Exogenous wt-p53 protein is active in transformed cells but not in their non-transformed counterparts: implications for cancer gene therapy without tumor targeting
✍ Scribed by Gabriella D'Orazi; Alessandra Marchetti; Marco Crescenzi; Sabrina Coen; Ada Sacchi; Silvia Soddu
- Publisher
- John Wiley and Sons
- Year
- 2000
- Tongue
- English
- Weight
- 320 KB
- Volume
- 2
- Category
- Article
- ISSN
- 1099-498X
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✦ Synopsis
Background:
Expression of exogenous wild-type p53 (wt-p53) protein in tumor cells can suppress the transformed phenotype whereas it does not apparently induce detrimental effects in non-transformed cells. this observation may provide a molecular basis for p53-mediated gene therapy of p53-sensitive cancers without the need for tumor targeting.
Methods:
To understand the molecular mechanisms responsible for this different behavior in tumor versus normal cells, biochemical and functional analyses of exogenous wt-p53 protein were performed on non-transformed c2c12 myoblasts and their transformed counterparts, the c2-ras cells.
Results:
The exogenous wt-p53 protein, which induced persistent growth arrest only in transformed c2-ras cells, was shown to be significantly more stable in transformed than in non-transformed cells. this different stability was due to different p53 proteolytic degradation. moreover, constitutively, exogenous wt-p53 protein was found to be transcriptionally active only in c2-ras cells but it could also be activated in c2c12 cells by genotoxic damage.
Conclusions:
Non-transformed c2c12 cells present regulatory system(s) which control the expression and the activity of exogenously expressed wt-p53 protein probably through degradation and maintenance in a latent form. this regulatory system is lost/inactivated upon transformation.