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v-jun oncogene suppresses both phorbol ester-induced cell invasion and stromelysin gene expression in a mouse
T C Tsang1, Y W Chu, M B Powell
1Department of Radiation Oncology, College of Medicine, University of Arizona, Tucson 85724.
Abstract:
The viral jun (v-jun) oncogene encodes a transcription factor that can participate in the transactivation of genes through the AP-1 complex. Evidence indicates that the ability of v-jun to transform cells and stimulate transcription depends on the cell type. We have asked whether expression of the v-jun gene in benign tumor forming mouse keratinocytes that already express an activated c-rasHa oncogene would cause malignant progression. Our results showed that the v-jun transfection did not result in malignant progression; instead, we made the unexpected observation that the ability of these cells to invade reconstituted basement membrane matrix (in vitro) in response to the phorbol ester, 12-O-tetradecanoylphorbol-13-acetate, was suppressed. This phenomenon could, in part, be explained by the suppression of the induction by phorbol ester of expression of the metalloproteinase, stromelysin (transin). Of interest was the finding that 12-O-tetradecanoylphorbol-13-acetate induction of other cellular genes known to be regulated by AP-1 was not inhibited in the benign tumor cells expressing v-jun.
Insights
Introducing the viral jun (v-jun) oncogene into benign mouse keratinocytes did not cause malignant progression. Unexpectedly, v-jun suppressed invasion and stromelysin gene induction in response to phorbol ester.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- The viral jun (v-jun) oncogene is a transcription factor involved in gene transactivation via the AP-1 complex.
- Cellular transformation and transcriptional activity of v-jun are cell-type dependent.
- Benign tumor-forming mouse keratinocytes expressing an activated c-rasHa oncogene provide a model to study malignant progression.
Purpose of the Study:
- To investigate whether v-jun expression in benign mouse keratinocytes with an activated c-rasHa oncogene induces malignant progression.
- To explore the effects of v-jun on cellular invasion and gene expression in this specific cellular context.
Main Methods:
- Transfection of benign mouse keratinocytes with the v-jun gene.
- Assessment of malignant progression.
- In vitro invasion assays using reconstituted basement membrane matrix.
- Analysis of gene expression, specifically stromelysin (transin) and other AP-1 regulated genes, in response to 12-O-tetradecanoylphorbol-13-acetate (TPA).
Main Results:
- v-jun transfection did not lead to malignant progression in the studied keratinocytes.
- Cellular invasion in response to TPA was unexpectedly suppressed.
- The suppression of invasion correlated with the inhibition of TPA-induced stromelysin (transin) expression.
- TPA induction of other AP-1 regulated genes remained unaffected in v-jun expressing cells.
Conclusions:
- v-jun oncogene expression in benign keratinocytes with activated c-rasHa does not induce malignant transformation.
- v-jun can suppress specific TPA-induced cellular functions, such as invasion, potentially through the downregulation of matrix metalloproteinases like stromelysin.
- The AP-1 complex's role in regulating gene expression and cellular behavior is complex and context-dependent.