Molecular cloning of a new transforming gene from a chemically transformed human cell line

Cooper, Christopher S.; Park, Morag; Blair, Donald G.; Tainsky, Michael A.; Huebner, Kay; Croce, Carlo M.; Woude, George F. Vande

doi:10.1038/311029a0

Cited by 887 publications

(500 citation statements)

References 45 publications

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“…This is in line with the observations that HGF/SF has been found in blood and bone marrow plasma of leukemia patients 30,32 as well as in supernatants of human leukemia cell lines 31,42,43 and myeloma cells. 44 Transfection of the HGF/SF gene and/or c-MET gene in several epithelial cell lines and NIH3T3 cells [45][46][47][48][49][50][51][52] has revealed that these genes influence the invasiveness of these cells. Furthermore, studies for the expression pattern in normal, premalignant and malignant lesions has demonstrated overexpression of the c-MET gene in different tumors.…”

Section: Discussionmentioning

confidence: 99%

Hepatocyte growth factor/scatter factor (HGF/SF) affects proliferation and migration of myeloid leukemic cells

et al. 1998

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Hepatocyte growth factor (HGF), also known as scatter factor (SF), is produced by mesenchymal cells, including bone marrow (BM) stromal cells, and has mitogenic and motogenic effects on a variety of cell types. Recently, a role has been assigned to HGF/SF and its receptor, c-MET, in both normal and malignant hemopoiesis. We investigated the function of HGF/SF on hemopoietic mononuclear cells (MNC) from patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) with circulating blasts. In contrast to results with normal MNC, HGF/SF alone stimulated the proliferation and colony formation of MNC from these patients. MNC from some (4/13) of the AML patients also produced HGF/SF (0.1-0.2 ng/ml/day), while we could not detect HGF/SF in cultures from normal MNC. Furthermore, it appeared that HGF/SF induced migration of leukemic cells in Boyden using KG1a cells as a model for leukemic blasts. The membranes dividing the two compartments of the Boyden chambers were coated with fibronectin. HGF/SF significantly promoted migration in 3/5 samples of MDS patients and in 5/7 samples of AML patients. Supernatant of human BM stromal cells, which is chemoattractive for normal human hemopoietic progenitor cells, also promoted migration of MNC from 4/5 MDS patients and 6/7 AML patients. Since HGF/SF is one of the growth factors produced by BM stromal cells, a neutralizing antibody directed against HGF/SF was added to the BM stroma supernatant, which reduced migration significantly in 2/3 MDS and in 3/6 AML responders to BM stroma supernatant. In conclusion, HGF/SF promotes proliferation and migration of hemopoietic cells from AML and MDS patients in vitro and may therefore contribute to the malignant potential of these cells.

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Section: Discussionmentioning

confidence: 99%

Hepatocyte growth factor/scatter factor (HGF/SF) affects proliferation and migration of myeloid leukemic cells

et al. 1998

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“…Recently, a direct genetic link between c-MET and human cancer was established by the identi®cation of activating mutations in the c-MET gene in hereditary papillary renal carcinomas (Schmidt et al, 1997;Fischer et al, 1998;Zhuang et al, 1998). c-MET was originally identi®ed as the cellular counterpart of a transforming gene, TPR ± MET, resulting from a chromosomal rearrangement (Cooper et al, 1984;Park et al, 1986). In Tpr ± Met, the extracellular domain of Met is replaced by Tpr sequences, which provide two strong dimerization motifs (Rodrigues and Park, 1993).…”

Section: Introductionmentioning

confidence: 99%

Concomitant activation of pathways downstream of Grb2 and PI 3-kinase is required for MET-mediated metastasis

et al. 1999

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The Met tyrosine kinase ± the HGF receptor ± induces cell transformation and metastasis when constitutively activated. Met signaling is mediated by phosphorylation of two carboxy-terminal tyrosines which act as docking sites for a number of SH2-containing molecules. These include Grb2 and p85 which couple the receptor, respectively, with Ras and PI 3-kinase. We previously showed that a Met mutant designed to obtain preferential coupling with Grb2 (Met 2xGrb2 ) is permissive for motility, increases transformation, but ± surprisingly ± is impaired in causing invasion and metastasis. In this work we used Met mutants optimized for binding either p85 alone (Met 2xPI3K ) or p85 and Grb2 (Met P13K/Grb2 ) to evaluate the relative importance of Ras and PI 3-kinase as downstream e ectors of Met. Met 2xPI3K was competent in eliciting motility, but not transformation, invasion, or metastasis. Conversely, Met P13K/Grb2 induced motility, transformation, invasion and metastasis as e ciently as wild type Met. Furthermore, the expression of constitutively active PI 3-kinase in cells transformed by the Met 2xGrb2 mutant, fully rescued their ability to invade and metastasize. These data point to a central role for PI 3-kinase in Met-mediated invasiveness, and indicate that simultaneous activation of Ras and PI 3-kinase is required to unleash the Met metastatic potential.

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“…The Ron homologue Met is converted into its transforming counterpart Tpr-Met, by rearrangement with Tpr sequences providing two leucine zippers (Cooper et al, 1984;Park et al, 1986). We have previously shown that a Tpr ± Ron chimaera induces constitutive activation of the Ron kinase but does not convert it into an oncogene.…”

Section: Introductionmentioning

confidence: 99%

Point mutations in the tyrosine kinase domain release the oncogenic and metastatic potential of the ron receptor

Santoro¹,

Penengo

Minetto

et al. 1998

Oncogene

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Ron (the receptor for Macrophage Stimulating Protein) has never been implicated before in human malignancies or in cell transformation. In this report we show that Ron can acquire oncogenic potential by means of two amino acid substitutions ± D1232V and M1254T ± a ecting highly conserved residues in the tyrosine kinase domain. The same mutations in Kit and Ret have been found associated with two human malignancies, mastocytosis and Multiple Endocrine Neoplasia type 2B (MEN2B), respectively. Both mutations caused Ronmediated transformation of 3T3 ®broblasts and tumour formation in nude mice. Moreover, cells transformed by the oncogenic Ron mutants displayed high metastatic potential. The Ron mutant receptors were constitutively active and the catalytic e ciency of the mutated kinase was higher than that of wild-type Ron. Oncogenic Ron mutants enhanced activation of the Ras/MAPK cascade with respect to wild type Ron, without a ecting the JNK/SAPK pathway. Expression of Ron mutants in 3T3 ®broblasts led to di erent patterns of tyrosine-phosphorylated proteins. These data show that point mutations altering catalytic properties and possibly substrate speci®city of the Ron kinase may force cells toward tumorigenesis and metastasis.

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Molecular cloning of a new transforming gene from a chemically transformed human cell line

Abstract: Molecular cloning of the transforming gene from a chemically transformed human osteosarcoma-derived cell line enables the gene to be mapped to chromosome 7 (7p11.4-7qter) and by this criterion and by direct hybridization to be shown to be unrelated to known oncogenes.

Cited by 887 publications

References 45 publications

Hepatocyte growth factor/scatter factor (HGF/SF) affects proliferation and migration of myeloid leukemic cells

Hepatocyte growth factor/scatter factor (HGF/SF) affects proliferation and migration of myeloid leukemic cells

Concomitant activation of pathways downstream of Grb2 and PI 3-kinase is required for MET-mediated metastasis

Point mutations in the tyrosine kinase domain release the oncogenic and metastatic potential of the ron receptor

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