Document Detail


Reversion of autocrine transformation by a dominant negative platelet-derived growth factor mutant.
MedLine Citation:
PMID:  8321214     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
A non-receptor-binding mutant of the platelet-derived growth factor (PDGF) A chain, PDGF-0, was generated by exchanging 7 amino acids in the sequence. The mutant chains formed dimers that were similar to wild-type PDGF-AA with regard to stability and rate of processing to the mature 30-kDa secreted forms. Moreover, the mutant chains formed disulfide-bonded heterodimers with the PDGF B chain in NIH 3T3 cells heterodimer underwent the same processing and secretion as PDGF-AB. Transfection of c-sis-expressing 3T3 cells with PDGF-0 significantly inhibited the transformed phenotype of these cells, as determined by the following criteria. (i) Compared with PDGF-0-negative clones, PDGF-0-producing clones showed a reverted morphology. (ii) Clones producing PDGF-0 grew more slowly than PDGF-0-negative clones, with a fivefold difference in cell number after 14 days in culture. (iii) The expression of PDGF-0 completely inhibited the ability of the c-sis-expressing 3T3 cells to form colonies in soft agar; this inhibition was overcome by the addition of recombinant PDGF-BB to the culture medium, showing that the lack of colony formation of these cells was not due to a general unresponsiveness to PDGF. The specific expression of a PDGF-0/PDGF wild-type heterodimer in COS cells revealed that the affinity of the mutant heterodimer for the PDGF alpha receptor was decreased by approximately 50-fold compared with that of PDGF-AA. Thus, we show that a non-receptor-binding PDGF A-chain mutant neutralizes in a trans-dominant manner the autocrine transforming potential of the c-sis/PDGF B chain by forming low-affinity heterodimers with wild-type PDGF chains. This method of specifically antagonizing the effect of PDGF may be useful in investigations of the role of PDGF in normal and pathological conditions.
Authors:
F S Vassbotn; M Andersson; B Westermark; C H Heldin; A Ostman
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Molecular and cellular biology     Volume:  13     ISSN:  0270-7306     ISO Abbreviation:  Mol. Cell. Biol.     Publication Date:  1993 Jul 
Date Detail:
Created Date:  1993-07-30     Completed Date:  1993-07-30     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  8109087     Medline TA:  Mol Cell Biol     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  4066-76     Citation Subset:  IM    
Affiliation:
Ludwig Institute for Cancer Research, Biomedical Center, Uppsala, Sweden.
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MeSH Terms
Descriptor/Qualifier:
3T3 Cells
Animals
Cell Line
Cell Transformation, Neoplastic / genetics*
Cells, Cultured
Chromatography, High Pressure Liquid
Cloning, Molecular
Humans
Kinetics
Mice
Mutation
Phenotype
Platelet-Derived Growth Factor / genetics*,  metabolism
Precipitin Tests
Receptors, Platelet-Derived Growth Factor / metabolism
Transfection
Tumor Cells, Cultured
Up-Regulation
Chemical
Reg. No./Substance:
0/Platelet-Derived Growth Factor; EC 2.7.10.1/Receptors, Platelet-Derived Growth Factor
Comments/Corrections

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