c-Myc antagonizes the effect of p53 on apoptosis and p21WAF1 transactivation in K562 leukemia cells
(2000) In Oncogene 19. p.2194-2204- Abstract
c-myc protooncogene positively regulates cell proliferation and overexpression of c-myc is found in many solid tumors and leukemias. In the present study we used the K562 human myeloid leukemia cell line as a model to study the functional interaction between c-Myc and p53. Using two different methods, we generated K562 transfectant cell lines with conditional expression of either c-Myc or p53. The cells expressed the p53Vall35 mutant, which adopts a wild-type conformation at 32 degrees C, while c-Myc induction was achieved with a zinc-inducible expression vector. We found that p53 in wild-type conformation induces growth arrest and apoptosis of K562. Expression of c-Myc significantly attenuated apoptosis and impaired the transcriptional... (More)
c-myc protooncogene positively regulates cell proliferation and overexpression of c-myc is found in many solid tumors and leukemias. In the present study we used the K562 human myeloid leukemia cell line as a model to study the functional interaction between c-Myc and p53. Using two different methods, we generated K562 transfectant cell lines with conditional expression of either c-Myc or p53. The cells expressed the p53Vall35 mutant, which adopts a wild-type conformation at 32 degrees C, while c-Myc induction was achieved with a zinc-inducible expression vector. We found that p53 in wild-type conformation induces growth arrest and apoptosis of K562. Expression of c-Myc significantly attenuated apoptosis and impaired the transcriptional activity of p53 on p21WAF1, Bax and cytomegalovirus promoters. The impairment of p21WAF1 transactivation by c-Myc was confirmed by transfection of a c-Myc-estrogen receptor fusion protein and by induction of c-myc by zinc in transfected cells. Also, p53-mediated up-regulation of p21WAF1 mRNA protein were significantly reduced by c-Myc, while Bax levels were unaffected. Consistently, c-Myc increased cyclin-dependent kinase 2 activity in K562 cells expressing p53 in wild-type conformation. These results suggest that c-Myc overexpression may antagonize the pro-apoptotic function of p53, thus providing a molecular mechanism for the frequently observed deregulation of c-myc in human cancer.
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- author
- Ceballos, Eva ; Delgado, M Dolores ; Gutierrez, Pilar ; Richard, Carlos ; Müller, Daniel ; Eilers, Martin ; Ehinger, Mats LU ; Gullberg, Urban LU and León, Javiér
- organization
- publishing date
- 2000
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Apoptosis, Blast Crisis/genetics, Cyclin-Dependent Kinase Inhibitor p21, Cyclins/genetics, Humans, K562 Cells, Proto-Oncogene Proteins c-myc/genetics, Recombinant Proteins/metabolism, Transcriptional Activation, Tumor Suppressor Protein p53/genetics, Up-Regulation
- in
- Oncogene
- volume
- 19
- pages
- 11 pages
- publisher
- Nature Publishing Group
- external identifiers
-
- scopus:0000418970
- pmid:10822369
- ISSN
- 0950-9232
- DOI
- 10.1038/sj.onc.1203541
- language
- English
- LU publication?
- yes
- id
- 70b2c0dc-4e01-4fd6-9e25-59b7be1b5f82
- date added to LUP
- 2022-01-23 15:29:40
- date last changed
- 2024-06-30 02:06:24
@article{70b2c0dc-4e01-4fd6-9e25-59b7be1b5f82, abstract = {{<p>c-myc protooncogene positively regulates cell proliferation and overexpression of c-myc is found in many solid tumors and leukemias. In the present study we used the K562 human myeloid leukemia cell line as a model to study the functional interaction between c-Myc and p53. Using two different methods, we generated K562 transfectant cell lines with conditional expression of either c-Myc or p53. The cells expressed the p53Vall35 mutant, which adopts a wild-type conformation at 32 degrees C, while c-Myc induction was achieved with a zinc-inducible expression vector. We found that p53 in wild-type conformation induces growth arrest and apoptosis of K562. Expression of c-Myc significantly attenuated apoptosis and impaired the transcriptional activity of p53 on p21WAF1, Bax and cytomegalovirus promoters. The impairment of p21WAF1 transactivation by c-Myc was confirmed by transfection of a c-Myc-estrogen receptor fusion protein and by induction of c-myc by zinc in transfected cells. Also, p53-mediated up-regulation of p21WAF1 mRNA protein were significantly reduced by c-Myc, while Bax levels were unaffected. Consistently, c-Myc increased cyclin-dependent kinase 2 activity in K562 cells expressing p53 in wild-type conformation. These results suggest that c-Myc overexpression may antagonize the pro-apoptotic function of p53, thus providing a molecular mechanism for the frequently observed deregulation of c-myc in human cancer.</p>}}, author = {{Ceballos, Eva and Delgado, M Dolores and Gutierrez, Pilar and Richard, Carlos and Müller, Daniel and Eilers, Martin and Ehinger, Mats and Gullberg, Urban and León, Javiér}}, issn = {{0950-9232}}, keywords = {{Apoptosis; Blast Crisis/genetics; Cyclin-Dependent Kinase Inhibitor p21; Cyclins/genetics; Humans; K562 Cells; Proto-Oncogene Proteins c-myc/genetics; Recombinant Proteins/metabolism; Transcriptional Activation; Tumor Suppressor Protein p53/genetics; Up-Regulation}}, language = {{eng}}, pages = {{2194--2204}}, publisher = {{Nature Publishing Group}}, series = {{Oncogene}}, title = {{c-Myc antagonizes the effect of p53 on apoptosis and p21WAF1 transactivation in K562 leukemia cells}}, url = {{http://dx.doi.org/10.1038/sj.onc.1203541}}, doi = {{10.1038/sj.onc.1203541}}, volume = {{19}}, year = {{2000}}, }