MDM2 gene amplification and protein expressions in colon carcinoma: is targeting MDM2 a new therapeutic option?

Hav, Monirath; Libbrecht, Louis; Ferdinande, Liesbeth; Pattyn, Piet; Laurent, Stéphanie; Peeters, Marc; Praet, Marleen; Pauwels, Patrick

doi:10.1007/s00428-010-1012-7

Cited by 15 publications

(10 citation statements)

References 31 publications

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“…The MDM2 regulation of disorders is associated with the development of cancer, which is confirmed by the evidence that MDM2 was over-expressed in some human cancers [18,19]. MDM2 single nucleotide polymorphism SNP ( rs2279744 ) has already been described as being associated with several types of cancer [20,21], and also with accelerated tumorigenesis and poor prognosis [22].…”

Section: Introductionmentioning

confidence: 89%

MDM2 polymorphism associated with the development of cervical lesions in women infected with Human papillomavirus and using of oral contraceptives

Cetkovská

Gurgel

Cardoso

et al. 2014

Infect Agents Cancer

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BackgroundThe MDM2 gene is the major negative regulator of p53, a tumor suppressor protein. Single nucleotide polymorphism in promoter region of MDM2 gene leads to increased expression resulting in higher levels of MDM2 protein. This event increases the attenuation of the p53 pathway. Polymorphisms in this gene can interfere in the regulation of cellular proliferation. We evaluated whether MDM2 SNP309 (rs2278744) associated or not with the use of oral contraceptive can heighten susceptibility to development of cervical lesions in women HPV infected.MethodsMDM2 SNP309 (rs2278744) was genotyped in a total of 287 patients using the PCR-RFLP technique. The results were analyzed by UNPHASED v.3.121 and SNPStats programs.ResultsThe three groups (SIL, LSIL and HSIL) showed no significant differences in either genotype or allelic frequencies for MDM2 polymorphisms, except when HSIL was compared with LSIL (p = 0.037; OR = 1.81). Furthermore, in the analysis of contraceptives, a significant association was found between the use of contraceptives and the MDM2 variant in the development of high-grade cervical lesions for the TG genotype (p = 0.019; OR = 2.21) when HSIL was compared with control. When HSIL was compared with LSIL (p = 0.006; OR = 2.27).ConclusionThe results of this study suggest that MDM2 SNP309 might be a good marker for assessing the progression of LSIL to HSIL. In addition, they also show that oral contraceptives alone, did not have any effect on the progression or development of cervical lesions. However, they may act synergistically with MDM2 SNP309 (rs2278744) and HPV infection in the development of cervical lesions.

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Section: Introductionmentioning

confidence: 89%

MDM2 polymorphism associated with the development of cervical lesions in women infected with Human papillomavirus and using of oral contraceptives

Cetkovská

Gurgel

Cardoso

et al. 2014

Infect Agents Cancer

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“…The array CGH values for the fluorescence intensities significantly correlated with chromosome wide low-level gene expression changes (log 2 ) as a consequence of genomic imbalances (data not shown). With respect to the oncogene Mdm2 that was amplified in our cell lines, this gene has also been associated with human primary CRC (Forslund et al, 2008;Hav et al, 2011;Sepideh et al, 2012). Interestingly, while copy number gains of MMU15 were observed, an increase in the expression of Myc (located at MMU15D2) was not found to be statistically significant in the mouse CRC lines, unlike the bladder and kidney cell lines.…”

Section: Discussionmentioning

confidence: 69%

Novel mouse model recapitulates genome and transcriptome alterations in human colorectal carcinomas

McNeil

Padilla‐Nash

Buishand

et al. 2016

Genes Chromosomes & Cancer

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Human colorectal carcinomas are defined by a nonrandom distribution of genomic imbalances that are characteristic for this disease. Often, these imbalances affect entire chromosomes. Understanding the role of these aneuploidies for carcinogenesis is of utmost importance. Currently, established transgenic mice do not recapitulate the pathognonomic genome aberration profile of human colorectal carcinomas. We have developed a novel model based on the spontaneous transformation of murine colon epithelial cells. During this process, cells progress through stages of pre-immortalization, immortalization and, finally, transformation, and result in tumors when injected into immunocompromised mice. We analyzed our model for genome and transcriptome alterations using ArrayCGH, spectral karyotyping (SKY), and array based gene expression profiling. ArrayCGH revealed a recurrent pattern of genomic imbalances. These results were confirmed by SKY. Comparing these imbalances with orthologous maps of human chromosomes revealed a remarkable overlap. We observed focal deletions of the tumor suppressor genes Trp53 and Cdkn2a/p16. High-level focal genomic amplification included the locus harboring the oncogene Mdm2, which was confirmed by FISH in the form of double minute chromosomes. Array-based global gene expression revealed distinct differences between the sequential steps of spontaneous transformation. Gene expression changes showed significant similarities with human colorectal carcinomas. Pathways most prominently affected included genes involved in chromosomal instability and in epithelial to mesenchymal transition. Our novel mouse model therefore recapitulates the most prominent genome and transcriptome alterations in human colorectal cancer, and might serve as a valuable tool for understanding the dynamic process of tumorigenesis, and for preclinical drug testing. © 2016 Wiley Periodicals, Inc.

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“…The human MDM2 gene is located on chromosome 12 (12q14–15), and its amplification is observed in colon cancer 76, 77 , gastric cancer 78, 79 , leukemia, breast cancer 80 , glioblastoma 81 , neuroblastoma 82 , leukemia 83 , and sarcoma 84 . Other UBLs subject to genetic amplification include SKP2, CUL-4A, SMURF1, WWP1 and are summarized in Table 4.…”

Section: Gene Amplificationmentioning

confidence: 99%

Dysregulation of ubiquitin ligases in cancer

Ronai

2015

Drug Resistance Updates

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Ubiquitin ligases are critical components of the ubiquitin proteasome system (UPS), which governs fundamental processes regulating normal cellular homeostasis, metabolism, and cell cycle in response to external stress signals and DNA damage. Among multiple steps of the UPS system required to regulate protein ubiquitination and stability, UBLs define specificity, as they recognize and interact with substrates in a temporally- and spatially-regulated manner. Such interactions are required for substrate modification by ubiquitin chains, which marks proteins for recognition and degradation by the proteasome, or alters their subcellular localization or assembly into functional complexes. UBLs are often deregulated in cancer, altering substrate availability or activity in a manner that can promote cellular transformation. Such deregulation can occur at the epigenetic, genomic, or post-translational levels. Alterations in UBL can be used to predict their contributions, affecting tumor suppressors or oncogenes in select tumors. Better understanding of mechanisms underlying UBL expression and activities is expected to drive the development of next generation modulators that can serve as novel therapeutic modalities. This review summarizes our current understanding of UBL deregulation in cancer and highlights novel opportunities for therapeutic interventions.

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MDM2 gene amplification and protein expressions in colon carcinoma: is targeting MDM2 a new therapeutic option?

Cited by 15 publications

References 31 publications

MDM2 polymorphism associated with the development of cervical lesions in women infected with Human papillomavirus and using of oral contraceptives

MDM2 polymorphism associated with the development of cervical lesions in women infected with Human papillomavirus and using of oral contraceptives

Novel mouse model recapitulates genome and transcriptome alterations in human colorectal carcinomas

Dysregulation of ubiquitin ligases in cancer

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