Structure and Organization of Amplified DNA on Double Minutes Containing the mdm2 Oncogene

Fakharzadeh, Steven; Rosenblum-Vos, Lynne S.; Murphy, Maureen E.; Hoffman, Edward L.; George, Donna L.

doi:10.1006/geno.1993.1058

Cited by 59 publications

(28 citation statements)

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“…In the other 50% of human cancers, p53 retains wild-type status but its tumor suppressor function can be compromised by multiple mechanisms, and one major inhibitory mechanism is mediated by its primary cellular inhibitor, the murine double minute 2 protein (MDM2; known as HDM2 in human). MDM2 was initially discovered by its overexpression in a spontaneously transformed mouse cell line [8][9][10][11][12]. MDM2 and p53 mutually regulate each other through an auto-regulatory feedback loop [13,14].…”

Section: Introduction P53 and Its Primary Cellular Inhibitor Mdm2mentioning

confidence: 99%

Small Molecule Inhibitors of MDM2-p53 and MDMX-p53 Interactions as New Cancer Therapeutics

Zhao¹,

Bernard²,

Wang³

2013

Biodiscovery

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Inactivation of the function of tumor suppressor p53 is common in human cancers. In approximately half of human cancers, the tumor suppressor function of p53 is inactivated by deletion or mutation of TP53, the gene encoding p53 protein. In the remaining 50% of human cancers, p53 tumor suppressor function can be effectively inhibited by oncoprotein MDM2 or its homolog MDMX. Since inhibition of p53 by MDM2 or MDMX protein is mediated by their direct interaction with p53, small-molecule inhibitors designed to block the MDM2-p53 or MDMX-p53 protein-protein interaction (MDM2 or MDMX inhibitors) can activate p53 in tumor cells retaining wild-type p53. In the last few years, several classes of potent, selective, and efficacious small molecule MDM2 inhibitors have been designed and developed, and six such compounds are being evaluated in clinical trials as new anticancer drugs. Additionally, non-peptide, small-molecule MDMX inhibitors have been reported. We review herein the design and development of potent small-molecule MDM2 and MDMX inhibitors.

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Section: Introduction P53 and Its Primary Cellular Inhibitor Mdm2mentioning

confidence: 99%

Small Molecule Inhibitors of MDM2-p53 and MDMX-p53 Interactions as New Cancer Therapeutics

Zhao¹,

Bernard²,

Wang³

2013

Biodiscovery

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“…They have been found in a vast number of human neoplasias since the first description (Spriggs et al 1962). Many oncogenes have been identified on DMs, for example, MYCN, C-MYC, EIF5A2, and MDM2 (Alitalo et al 1983;Fakharzadeh et al 1993;Guan et al 2001;VanDevanter et al 1990). Recently, some amplicon junctions were sequenced (Storlazzi et al 2006).…”

Section: Introductionmentioning

confidence: 99%

Frequency of double minute chromosomes and combined cytogenetic abnormalities and their characteristics

Fan

Mao

et al. 2010

J Appl Genetics

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Double minute chromosomes (DMs) are the cytogenetic hallmark of extra-chromosomal genomic amplification. The frequency of DMs in primary cancer and the cytogenetic features of DMs-positive primary cancer cases are largely unknown. To unravel these issues, we retrieved the Mitelman database and analyzed all DMs-positive primary cancerous karyotypes (787 karyotypes). The overall frequency of DMs is 1.4% (787 DMs-positive cases; total 54,398 cases). We found that DMs have the highest frequency in adrenal carcinoma (28.6%, topography) and neuroblastoma (31.7%, morphology). The frequencies of DMs in each tumor were much lower than in previous reports. The frequency of DMs in malignant cancers is significantly higher than in benign cancers, which confirms that DMs are malignant cytogenetic markers. DMs combined cytogenetic abnormalities are identified and sorted into two groups by principal component analysis (PCA), with one group containing −4, −5, −8, −9, −10, −13, −14, −15, −16, −17, −18, −20, −21, and −22, and the other containing −1p, −5q, +7, and +20. The prominent imbalance in DMs-positive cancer cases is chromosome loss. However, DMs-positive cancer cases, deriving from different morphologic cancers, cannot be clearly divided into subgroups. Our large database analysis provides novel knowledge of DMs and their combined cytogenetic abnormalities in primary cancer.

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“…In some cases, each circular element comprises two copies of the amplified sequence linked in inverted orientation (5,6). In other cases, a single copy of a chromosome fragment appears to be circularized by simple ligation of its extremities (7,8).…”

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confidence: 99%

Molecular structure of double-minute chromosomes bearing amplified copies of the epidermal growth factor receptor gene in gliomas

Vogt

Lefevre

Apiou

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

149

167

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Amplification of the epidermal growth factor receptor gene on double minutes is recurrently observed in cells of advanced gliomas, but the structure of these extrachromosomal circular DNA molecules and the mechanisms responsible for their formation are still poorly understood. By using quantitative PCR and chromosome walking, we investigated the genetic content and the organization of the repeats in the double minutes of seven gliomas. It was established that all of the amplicons of a given tumor derive from a single founding extrachromosomal DNA molecule. In each of these gliomas, the founding molecule was generated by a simple event that circularizes a chromosome fragment overlapping the epidermal growth factor receptor gene. In all cases, the fusion of the two ends of this initial amplicon resulted from microhomologybased nonhomologous end-joining. Furthermore, the corresponding chromosomal loci were not rearranged, which strongly suggests that a postreplicative event was responsible for the formation of each of these initial amplicons.

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Structure and Organization of Amplified DNA on Double Minutes Containing the mdm2 Oncogene

Cited by 59 publications

References 0 publications

Small Molecule Inhibitors of MDM2-p53 and MDMX-p53 Interactions as New Cancer Therapeutics

Small Molecule Inhibitors of MDM2-p53 and MDMX-p53 Interactions as New Cancer Therapeutics

Frequency of double minute chromosomes and combined cytogenetic abnormalities and their characteristics

Molecular structure of double-minute chromosomes bearing amplified copies of the epidermal growth factor receptor gene in gliomas

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