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c-Myc antagonizes the effect of p53 on apoptosis and p21WAF1 transactivation in K562 leukemia cells

Ceballos, Eva ; Delgado, M Dolores ; Gutierrez, Pilar ; Richard, Carlos ; Müller, Daniel ; Eilers, Martin ; Ehinger, Mats LU ; Gullberg, Urban LU and León, Javiér (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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; ; ; ; ; ; ; and
organization
publishing date
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
2024-01-06 00:04:19
@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}},
}