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Restoration of p53 function leads to tumour regression in vivo.

Publication ,  Journal Article
Ventura, A; Kirsch, DG; McLaughlin, ME; Tuveson, DA; Grimm, J; Lintault, L; Newman, J; Reczek, EE; Weissleder, R; Jacks, T
Published in: Nature
February 2007

Tumorigenesis is a multi-step process that requires activation of oncogenes and inactivation of tumour suppressor genes. Mouse models of human cancers have recently demonstrated that continuous expression of a dominantly acting oncogene (for example, Hras, Kras and Myc) is often required for tumour maintenance; this phenotype is referred to as oncogene addiction. This concept has received clinical validation by the development of active anticancer drugs that specifically inhibit the function of oncoproteins such as BCR-ABL, c-KIT and EGFR. Identifying additional gene mutations that are required for tumour maintenance may therefore yield clinically useful targets for new cancer therapies. Although loss of p53 function is a common feature of human cancers, it is not known whether sustained inactivation of this or other tumour suppressor pathways is required for tumour maintenance. To explore this issue, we developed a Cre-loxP-based strategy to temporally control tumour suppressor gene expression in vivo. Here we show that restoring endogenous p53 expression leads to regression of autochthonous lymphomas and sarcomas in mice without affecting normal tissues. The mechanism responsible for tumour regression is dependent on the tumour type, with the main consequence of p53 restoration being apoptosis in lymphomas and suppression of cell growth with features of cellular senescence in sarcomas. These results support efforts to treat human cancers by way of pharmacological reactivation of p53.

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Published In

Nature

DOI

EISSN

1476-4687

ISSN

0028-0836

Publication Date

February 2007

Volume

445

Issue

7128

Start / End Page

661 / 665

Related Subject Headings

  • Tumor Suppressor Protein p53
  • Sarcoma
  • Organ Specificity
  • Neoplasms
  • Mice
  • Lymphoma
  • Humans
  • General Science & Technology
  • Disease Models, Animal
  • Cellular Senescence
 

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Ventura, A., Kirsch, D. G., McLaughlin, M. E., Tuveson, D. A., Grimm, J., Lintault, L., … Jacks, T. (2007). Restoration of p53 function leads to tumour regression in vivo. Nature, 445(7128), 661–665. https://doi.org/10.1038/nature05541
Ventura, Andrea, David G. Kirsch, Margaret E. McLaughlin, David A. Tuveson, Jan Grimm, Laura Lintault, Jamie Newman, Elizabeth E. Reczek, Ralph Weissleder, and Tyler Jacks. “Restoration of p53 function leads to tumour regression in vivo.Nature 445, no. 7128 (February 2007): 661–65. https://doi.org/10.1038/nature05541.
Ventura A, Kirsch DG, McLaughlin ME, Tuveson DA, Grimm J, Lintault L, et al. Restoration of p53 function leads to tumour regression in vivo. Nature. 2007 Feb;445(7128):661–5.
Ventura, Andrea, et al. “Restoration of p53 function leads to tumour regression in vivo.Nature, vol. 445, no. 7128, Feb. 2007, pp. 661–65. Epmc, doi:10.1038/nature05541.
Ventura A, Kirsch DG, McLaughlin ME, Tuveson DA, Grimm J, Lintault L, Newman J, Reczek EE, Weissleder R, Jacks T. Restoration of p53 function leads to tumour regression in vivo. Nature. 2007 Feb;445(7128):661–665.
Journal cover image

Published In

Nature

DOI

EISSN

1476-4687

ISSN

0028-0836

Publication Date

February 2007

Volume

445

Issue

7128

Start / End Page

661 / 665

Related Subject Headings

  • Tumor Suppressor Protein p53
  • Sarcoma
  • Organ Specificity
  • Neoplasms
  • Mice
  • Lymphoma
  • Humans
  • General Science & Technology
  • Disease Models, Animal
  • Cellular Senescence