Adenovirus E1A represses protease gene expression and inhibits metastasis of human tumor cells

Oncogene. 1990 Jan;5(1):75-83.


Stable transfection of human tumor cell lines with the adenovirus-5 E1A gene repressed the expression of the secreted proteases, type IV collagenase, interstitial collagenase and urokinase. In addition, E1A blocked the 12-O-tetradecanoyl phorbol acetate (TPA) induction of interstitial collagenase transcription in HT1080 fibrosarcoma cells. Plasmids bearing the interstitial collagenase or type IV collagenase 5' flanking regions linked to a chloramphenicol acetyl transferase coding sequence were constructed and analysed for expression by transient cotransfections into HT1080 cells. Cotransfection with a plasmid bearing a functional E1A gene repressed transcription of the type IV collagenase promoter and blocked the TPA induction of the interstitial collagenase promoter. Furthermore, E1A repressed transcription from a TK promoter driven by AP-1 complex binding sites (TRE), suggesting that E1A interferes with the AP-1 trans-activation pathway. This effect was not, however, due to the repression of c-jun gene transcription by E1A. In fact, the expression of E1A rendered the c-jun gene hypersensitive to TPA induction. Concomitant with reduction in expression levels of secreted proteases, stable E1A transfectants showed reduced metastatic activity in vivo and reduced ability to traverse a reconstituted basement membrane in vitro. Monospecific anti-type IV collagenase antibodies inhibited invasive activity of parental tumor cell lines in the in vitro assay, suggesting a possible causal relationship between the repression of secreted proteases and loss of metastatic properties of the transformants.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenovirus Early Proteins
  • Base Sequence
  • Cell Transformation, Neoplastic
  • Chloramphenicol O-Acetyltransferase / analysis
  • Chloramphenicol O-Acetyltransferase / genetics
  • DNA-Binding Proteins / genetics
  • Gene Expression*
  • Humans
  • Metalloendopeptidases / genetics
  • Microbial Collagenase / genetics
  • Molecular Sequence Data
  • Neoplasm Invasiveness
  • Neoplasm Metastasis*
  • Oncogene Proteins, Viral / physiology*
  • Peptide Hydrolases / genetics*
  • Peptide Hydrolases / physiology
  • Proto-Oncogene Proteins c-jun
  • Proto-Oncogenes
  • Tetradecanoylphorbol Acetate / pharmacology
  • Transcription Factors / genetics
  • Transcription, Genetic
  • Transfection


  • Adenovirus Early Proteins
  • DNA-Binding Proteins
  • Oncogene Proteins, Viral
  • Proto-Oncogene Proteins c-jun
  • Transcription Factors
  • Chloramphenicol O-Acetyltransferase
  • Peptide Hydrolases
  • Metalloendopeptidases
  • Microbial Collagenase
  • Tetradecanoylphorbol Acetate