatic dissemination. While Ron overexpression appears to be a hallmark of many human cancers, the mechanisms by which Ron induces tumorigenesis and metastasis are still unclear. Several strategies are currently being undertaken to inhibit Ron as a potential therapeutic target; current strategies include the use of Ron blocking proteins, siRNA, monoclonal antibodies, and small molecule inhibitors. In total, these data suggest that Ron is a critical factor in tumorigenesis and that inhibition of this protein, alone or in combination with current therapies, may prove beneficial in the treatment of cancer patients.

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“…Transfections were performed using the calcium-phosphate precipitation method as previously described (Waltz et al, 1996). Cells were maintained in Dulbecco's Modi®ed Eagle's Medium (DMEM, Gibco) supplemented with 10% fetal calf serum, 2 mM 1-glutamine, and 50 ug/ml gentamicin (Gibco).…”

Section: Cell Culture Transfection and Rna Analysismentioning

confidence: 99%

Point mutations and overexpression of Ron induce transformation, tumor formation, and metastasis

et al. 2001

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The receptor tyrosine kinase Ron is a member of the receptor family that includes the proto-oncogene Met and the avian oncogene Sea. The interaction of Ron with its ligand, known as hepatocyte growth factor-like protein (HGFL) or macrophage stimulating protein (MSP), induces crucial cellular responses including invasive growth, proliferation, cell scattering, and branching morphogenesis. Based on the homology and functional similarities between Met and Ron it was hypothesized that Ron may be important in tumor formation and metastasis. To test this hypothesis, wildtype mouse Ron and three mutant forms of Ron containing mutations similar to those found in the Met gene in human hereditary papillary renal carcinoma (HPRC), were expressed in NIH3T3 cells. A transformed phenotype was produced in cell lines expressing either wild-type Ron or the mutated Ron proteins. Further, these cell lines displayed oncogenic potential by exhibiting increased proliferation and constitutive phosphorylation of Ron. These cell lines were also tested for the ability to form solid tumors. Cells expressing wild-type Ron and the three proteins with single amino acid substitutions were highly tumorigenic in vivo. In a model of experimental metastasis, two of the cell lines with altered Ron protein formed highly aggressive tumors in the lungs. These results suggest that Ron may be an aggressive oncogene when either overexpressed or when activated by mutation. Oncogene (2001) 20, 6142 ± 6151.

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Hepatocyte Nuclear Factor-4 Is Responsible for the Liver-specific Expression of the Gene Coding for Hepatocyte Growth Factor-like Protein

Cited by 20 publications

References 34 publications

Short-form Ron receptor is required for normal IFN-γ production in concanavalin A-induced acute liver injury

Short-form Ron receptor is required for normal IFN-γ production in concanavalin A-induced acute liver injury

Met‐Related Receptor Tyrosine Kinase Ron in Tumor Growth and Metastasis

Point mutations and overexpression of Ron induce transformation, tumor formation, and metastasis

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