Characterization of the molecular mechanisms for p53-mediated differentiation
(2000) In Cell Growth and Differentiation 11(11). p.561-571- Abstract
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... (More)
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.
(Less)
- author
- Chylicki, Kristina ; Ehinger, Mats LU ; Svedberg, Helena LU and Gullberg, Urban LU
- organization
- publishing date
- 2000
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Apoptosis/drug effects, Cell Cycle/drug effects, Cell Differentiation/drug effects, Cell Division/drug effects, Cell Survival, Cholecalciferol/pharmacology, Clone Cells/metabolism, Cyclin-Dependent Kinase Inhibitor p21, Cyclins/genetics, Flow Cytometry, Gene Expression Regulation, Neoplastic, Humans, Integrin alphaXbeta2/metabolism, Kinetics, Mutation/genetics, Promoter Regions, Genetic/genetics, Proto-Oncogene Mas, Proto-Oncogene Proteins c-bcl-2/genetics, Temperature, Transcriptional Activation, Transfection, Tumor Suppressor Protein p53/chemistry, U937 Cells
- in
- Cell Growth and Differentiation
- volume
- 11
- issue
- 11
- pages
- 561 - 571
- publisher
- American Association for Cancer Research
- external identifiers
-
- pmid:11095245
- scopus:0033708076
- ISSN
- 1044-9523
- language
- English
- LU publication?
- yes
- id
- bbf0db3e-19f6-4b9c-817a-02ae16615968
- alternative location
- http://cgd.aacrjournals.org/cgi/reprint/11/11/561
- date added to LUP
- 2022-01-23 15:27:21
- date last changed
- 2024-04-06 17:56:04
@article{bbf0db3e-19f6-4b9c-817a-02ae16615968,
abstract = {{<p>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.</p>}},
author = {{Chylicki, Kristina and Ehinger, Mats and Svedberg, Helena and Gullberg, Urban}},
issn = {{1044-9523}},
keywords = {{Apoptosis/drug effects; Cell Cycle/drug effects; Cell Differentiation/drug effects; Cell Division/drug effects; Cell Survival; Cholecalciferol/pharmacology; Clone Cells/metabolism; Cyclin-Dependent Kinase Inhibitor p21; Cyclins/genetics; Flow Cytometry; Gene Expression Regulation, Neoplastic; Humans; Integrin alphaXbeta2/metabolism; Kinetics; Mutation/genetics; Promoter Regions, Genetic/genetics; Proto-Oncogene Mas; Proto-Oncogene Proteins c-bcl-2/genetics; Temperature; Transcriptional Activation; Transfection; Tumor Suppressor Protein p53/chemistry; U937 Cells}},
language = {{eng}},
number = {{11}},
pages = {{561--571}},
publisher = {{American Association for Cancer Research}},
series = {{Cell Growth and Differentiation}},
title = {{Characterization of the molecular mechanisms for p53-mediated differentiation}},
url = {{http://cgd.aacrjournals.org/cgi/reprint/11/11/561}},
volume = {{11}},
year = {{2000}},
}