MDM2 gene amplification: a new independent factor of adverse prognosis in non-small cell lung cancer (NSCLC)

Dworakowska, Dorota; Jassem, Ewa; Jassem, Jacek; Peters, Brigitte; Dziadziuszko, Rafał; Żylicz, Maciej; Jakóbkiewicz‐Banecka, Joanna; Kobierska‐Gulida, Grażyna; Szymanowska, Amelia; Skokowski, Jan; Roessner, Albert; Schneider‐Stock, Regine

doi:10.1016/j.lungcan.2003.09.010

Cited by 61 publications

(47 citation statements)

References 35 publications

(45 reference statements)

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“…The mdm2 gene itself is a downstream target of p53, thus forming a tight autoregulatory feedback loop (9-11). Consistent with this notion, gene amplification and overexpression of MDM2 have also been shown in a variety of tumors, particularly in soft tissue sarcomas, lymphomas, and breast and lung cancers (12)(13)(14)(15)(16). Interfering with the MDM2-p53 feedback loop leads to p53 activation, ultimately preventing neoplasia.…”

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confidence: 69%

Regulation of the MDM2-p53 Pathway by Ribosomal Protein L11 Involves a Post-ubiquitination Mechanism

Dai

Shi

Jin

et al. 2006

Journal of Biological Chemistry

110

119

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Inhibition of the MDM2-p53 feedback loop is critical for p53 activation in response to cellular stresses. The ribosomal proteins L5, L11, and L23 can block this loop by inhibiting MDM2-mediated p53 ubiquitination and degradation in response to ribosomal stress. Here, we show that L11, but not L5 and L23, leads to a drastic accumulation of ubiquitinated and native MDM2. This effect is dependent on the ubiquitin ligase activity of MDM2, but not p53, and requires the central MDM2 binding domain (residues 51-108) of L11. We further show that L11 inhibited 26 S proteasomemediated degradation of ubiquitinated MDM2 in vitro and consistently prolonged the half-life of MDM2 in cells. These results suggest that L11, unlike L5 and L23, differentially regulates the levels of ubiquitinated p53 and MDM2 and inhibits the turnover and activity of MDM2 through a postubiquitination mechanism.The tumor suppressor protein p53 is a transcription factor activated in response to stress to induce expression of its target genes. The proteins encoded by these genes then mediate multiple cellular responses, such as cell cycle arrest, apoptosis, differentiation, cell senescence, or DNA repair (1). Also, p53 can directly trigger mitochondria-mediated apoptosis in response to DNA damage (2-4). The tumor suppression function of p53 is well reflected in the fact that more than half of human tumors harbor mutations in the p53 gene, and many others retain impaired function of the p53 pathway (5,6). Because of its inhibitory effect on cell growth, p53 is maintained at a low steady-state level and in an inert form in physiological conditions. This duty is mainly fulfilled by the E3 2 ubiquitin ligase MDM2 that mediates p53 constant degradation through a ubiquitin-dependent proteasome pathway (7,8). The mdm2 gene itself is a downstream target of p53, thus forming a tight autoregulatory feedback loop (9-11). Consistent with this notion, gene amplification and overexpression of MDM2 have also been shown in a variety of tumors, particularly in soft tissue sarcomas, lymphomas, and breast and lung cancers (12)(13)(14)(15)(16). Interfering with the MDM2-p53 feedback loop leads to p53 activation, ultimately preventing neoplasia. One example of this regulation is alternative reading frame (ARF) (p14 ARF in human, p19 ARF in mouse)-mediated inhibition of this loop in response to * This work was supported in part by NCI, National Institutes of Health Grants CA93614, CA095441, and CA079721 (to H. L.) and CA107532 (to S. R. G.). 1 To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, OR Health and Science University, 3181 SW Sam Jackson Park Rd., Portland,; E-mail: luh@ohsu.edu.. 2 The abbreviations used are: E3, ubiquitin-protein isopeptide ligase; ARF, alternative reading frame; E1, ubiquitin activating enzyme (UBA); E2, ubiquitin carrier protein; HA, hemagglutinin; Ni-NTA, nickel nitrilotriacetic acid; GFP, green fluorescent protein; MEF, murine embryonic fibroblast cell. 18). Also, in response to DNAdamaging agen...

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confidence: 69%

Regulation of the MDM2-p53 Pathway by Ribosomal Protein L11 Involves a Post-ubiquitination Mechanism

Dai

Shi

Jin

et al. 2006

Journal of Biological Chemistry

110

119

View full text Add to dashboard Cite

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“…Mdm2 overexpression could be linked to gene amplification in several malignancies (eg, malignant melanoma, non-small cell lung cancer and lipomatous tumours (Dworakowska et al, 2004;Nilsson et al, 2004;Muthusamy et al, 2006) but in PCa a specific Mdm2 gene amplification could not be demonstrated by Southern blot analysis so far (Ittmann et al, 1994). Interestingly, frequent gains of chromosome 12q including the regions 12q13-q14 that are in close proximity to the Mdm2 gene locus have been reported in various studies using comparative genomic hybridisation (Sattler et al, 1999;Zitzelsberger et al, 2001) but to date no gene copy number Figure 2 Graphical illustration of the genotype distribution in cases and controls.…”

Section: Discussionmentioning

confidence: 99%

Mdm2-SNP309 polymorphism in prostate cancer: no evidence for association with increased risk or histopathological tumour characteristics

et al. 2008

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The search for inherited cancer susceptibility factors is a major focus of epidemiologic cancer studies. Analyses of single-nucleotide polymorphisms (SNP) in a variety of genes revealed a correlation between a specific allele variant and cancer predisposition. Human mouse double-minute 2 protein (Mdm2) is a cellular E3 ligase capable of ubiquitination and degradation of p53. Therefore, Mdm2 is a crucial factor of cell cycle control and cell survival. The Mdm2 promoter SNP309 was shown to increase Mdm2 expression and can, thereby, inhibit the p53 pathway. This SNP was found to be associated with increased risk and early onset of various malignancies. For prostate cancer no studies are reported to date. In a case -control study we determined the distribution of the Mdm2 SNP309 in 145 male subjects with prostate cancer and in 124 male controls without any malignancy using RFLP analysis. Cases and controls showed a similar distribution of the SNP (P ¼ 0.299). Genotype distribution showed neither an association with histopathological characteristics of the tumours nor with prognosis. Age at disease onset was also not modified by the SNP. This first study of the Mdm2 SNP309 in prostate cancer patients suggests no correlation between a certain allelic variant and an increased cancer risk.

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“…It has been shown that even in cancer types that lack TP53 mutations, TP53 function is abolished or attenuated by other mechanisms, such as interaction with virus protein or overexpressed MDM2 protein [Oliner et al, 1992;Bond et al, 2004]. MDM2 is a key negative regulator of the TP53 pathway that targets TP53 for degradation, and overexpression or amplification of MDM2 has been frequently observed in many human cancer types, including lung cancer [Oliner et al, 1992;Higashiyama et al, 1997;Momand et al, 1998;Eymin et al, 2002;Dworakowska et al, 2004]. Second, the association between a high level of constitutive expression of MDM2 and susceptibility to carcinogenesis was previously tested in genetically modified animals.…”

Section: Discussionmentioning

confidence: 99%

Genetic polymorphisms in cell cycle regulatory genesMDM2 andTP53 are associated with susceptibility to lung cancer

et al. 2005

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Communicated by Georgia Chenevix-TrenchThe tumor suppressor TP53 pathway plays a crucial role in preventing carcinogenesis through its ability to impose cell cycle arrest and apoptosis following DNA damage and oncogene activation. MDM2 is a key negative regulator of the TP53 pathway and is overexpressed in many cancers as oncoprotein. We investigated the association between genetic variation in the promoter region of MDM2 (c.-51309G4T, rs2279744:g.G4T) and the coding region of TP53 (c.215G4C, rs1042522:g.G4C, designated Arg72Pro) and the risk of developing lung cancer. The genotypes of 1,106 patients and 1,420 controls were determined by tetra-primer amplification refractory mutation system (ARMS)-PCR or PCR-based restriction fragment length polymorphism (RFLP

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MDM2 gene amplification: a new independent factor of adverse prognosis in non-small cell lung cancer (NSCLC)

Cited by 61 publications

References 35 publications

Regulation of the MDM2-p53 Pathway by Ribosomal Protein L11 Involves a Post-ubiquitination Mechanism

Regulation of the MDM2-p53 Pathway by Ribosomal Protein L11 Involves a Post-ubiquitination Mechanism

Mdm2-SNP309 polymorphism in prostate cancer: no evidence for association with increased risk or histopathological tumour characteristics

Genetic polymorphisms in cell cycle regulatory genesMDM2 andTP53 are associated with susceptibility to lung cancer

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