| A dominant negative RAS-specific guanine nucleotide exchange factor reverses neoplastic phenotype in K-ras transformed mouse fibroblasts. | |
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MedLine Citation:
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PMID: 10815806 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Ras proteins are small GTPases playing a pivotal role in cell proliferation and differentiation. Their activation state depends on the competing action of GTPase Activating Proteins (GAP) and Guanine nucleotide Exchange Factors (GEF). A tryptophan residue (Trp1056 in CDC25Mm-GEF), conserved in all ras-specific GEFs identified so far has been previously shown to be essential for GEF activity. Its substitution with glutamic acid results in a catalytically inactive mutant, which is able to efficiently displace wild-type GEF from p21ras and to originate a stable ras/GEF binary complex due to the reduced affinity of the nucleotide-free ras/GEF complex for the incoming nucleotide. We show here that this 'ras-sequestering property' can be utilized to attenuate ras signal transduction pathways in mouse fibroblasts transformed by oncogenic ras. In fact overexpression of the dominant negative GEFW1056E in stable transfected cells strongly reduces intracellular ras-GTP levels in k-ras transformed fibroblasts. Accordingly, the transfected fibroblasts revert to wild-type phenotype on the basis of morphology, cell cycle and anchorage independent growth. The reversion of the transformed phenotype is accompanied by DNA endoreduplication. The possible use of dominant negative ras-specific GEFs as a tool to down-regulate tumor growth is discussed. |
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Authors:
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P Bossù; M Vanoni; V Wanke; M P Cesaroni; F Tropea; G Melillo; C Asti; S Porzio; P Ruggiero; V Di Cioccio; G Maurizi; A Ciabini; L Alberghina |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Oncogene Volume: 19 ISSN: 0950-9232 ISO Abbreviation: Oncogene Publication Date: 2000 Apr |
Date Detail:
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Created Date: 2000-06-08 Completed Date: 2000-06-08 Revised Date: 2006-11-15 |
Medline Journal Info:
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Nlm Unique ID: 8711562 Medline TA: Oncogene Country: ENGLAND |
Other Details:
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Languages: eng Pagination: 2147-54 Citation Subset: IM |
Affiliation:
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Centro Ricerche Dompé, L'Aquila, Italy. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Carcinogenicity Tests Cell Division / genetics Cell Line, Transformed Cell Transformation, Neoplastic / genetics* Down-Regulation Female Fibroblasts / pathology Genes, Dominant Genes, ras* Guanine Nucleotide Exchange Factors / genetics*, metabolism Guanosine Triphosphate / genetics, metabolism Mice Mice, Nude Mutation, Missense Signal Transduction ras Proteins / genetics, metabolism* ras-GRF1 / genetics, metabolism |
| Chemical | |
Reg. No./Substance:
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0/Guanine Nucleotide Exchange Factors; 0/ras-GRF1; 86-01-1/Guanosine Triphosphate; EC 3.6.5.2/ras Proteins |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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