Journal Article

Reduced expression of the CDK inhibitor p27<sup>KIP1</sup> in rat two-stage bladder carcinogenesis and its association with expression profiles of p21<sup>WAF1/Cip1</sup> and p53

Chyi Chia R. Lee, Toshio Ichihara, Shinji Yamamoto, Hideki Wanibuchi, Kazunobu Sugimura, Seiji Wada, Taketoshi Kishimoto and Shoji Fukushima

in Carcinogenesis

Volume 20, issue 9, pages 1697-1708
Published in print September 1999 | ISSN: 0143-3334
Published online September 1999 | e-ISSN: 1460-2180 | DOI:
Reduced expression of the CDK inhibitor p27KIP1 in rat two-stage bladder carcinogenesis and its association with expression profiles of p21WAF1/Cip1 and p53

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The cyclin-dependent kinase (CDK) inhibitor p27KIP1 exerts its growth suppressive effects by targeting the cyclin–CDK complexes. Reduced protein levels of p27KIP1 have been reported in numerous human cancers and this has been attributed to increased degradation. However, few reports have addressed the significance of p27KIP1 expression in chemical carcinogenesis of rodents. In a rat two-stage urinary bladder carcinogenesis model, with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) initiation followed by promotion with sodium L-ascorbate (Na-AsA), we evaluated the expression of p27KIP1 protein using immunohistochemistry during various stages of urinary bladder carcinogenesis. In addition, we evaluated the mRNA expression profiles for p27KIP1, p21WAF1/Cip1 and p53 in tumors. Fisher 344 rats were initiated with 0.05% BBN in the drinking water for 4 weeks and then administered 5% Na-AsA in the diet. Immunohistochemical examination revealed p27KIP1 protein to be constitutively expressed in normal urothelium, simple hyperplasia and in most papillary and nodular (PN) hyperplasias and small papillomas, but diminished or absent in large papillomas and in transitional cell carcinomas. An inverse correlation between expression of p27KIP1 and cell proliferation was generally observed. Quantitation of mRNA by multiplex reverse transcription-PCR showed a significant downregulaton of p27KIP1, p21WAF1/Cip1 and p53 mRNA in tumors. More than 50% reduction in p27KIP1 mRNA expression was observed in 42 and 47% of tumors at weeks 18 and 24, respectively; similar reduction in p21WAF1/Cip1 mRNA expression was observed in 58 and 73% of tumors at weeks 18 and 24, and in p53 mRNA expression in 50 and 73% of tumors at weeks 18 and 24, respectively. None of the 25 tumors we examined by PCR-single-strand conformational polymorphism analysis had p53 mutations. These data imply that abnormal down-regulation of p27KIP1, p21WAF1/Cip1 and/or p53 in tumor cells may contribute to the malignant progression of tumors during rat two-stage bladder carcinogenesis.

Keywords: BBN, N-butyl-N-(4-hydroxybutyl)nitrosamine; CDK, cyclin-dependent kinase; GAPDH, glyceraldehyde-3-phosphate-dehydrogenase; Na-AsA, sodium l-ascorbate; PCNA, proliferating cell nuclear antigen; PN, papillary and nodular; RT, reverse transcription; SCC, squamous cell carcinoma; SSCP, single-strand conformation polymorphism; TCC, ransitional cell carcinoma.

Journal Article.  8809 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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