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Cdk2 and Cdk4 activities are dispensable for tumorigenesis caused by the loss of p53

Padmakumar, V. C. ; Aleem, Eiman ; Berthet, Cyril ; Hilton, Mary Beth and Kaldis, Philipp LU (2009) In Molecular and Cellular Biology 29(10). p.2582-2593
Abstract

The loss of p53 induces spontaneous tumors in mice, and p53 mutations are found in approximately 50% of human tumors. These tumors are generally caused by a number of events, including genomic instability, checkpoint defects, mitotic defects, deregulation of transcriptional targets, impaired apoptosis, and G 1 deregulation or a combination of these effects. In order to determine the role of proteins involved in G1 control in tumorigenesis, we focused on Cdk2 and Cdk4, two cyclin-dependent kinases that in association with cyclin E and cyclin D promote the G1/S phase transition. We analyzed the consequence of loss of Cdk2 in p53-null animals by generating Cdk2-/- p53-/- mice. These... (More)

The loss of p53 induces spontaneous tumors in mice, and p53 mutations are found in approximately 50% of human tumors. These tumors are generally caused by a number of events, including genomic instability, checkpoint defects, mitotic defects, deregulation of transcriptional targets, impaired apoptosis, and G 1 deregulation or a combination of these effects. In order to determine the role of proteins involved in G1 control in tumorigenesis, we focused on Cdk2 and Cdk4, two cyclin-dependent kinases that in association with cyclin E and cyclin D promote the G1/S phase transition. We analyzed the consequence of loss of Cdk2 in p53-null animals by generating Cdk2-/- p53-/- mice. These mice are viable and developed spontaneous tumors, predominantly lymphoblastic lymphomas, similar to p53-/- mice. In contrast, the genotypes Cdk4-/- p53 -/- were mostly lethal, with few exceptions, and Cdk2-/- Cdk4-/-p53-/- mice die during embryogenesis at embryonic day 13.5. To study the oncogenic potential, we generated mouse embryonic fibroblasts (MEFs) and found that p53-/-, Cdk2-/- p53 -/-, Cdk4-/- p53-/-, and Cdk2-/- Cdk4-/- p53-/- MEFs grew at similar rates without entering senescence. Ras-transformed MEFs of these genotypes were able to form colonies in vitro and induce tumors in nude mice. Our results suggest that tumorigenicity mediated by p53 loss does not require either Cdk2 or Cdk4, which necessitates considering the use of broad-spectrum cell cycle inhibitors as a means of effective anti-Cdk cancer therapy.

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Contribution to journal
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published
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Molecular and Cellular Biology
volume
29
issue
10
pages
12 pages
publisher
American Society for Microbiology
external identifiers
  • scopus:66349114807
  • pmid:19307310
ISSN
0270-7306
DOI
10.1128/MCB.00952-08
language
English
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no
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18420e1c-b91e-450c-99eb-e9d084f89142
date added to LUP
2019-09-18 14:10:47
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2020-04-02 02:41:57
@article{18420e1c-b91e-450c-99eb-e9d084f89142,
  abstract     = {<p>The loss of p53 induces spontaneous tumors in mice, and p53 mutations are found in approximately 50% of human tumors. These tumors are generally caused by a number of events, including genomic instability, checkpoint defects, mitotic defects, deregulation of transcriptional targets, impaired apoptosis, and G <sub>1</sub> deregulation or a combination of these effects. In order to determine the role of proteins involved in G<sub>1</sub> control in tumorigenesis, we focused on Cdk2 and Cdk4, two cyclin-dependent kinases that in association with cyclin E and cyclin D promote the G<sub>1</sub>/S phase transition. We analyzed the consequence of loss of Cdk2 in p53-null animals by generating Cdk2<sup>-/-</sup> p53<sup>-/-</sup> mice. These mice are viable and developed spontaneous tumors, predominantly lymphoblastic lymphomas, similar to p53<sup>-/-</sup> mice. In contrast, the genotypes Cdk4<sup>-/-</sup> p53 <sup>-/-</sup> were mostly lethal, with few exceptions, and Cdk2<sup>-/-</sup> Cdk4<sup>-/-</sup>p53<sup>-/-</sup> mice die during embryogenesis at embryonic day 13.5. To study the oncogenic potential, we generated mouse embryonic fibroblasts (MEFs) and found that p53<sup>-/-</sup>, Cdk2<sup>-/-</sup> p53 <sup>-/-</sup>, Cdk4<sup>-/-</sup> p53<sup>-/-</sup>, and Cdk2<sup>-/-</sup> Cdk4<sup>-/-</sup> p53<sup>-/-</sup> MEFs grew at similar rates without entering senescence. Ras-transformed MEFs of these genotypes were able to form colonies in vitro and induce tumors in nude mice. Our results suggest that tumorigenicity mediated by p53 loss does not require either Cdk2 or Cdk4, which necessitates considering the use of broad-spectrum cell cycle inhibitors as a means of effective anti-Cdk cancer therapy.</p>},
  author       = {Padmakumar, V. C. and Aleem, Eiman and Berthet, Cyril and Hilton, Mary Beth and Kaldis, Philipp},
  issn         = {0270-7306},
  language     = {eng},
  month        = {05},
  number       = {10},
  pages        = {2582--2593},
  publisher    = {American Society for Microbiology},
  series       = {Molecular and Cellular Biology},
  title        = {Cdk2 and Cdk4 activities are dispensable for tumorigenesis caused by the loss of p53},
  url          = {http://dx.doi.org/10.1128/MCB.00952-08},
  doi          = {10.1128/MCB.00952-08},
  volume       = {29},
  year         = {2009},
}