Expression of mdm-2 Protein in Neoplastic, Preneoplastic, and Normal Bronchial Mucosa Specimens: Comparative Study with p53 Expression

Rasidakis, Antonios; Orphanidou, Dora; Kalomenidis, J; Papamichalis, George; Toumbis, Michael; Lambadlos, John; Sacharidou, Anastasia; Papastamatiou, Hera; Jordanoglou, J.

doi:10.1089/hyb.1998.17.339

Cited by 12 publications

(8 citation statements)

References 32 publications

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“…The current study is the first to assess MDM2 protein overexpression at every stage of SQCC development. Previously, MDM2 expression has been detected in some cases of hyperplasia, metaplasia and dysplasia, but the proportion of lesions expressing MDM2 was not determined nor compared with normal tissue expression [14]. MDM2 was initially overexpressed at the MiD stage in the current study, with 80% of the biopsies showing a high MDM2 expression, compared with only 19% of normal bronchial tissue.…”

Section: Discussioncontrasting

confidence: 53%

“…Indeed, MDM2 and p14arf have been widely studied in invasive lung cancer [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25]. However, limited data suggest that MDM2 expression is modified in the early stages of carcinogenesis [14], while p14arf has not been assessed in bronchial pre-invasive tissues. To the current authors' knowledge, NPM expression has not been studied in lung cancer, either at invasive or early stages.…”

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confidence: 99%

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The role of NPM, p14arf and MDM2 in precursors of bronchial squamous cell carcinoma

Mascaux

Bex²,

Martin³

et al. 2008

European Respiratory Journal

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Murine double minute clone 2 (MDM2), p14 alternate reading frame (p14arf), and nucleophosmin (NPM) regulate p53 activity.A total of 200 biopsies, including normal bronchial, pre-invasive and invasive tissues, were examined for changes in NPM, p14arf, MDM2 and p53 expression patterns by immunohistochemistry and immunofluorescence with confocal microscopy.NPM and p14arf displayed a diffuse nuclear staining in most normal bronchial tissue. The fraction of biopsies displaying an increased MDM2 staining or a nucleolar relocalisation of NPM increased at mild and moderate dysplasia, respectively. Two different modifications occurred in p14arf expression, i.e. its loss or its nucleolar relocalisation, both increasing at severe dysplasia and both being associated with high MDM2 expression. In addition, the nucleolar relocalisation of p14arf was associated with that of NPM. Immunofluorescence staining indicated that NPM and p14arf either co-localised in the nucleoplasm or in the nucleoli, before and as a result of severe dysplasia, respectively. MDM2 was not detected in the nucleoli.Thus, changes occur in murine double minute clone 2, p14 alternate reading frame and nucleophosmin level of expression and/or cellular distribution during early steps of lung carcinogenesis. Their relative localisation as determined by immunofluorescence, supports the hypothesis that p14 alternate reading frame nucleolar relocalisation impairs p14 alternate reading frame-murine double minute clone 2 complex formation and that nucleophosmin might sequester p14 alternate reading frame. The demonstration of this hypothesis requires further functional studies.

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Section: Discussioncontrasting

confidence: 53%

mentioning

confidence: 99%

The role of NPM, p14arf and MDM2 in precursors of bronchial squamous cell carcinoma

Mascaux

Bex²,

Martin³

et al. 2008

European Respiratory Journal

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“…27) No association was found between the expressions of p53 and MDM2 in colorectal and bronchial neoplasms. 28,29) In this study, it was found that the MDM2 overexpression was not significantly associated with either p53 expression or the absence of p53 gene mutation in oral SCC. These findings suggest that p53-independent mechanisms may also be important in oral SCC, and that MDM2 expression may not be specifically linked to the functional status of p53.…”

Section: Discussionmentioning

confidence: 57%

MDM2 Overexpression with Alteration of the p53 Protein and Gene Status in Oral Carcinogenesis

Murai

Koyama

et al. 2000

Japanese Journal of Cancer Research

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In this study, to better understand the mechanism of oral squamous cell carcinoma (SCC) carcinogenesis, alterations of the p53 gene and overexpression of MDM2 and p53 were analyzed in 38 oral SCC samples. Twelve of the 38 specimens revealed mutant-type p53. Moreover, coexpression of MDM2 and p53 was found most frequently in dysplastic lesions (P < < < <0.05). Expression of MDM2 and p53 was significantly increased in accordance with the histological progression of multistep carcinogenesis (P < < < <0.05). No significant correlation was found between the expression of MDM2 and the alteration of p53 protein or p53 gene status. MDM2 overexpression with mutant p53 was significantly associated with poorly differentiated SCCs (P < < < <0.05) and tumor stages III and IV of oral SCCs (P < < < <0.05). These results suggest that MDM2 overexpression is an early event in oral carcinogenesis through the functional inactivation of the wild-type p53, and corresponding alterations of MDM2 and p53 contribute to the oral carcinogenesis. We propose that it would be clinically more instructive to evaluate MDM2 overexpression combined with p53 gene status, compared to the evaluation of either MDM2 or p53 alteration alone. Key words: MDM2 -p53 -Oral carcinogenesisOral squamous cell carcinoma (SCC) is the most common malignant tumor in the oral cavity.1) Nevertheless, the mechanism of oral carcinogenesis is still poorly understood.2) Previous studies have shown that inactivation of wild-type p53 function by mutation or interaction with a viral oncogene product plays an important role in carcinogenesis, including oral SCC.3-6) However, there are still oral SCCs which do not contain mutant p53 or viral protein. Therefore, it is reasonable to assume the presence of a p53-independent oral carcinogenesis pathway.It was found that MDM2, a cellular oncogene product, can bind to the p53 N-terminal acidic domain to inactivate its transcription factor activity.7, 8) Also, p53 can bind to the first intron of the MDM2 gene to activate MDM2 transcription, thus establishing a negative feedback loop 9) to control the cell cycle.MDM2 can inhibit wild-type p53-mediated G1 arrest and apoptosis.10, 11) MDM2 also plays a role in promoting the S phase in the p53-independent pathway.12) It has been reported that overexpressions of both p53 and MDM2 are more frequent in high-grade bladder cancer.13) MDM2 overexpression is observed in various tumors with or without p53 mutation.14-17) However, the significance of the correlation between the overexpression of MDM2 and the p53 status in the multistep processes of oral SCC development has not yet been clearly elucidated. 18)In this study, to reach a better understanding of the mechanism of oral carcinogenesis, the alterations of the p53 gene in oral SCC specimens were investigated. Furthermore, using the same specimens, the overexpression of MDM2 and p53 was analyzed in normal mucosa adjacent to the tumor, and in premalignant and malignant lesions. MATERIALS AND METHODS MaterialsThe 38 oral SCC specimens used in...

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“…The protein MDM-2 binds to p53 and eliminates its ability to function as a transcription factor. Alterations in MDM-2 expression have been found in preneoplastic lesions [47]. Other authors have found an apparent deregulation of the p53 apoptosis transcription pathway in precursor bronchial lesions of lung cancer.…”

Section: Data Supporting the Preneoplastic Nature Of Lesionsmentioning

confidence: 99%

Preneoplastic lesions of the lung

2002

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Lung cancer is the leading cause of cancer deaths worldwide. If we can define and detect preneoplastic lesions, we might have a chance of improving survival. The World Health Organization has defined three preneoplastic lesions of the bronchial epithelium: squamous dysplasia/carcinoma in situ; atypical adenomatous hyperplasia; and diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. These lesions are believed to progress to squamous cell carcinoma, adenocarcinoma and carcinoid tumors, respectively. In this review we summarize the data supporting the preneoplastic nature of these lesions, and delve into some of the genetic changes found in atypical adenomatous hyperplasia and squamous dysplasia/carcinoma in situ.

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Expression of mdm-2 Protein in Neoplastic, Preneoplastic, and Normal Bronchial Mucosa Specimens: Comparative Study with p53 Expression

Cited by 12 publications

References 32 publications

The role of NPM, p14arf and MDM2 in precursors of bronchial squamous cell carcinoma

The role of NPM, p14arf and MDM2 in precursors of bronchial squamous cell carcinoma

MDM2 Overexpression with Alteration of the p53 Protein and Gene Status in Oral Carcinogenesis

Preneoplastic lesions of the lung

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