Establishment of a dog model for the p53 family pathway and identification of a novel isoform of p21 cyclin-dependent kinase inhibitor

Jin Zhang, Xinbin Chen, Xiangling Chen, Michael S Kent, Carlos O. Rodriguez

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Spontaneous tumors in the dog offer a unique opportunity as models to study human cancer etiology and therapy. p53, the most commonly mutated gene in human cancers, is found to be altered in dog cancers. However, little is known about the role of p53 in dog tumorigenesis. Here, we found that on exposure to DNA damage agents or MDM2 inhibitor nutlin-3, canine p53 is accumulated and capable of inducing its target genes, MDM2 and p21. We also found that on DNA damage, canine p53 is accumulated in the nucleus, followed by MDM2 nuclear translocation and increased 53BP1 foci formation. In addition, we found that canine p63 and p73 are up-regulated by DNA damage agents. Furthermore, colony formation assay showed that canine tumor cells are sensitive to DNA damage agents and nutlin-3 in a p53-dependent manner. Surprisingly, canine p21 is expressed as two isoforms. Thus, we generated multiple canine p21 mutants and found that amino acids 129 to 142 are required, whereas amino acid 139 is one of the key determinants, for the expression of two p21 isoforms. Finally, we showed that although the full-length human p21 cDNA expresses one polypeptide, amino acid 139 seems to play a similar role as that in canine p21 for various migration patterns. Taken together, our results indicate that canine p53 family proteins have biological activities similar to human counterparts. These similarities make the dog an excellent outbred spontaneous tumor model, and the dog can serve as a translation model from benchtop to cage side and then to bedside. (Mol Cancer Res 2009;7(1): 67-78)

Original languageEnglish (US)
Pages (from-to)67-78
Number of pages12
JournalMolecular Cancer Research
Volume7
Issue number1
DOIs
StatePublished - Jan 1 2009

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Cyclin-Dependent Kinase Inhibitor p21
Canidae
Protein Isoforms
Dogs
DNA Damage
Neoplasms
Amino Acids
Genes
Carcinogenesis
Complementary DNA
Peptides

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Oncology

Cite this

Establishment of a dog model for the p53 family pathway and identification of a novel isoform of p21 cyclin-dependent kinase inhibitor. / Zhang, Jin; Chen, Xinbin; Chen, Xiangling; Kent, Michael S; Rodriguez, Carlos O.

In: Molecular Cancer Research, Vol. 7, No. 1, 01.01.2009, p. 67-78.

Research output: Contribution to journalArticle

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