Wild-type p53 overexpression and its correlation with MDM2 and p14ARF alterations: An alternative pathway to non-small-cell lung cancer

Yu Chien Wang, Ruo Kai Lin, Yi Hung Tan, Jung Ta Chen, Chih Yi Chen, Yi Ching Wang

Research output: Contribution to journalArticle

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Abstract

Purpose: We found a relatively reduced frequency of p53 mutation with a much greater frequency of p53 protein overexpression, which reflected stabilization of p53 protein in the absence of p53 gene mutation. Therefore, we investigated the possibility of alternative mechanisms leading to p53 protein stabilization. Patients and Methods: We performed gene and protein alteration studies on p53 and its upstream effectors, MDM2 and p14ARF, in tumors from 94 non-small-cell lung cancer (NSCLC) patients. Results: lmmunohistochemical and sequencing analyses indicated that 37 tumors showed overexpression of wild-type p53. An absence of nuclear staining of MDM2 protein was found in 95% of these tumors (35 of 37; P <.001). The tumors with negative MDM2 staining showed a significantly high concordance of loss of Akt activity and low MDM2 mRNA expression (P <.001). Sequencing analysis revealed five distinct MDM2 splicing variants disrupting the conserved p53 binding domain. Corresponding variant proteins were detected in three lung cancer cell lines using the Western blot analysis. Our results also indicated that among the tumors with overexpression of the wild-type p53, 92% (34 of 37) showed immunoreactivity to p14ARF (P = .001). In addition, the deregulation of p53 and MDM2 genes was significantly associated with squamous lung cancer (P <.05) and was correlated with advanced stages (P <.05) and poor prognosis (P <.05). Conclusion: Our data suggest that immunopositivity of p14ARF together with a low expression of MDM2 contributes to accumulation of the wild-type p53, and that deregulation of the p53-MDM2-p14ARF pathway is important in the pathogenesis and outcome of a subset of NSCLC.

Original languageEnglish
Pages (from-to)154-164
Number of pages11
JournalJournal of Clinical Oncology
Volume23
Issue number1
DOIs
Publication statusPublished - Jan 1 2005
Externally publishedYes

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Tumor Suppressor Protein p14ARF
Non-Small Cell Lung Carcinoma
Proteins
p53 Genes
Neoplasms
Lung Neoplasms
Negative Staining
Mutation Rate
Western Blotting
Staining and Labeling
Cell Line
Messenger RNA
Mutation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Wild-type p53 overexpression and its correlation with MDM2 and p14ARF alterations : An alternative pathway to non-small-cell lung cancer. / Wang, Yu Chien; Lin, Ruo Kai; Tan, Yi Hung; Chen, Jung Ta; Chen, Chih Yi; Wang, Yi Ching.

In: Journal of Clinical Oncology, Vol. 23, No. 1, 01.01.2005, p. 154-164.

Research output: Contribution to journalArticle

Wang, Yu Chien ; Lin, Ruo Kai ; Tan, Yi Hung ; Chen, Jung Ta ; Chen, Chih Yi ; Wang, Yi Ching. / Wild-type p53 overexpression and its correlation with MDM2 and p14ARF alterations : An alternative pathway to non-small-cell lung cancer. In: Journal of Clinical Oncology. 2005 ; Vol. 23, No. 1. pp. 154-164.
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abstract = "Purpose: We found a relatively reduced frequency of p53 mutation with a much greater frequency of p53 protein overexpression, which reflected stabilization of p53 protein in the absence of p53 gene mutation. Therefore, we investigated the possibility of alternative mechanisms leading to p53 protein stabilization. Patients and Methods: We performed gene and protein alteration studies on p53 and its upstream effectors, MDM2 and p14ARF, in tumors from 94 non-small-cell lung cancer (NSCLC) patients. Results: lmmunohistochemical and sequencing analyses indicated that 37 tumors showed overexpression of wild-type p53. An absence of nuclear staining of MDM2 protein was found in 95{\%} of these tumors (35 of 37; P <.001). The tumors with negative MDM2 staining showed a significantly high concordance of loss of Akt activity and low MDM2 mRNA expression (P <.001). Sequencing analysis revealed five distinct MDM2 splicing variants disrupting the conserved p53 binding domain. Corresponding variant proteins were detected in three lung cancer cell lines using the Western blot analysis. Our results also indicated that among the tumors with overexpression of the wild-type p53, 92{\%} (34 of 37) showed immunoreactivity to p14ARF (P = .001). In addition, the deregulation of p53 and MDM2 genes was significantly associated with squamous lung cancer (P <.05) and was correlated with advanced stages (P <.05) and poor prognosis (P <.05). Conclusion: Our data suggest that immunopositivity of p14ARF together with a low expression of MDM2 contributes to accumulation of the wild-type p53, and that deregulation of the p53-MDM2-p14ARF pathway is important in the pathogenesis and outcome of a subset of NSCLC.",
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AU - Chen, Jung Ta

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AU - Wang, Yi Ching

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N2 - Purpose: We found a relatively reduced frequency of p53 mutation with a much greater frequency of p53 protein overexpression, which reflected stabilization of p53 protein in the absence of p53 gene mutation. Therefore, we investigated the possibility of alternative mechanisms leading to p53 protein stabilization. Patients and Methods: We performed gene and protein alteration studies on p53 and its upstream effectors, MDM2 and p14ARF, in tumors from 94 non-small-cell lung cancer (NSCLC) patients. Results: lmmunohistochemical and sequencing analyses indicated that 37 tumors showed overexpression of wild-type p53. An absence of nuclear staining of MDM2 protein was found in 95% of these tumors (35 of 37; P <.001). The tumors with negative MDM2 staining showed a significantly high concordance of loss of Akt activity and low MDM2 mRNA expression (P <.001). Sequencing analysis revealed five distinct MDM2 splicing variants disrupting the conserved p53 binding domain. Corresponding variant proteins were detected in three lung cancer cell lines using the Western blot analysis. Our results also indicated that among the tumors with overexpression of the wild-type p53, 92% (34 of 37) showed immunoreactivity to p14ARF (P = .001). In addition, the deregulation of p53 and MDM2 genes was significantly associated with squamous lung cancer (P <.05) and was correlated with advanced stages (P <.05) and poor prognosis (P <.05). Conclusion: Our data suggest that immunopositivity of p14ARF together with a low expression of MDM2 contributes to accumulation of the wild-type p53, and that deregulation of the p53-MDM2-p14ARF pathway is important in the pathogenesis and outcome of a subset of NSCLC.

AB - Purpose: We found a relatively reduced frequency of p53 mutation with a much greater frequency of p53 protein overexpression, which reflected stabilization of p53 protein in the absence of p53 gene mutation. Therefore, we investigated the possibility of alternative mechanisms leading to p53 protein stabilization. Patients and Methods: We performed gene and protein alteration studies on p53 and its upstream effectors, MDM2 and p14ARF, in tumors from 94 non-small-cell lung cancer (NSCLC) patients. Results: lmmunohistochemical and sequencing analyses indicated that 37 tumors showed overexpression of wild-type p53. An absence of nuclear staining of MDM2 protein was found in 95% of these tumors (35 of 37; P <.001). The tumors with negative MDM2 staining showed a significantly high concordance of loss of Akt activity and low MDM2 mRNA expression (P <.001). Sequencing analysis revealed five distinct MDM2 splicing variants disrupting the conserved p53 binding domain. Corresponding variant proteins were detected in three lung cancer cell lines using the Western blot analysis. Our results also indicated that among the tumors with overexpression of the wild-type p53, 92% (34 of 37) showed immunoreactivity to p14ARF (P = .001). In addition, the deregulation of p53 and MDM2 genes was significantly associated with squamous lung cancer (P <.05) and was correlated with advanced stages (P <.05) and poor prognosis (P <.05). Conclusion: Our data suggest that immunopositivity of p14ARF together with a low expression of MDM2 contributes to accumulation of the wild-type p53, and that deregulation of the p53-MDM2-p14ARF pathway is important in the pathogenesis and outcome of a subset of NSCLC.

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