Characterization of the molecular mechanisms for p53-mediated differentiation
| Autor: | K, Chylicki, M, Ehinger, H, Svedberg, U, Gullberg |
|---|---|
| Rok vydání: | 2000 |
| Předmět: |
Cyclin-Dependent Kinase Inhibitor p21
Transcriptional Activation Cell Survival Cell Cycle Temperature Integrin alphaXbeta2 Apoptosis Cell Differentiation U937 Cells Flow Cytometry Transfection Proto-Oncogene Mas Clone Cells Gene Expression Regulation Neoplastic Kinetics Proto-Oncogene Proteins c-bcl-2 Cyclins Mutation Humans Tumor Suppressor Protein p53 Promoter Regions Genetic Cell Division Cholecalciferol |
| Zdroj: | Cell growthdifferentiation : the molecular biology journal of the American Association for Cancer Research. 11(11) |
| ISSN: | 1044-9523 |
| Popis: | The p53 tumor suppressor protein can induce both apoptosis and cell cycle arrest. Moreover, we and others have shown previously that p53 is a potent mediator of differentiation. For example, expression of ptsp53, a temperature-inducible form of p53, induces differentiation of leukemic monoblastic U-937 cells. The functions of p53 have for long been believed to be dependent on the transactivating capacity of p53. However, recent data show that both p53-induced cell cycle arrest and apoptosis can be induced independently of p53-mediated transcriptional activation, indicating alternative pathways for p53-induced apoptosis and cell cycle arrest. The bcl-2 proto-oncogene contributes to the development of certain malignancies, probably by inhibition of apoptosis. Interestingly, Bcl-2 has been shown to inhibit p53-mediated apoptosis as well as p53-mediated transcriptional activation. Asking whether Bcl-2 would interfere with the p53-mediated differentiation of U-937 cells, we stably transfected bcl-2 to U-937 cells inducibly expressing p53. Although the established Bcl-2-expressing clones were resistant to p53-mediated apoptosis, we did not observe any interference of Bcl-2 with the p53-mediated differentiation, suggesting separable pathways for p53 in mediating apoptosis and differentiation of U-937 cells. Neither did expression of Bcl-2 interfere with p53-induced expression of endogenous p21, suggesting that p53-induced differentiation might be dependent on the transcriptional activity of p53. To further investigate whether the p53-mediated differentiation of U-937 cells depends on the transcriptional activity of p53, we overexpressed transactivation-deficient p53, a transcriptionally inactive p53 mutant in these cells. However, in contrast to the effects of wild-type p53, expression of trans-activation-deficient p53 did neither induce signs of apoptosis nor of differentiation in U-937 cells. Our results indicate that the transcriptional activity of p53 is essential both for p53-mediated apoptosis and differentiation of U-937 cells. |
| Databáze: | OpenAIRE |
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