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Synergistic induction of anchorage-independent growth of NIH3T3 mouse fibroblasts by cysteine proteinase inhibitors and a tumor promoter.

Abstract
We have previously reported that Ras protein is a potent cysteine proteinase inhibitor. In order to examine whether the cysteine proteinase-inhibitory activity of Ras is involved in carcinogenesis, the effects of the following probes were investigated. Cystatin alpha is a cysteine proteinase-specific inhibitor and has some amino acid sequence homology with Ras. Ras has a CAAX motif (C, cysteine; A, aliphatic amino acid; X, any amino acid) at the carboxyl terminus, which is indispensable for the biological activity. Thus, cystatin alpha carrying a CAAX motif (cystatin alpha-CVLS) was examined. A v-Ha-Ras deletion mutant, Ras delta 42-49, has undetectable GTP binding activity, yet it retains a similar protease inhibitory activity to that of wild-type v-Ras. These genes were inserted into a eukaryotic inducible expression vector and transfected into NIH3T3 cells. The expression was effectively induced by treatment with a glucocorticoid hormone, dexamethasone. The expression of cystatin alpha-CVLS or Ras delta 42-49 alone induced neither transformation nor morphological changes. However, when their expression was induced in the presence of a tumor-promoting phorbol ester, a remarkable increase in the anchorage-independent growth was observed in cystatin alpha-CVLS- and Ras delta 42-49-transfected clones. These results suggest that cysteine proteinase inhibitors and a tumor promoter synergistically transformed NIH3T3 cells. It is thus possible that the cysteine proteinase-inhibitory activity of Ras might play a key role in the early stage of carcinogenesis.
AuthorsT Hiwasa, T Sawada, S Sakiyama
JournalThe Journal of biological chemistry (J Biol Chem) Vol. 271 Issue 16 Pg. 9181-4 (Apr 19 1996) ISSN: 0021-9258 [Print] United States
PMID8621572 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Carcinogens
  • Cystatins
  • Proto-Oncogene Proteins
  • Recombinant Proteins
  • Dexamethasone
  • Guanosine Triphosphate
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-raf
  • ras Proteins
  • Tetradecanoylphorbol Acetate
Topics
  • 3T3 Cells
  • Amino Acid Sequence
  • Animals
  • Carcinogens (pharmacology)
  • Cell Adhesion
  • Cell Division (drug effects)
  • Cell Line, Transformed
  • Cystatins (biosynthesis, metabolism)
  • Dexamethasone (pharmacology)
  • Drug Synergism
  • Gene Expression (drug effects)
  • Guanosine Triphosphate (metabolism)
  • Mice
  • Molecular Sequence Data
  • Protein Serine-Threonine Kinases (metabolism)
  • Proto-Oncogene Proteins (metabolism)
  • Proto-Oncogene Proteins c-raf
  • Recombinant Proteins (biosynthesis, metabolism)
  • Tetradecanoylphorbol Acetate (pharmacology)
  • Transfection
  • ras Proteins (metabolism)

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