• Asian Pacific Journal of Cancer Prevention
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• 제16권14호
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• pp.5767-5772
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• 2015

Background: Polymorphisms in the MDM2 309 (T>G) and TP53 72 (G>C) genes are reported to increase the susceptibility to head and neck cancer (HNC) in various populations. The risk for HNC is also strongly associated with etiologic habits such as smoking, alcohol consumption and/or chewing of betel quid (BQ). In a case-control study, we investigated the significance of the above polymorphisms alone, and upon interaction with one another as well as with various etiologic habits in determining HNC risk in a Northeast Indian population. Materials and Methods: Genotyping at 309 MDM2 and 72 TP53 in 122 HNC patients and 86 cancer free healthy controls was performed by PCR using allele specific primers, and the results were confirmed by DNA sequencing. Results: Individuals with the GG mutant allele of MDM2 showed a higher risk for HNC in comparison to those with the TT wild type allele (OR=1.9, 95%CI: 1.1-3.3) (p=0.022). The risk was further increased in females by ~4-fold (OR=4.6, 95% CI: 1.1-19.4) (P=0.04). TP53 polymorphism did not contribute to HNC risk alone; however, interaction between the TP53 GC and MDM2 GG genotypes resulted in significant risk (OR=4.9, 95% CI: 0.2-105.1) (p=0.04). Smokers, BQ- chewers and alcohol consumers showed statistically significant and dose-dependent increase in HNC risk, irrespective of the MDM2 genotype. Conclusions: MDM2 genotype could serve as an important predictive biomarker for HNC risk in the population of Northeast India.

• 한국식품과학회지
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• 제13권3호
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• pp.176-180
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• 1981

국내의 산란노계와 브로일러로부터 생산(生産)된 수동발골육(HDM) 및 기계발골육(MDM)을 여러가지 비율(比率)로 배합(配合)하여 제조(製造)한 치큰 패티와 프랑크푸르트 소시지의 특성(特性), 보존성(保存性), 기호성(嗜好性)을 평가(評價)하였던 바 다음과 같은 결과(結果)를 얻었다. 1. HDM을 사용한 치큰 패티의 TBA시험에 의한 지방산패도는 냉동저장중 계속 증가하였으나 8주(週)까지는 보존성이 양호(良好)였다. 2. 치큰 패티의 색(色)과 기호성(嗜好性)에 있어 MDM을 50%까지 첨가한 것이 가장 우수하였고 50%까지도 양호(良好)하였으나 70%이상 첨가는 권장할 수 없었다. 3.프랑크푸르트 소시지의 제조에 있어 MDM을 50%까지 첨가한 것의 기호성이나 조직적 특성은 HDM으로만 만든 제품과 비등하게 양호(良好)하였으나 70% 이상 첨가한 것은 불량(不良)하였다. 4. MDM을 함유(含有)한 프랑크푸르트 소시지의 보존성(保存性)은 $4^{\circ}C$에서 4주까지 무난하였으며 저장 기간에 따른 TBA 값의 변화는 거의 없었다. 5. 결론적으로 치큰 패티나 프랑크푸르트 소시지등의 육제품(肉製品) 제조에 있어서 MDM을 총원료육의 $30{\sim}35%$까지 첨가하여도 조직이나 기호성이 우수한 제품을 생산(生産)할 수 있었다.

• BMB Reports
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• 제50권10호
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• pp.485-486
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• 2017

Many intrinsically unstructured/unfolded proteins (IUPs) contain transient local secondary structures even though they are "unstructured" in a tertiary sense. These local secondary structures are named "pre-structured motifs (PreSMos)" and in fact are the specificity determinants for IUP-target binding, i.e., the active sites in IUPs. Using high-resolution NMR we have delineated a PreSMo active site in the intrinsically unfolded mid-domain (residues 201-300) of SUMO-specific protease 4 (SUSP4). This 29-residue motif which we termed a p53 rescue motif can protect p53 from mdm2 quenching by binding to the p53-helix binding pocket in mdm2(3-109). Our work demonstrates that the PreSMo approach is quite effective in providing a structural rationale for interactions of p53-mdm2-SUSP4 and opens a novel avenue for designing mdm2-inhibiting anticancer compounds.

• Asian Pacific Journal of Cancer Prevention
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• 제15권8호
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• pp.3817-3823
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• 2014

Background: The MDM2 oncogene, a negative regulator of p53, has a functional polymorphism in the promoter region (SNP309) that is associated with multiple kinds of cancers including non-melanoma skin cancer. SNP309 has been shown to associate with accelerated tumor formation by increasing the affinity of the transcriptional activator Sp1. It remains unknown whether there are other factors involved in the regulation of MDM2 transcription through a trans-regulatory mechanism. Methods: In this study, SNP309 was verified to be associated with overexpression of MDM2 in tumor cells. Bioinformatics predicts that the T to G substitution at SNP309 generates a stronger E2F1 binding site, which was confirmed by ChIP and luciferase assays. Results: E2F1 knockdown downregulates the expression of MDM2, which confirms that E2F1 is a functional upstream regulator. Furthermore, tumor cells with the GG genotype exhibited a higher proliferation rate than TT, correlating with cyclin D1 expression. E2F1 depletion significantly inhibits the proliferation capacity and downregulates cyclin D1 expression, especially in GG genotype skin fibroblasts. Notably, E2F1 siRNA effects could be rescued by cyclin D1 overexpression. Conclusion: Taken together, a novel modulator E2F1 was identified as regulating MDM2 expression dependent on SNP309 and further mediates cyclin D1 expression and tumor cell proliferation. E2F1 might act as an important factor for SNP309 serving as a rate-limiting event in carcinogenesis.

• Asian Pacific Journal of Cancer Prevention
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• 제14권9호
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• pp.5415-5420
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• 2013

Background: Cell cycle deregulation is a major component of carcinogenesis. The p53 tumor suppressor gene plays an important role in regulating cell cycle arrest, and mouse double minute 2 (MDM2) is a key regulator of p53 activity and degradation. Abnormal expression of p53 and MDM2 occurs in various cancers including lung cancer. Methods: We investigated the distribution of the p53 Arg72Pro (rs1042522) and MDM2 SNP309 (rs2279744) genotypes in patients and healthy control subjects to assess whether these single nucleotide polymorphisms (SNPs) are associated with an increased risk of lung adenocarcinomas in Chinese female non-smokers. Genotypes of 764 patients and 983 healthy controls were determined using the TaqMan SNP genotyping assay. Results: The p53 Pro/Pro genotype (adjusted OR = 1.55, 95% CI = 1.17-2.06) significantly correlated with an increased risk of lung adenocarcinoma, compared with the Arg/Arg genotype. An increased risk was also noted for MDM2 GG genotype (adjusted OR = 1.68, 95% CI = 1.27-2.21) compared with the TT genotype. Combined p53 Pro/Pro and MDM2 GG genotypes (adjusted OR = 2.66, 95% CI = 1.54-4.60) had a supermultiplicative interaction with respect to lung adenocarcinoma risk. We also found that cooking oil fumes, fuel smoke, and passive smoking may increase the risk of lung adenocarcinomas in Chinese female non-smokers who carry p53 or MDM2 mutant alleles. Conclusions: P53 Arg72Pro and MDM2 SNP309 polymorphisms, either alone or in combination, are associated with an increased lung adenocarcinoma risk in Chinese female non-smokers.

• Radiation Oncology Journal
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• 제25권4호
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• pp.193-200
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• 2007

목적: 식도암에서 동시적 항암화학방사선치료 전 MDM2, p53, pRb 발현양상이 치료반응 및 생존율 등 치료결과와 연관성이 있는지 알아보고자 하였다. 대상 및 방법: AJCC 병기 $I{\sim}IVa$로 근치적 목적의 동시적 항암화학방사선요법을 받은 51명의 환자를 대상으로 하였다. 방사선치료는 일일 $1.8{\sim}2.0$ Gy씩 원발병소에 중앙값 54 Gy를 시행하였고 항암화학요법은 CDDP/5-FU를 4주 간격으로 4회 시행하고 첫 2회는 방사선치료와 동시에 시행하였다. MDM2, p53, pRb 발현의 검출은 치료 전 내시경하 조직생검을 이용하여 면역조직화학 염색방법을 이용하였다. 단백발현 양성종양세포가 50%이상인 경우를 고발현군으로 정의하였다. 전체 환자의 중앙 추적관찰기간은 26개월이었다. MDM2, p53, pRb 고발현군은 각각 19.6%, 27.5%, 66.7% 이었다. 그러나 이들의 발현 정도와 치료반응, 종양특이 생존율, 전체 생존율 등 모두 유의한 연관성은 없었다. 연령(65세 이하 vs. 초과), 종양의 위치(상부, 중앙부, 하부),종양의 길이(5 cm이하 vs. 초과). 병기($I{\sim}II$ vs. $III{\sim}IVa$), MDM2 (저발현 vs. 고발현), p53 (저발현 vs. 고발현), pRb (저발현 vs. 고발현), 병리학적 완전관해여부, 임상적 완전관해여부 등 9개 요인들을 대상으로 종양특성 생존율에 대한 다변량 분석에서 병리학적 완전관해여부(RR 12.100, p<0.001)와 병기(RR 3.300, p=0.028) 만이 유의한 인자들이었다. 결 론: 본 연구에서 MDM2, p53, pRb의 치료 전 발현양상과 치료결과와 의미있는 연관성은 발견할 수 없었다. 향후 상기 발현인자들을 포함하여 잠재적인 예후인자로서 새로운 다른 발현인자들을 발굴하고 보다 많은 증례 수를 대상으로 추적기간을 보강하여 이들을 재평가하는 연구가 요망된다.

• Toxicological Research
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• 제24권1호
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• pp.45-49
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• 2008

Formaldehyde has been identified as the most prevalent cause of sick building syndrome (SBS), which has become a major social problem, especially in developing urban areas. However, studies on the molecular mechanisms associated with formaldehyde toxicity have been limited, probably because it is difficult to relate the experimental results obtained from in vitro studies to human exposure in vivo. Using polymerase chain reaction-based suppression subtractive hybridization, we recently identified 27 different formaldehyde-inducible genes including platelet-derived growth factor receptor alpha gene (PDGFRA) and mouse double minute 2 (MDM2) gene which were increased significantly in both formaldehyde-exposed human trachea cells, 680.Tr, and rat tracheas. To establish a possible relationship between induction of these formaldehyde-inducible genes and symptoms of SBS, we examined expression levels of these genes in peripheral lymphocytes of residents of new apartments. Here, we report that the expression of PDGFRA and MDM2 transcripts was significantly higher in peripheral blood lymphocytes obtained from 15 residents in new buildings than in seven control individuals. Our results suggest that the elevated levels of PDGFRA and MDM2 may be associated with the formaldehyde-induced pathophysiology that is closely related with SBS, and that they deserve evaluation as potential biomarkers for formaldehyde intoxication.

• Asian Pacific Journal of Cancer Prevention
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• 제13권6호
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• pp.2841-2846
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• 2012

Background: Many studies have investigated the association between the MDM2 promoter SNP309 T/G polymorphism and liver cancer risk, but inconsistencies make drawwing definitive conclusions difficult. Methods: We therefore searched main databases for articles relating MDM2 SNP309 T/G polymorphism to risk of liver cancer in humans and estimated summary odds ratio (OR) with 95% confidence intervals (95% CI) to assess the possible association in a meta-analysis. Results: The main analysis revealed no significant heterogeneity, and the pooled ORs of fixed-effects were all significant (for G versus T, OR = 1.59, 95% CI 1.42-1.78; for GG versus TT, OR = 2.45, 95% CI 1.93-3.12; for GT versus TT, OR = 1.70, 95% CI 1.38-2.09; for GG versus GT, OR = 1.49, 95% CI 1.24-1.79; for GG and GT versus TT, OR = 1.95, 95% CI 1.61-2.38; for GG versus TT and GT, OR = 1.73, 95% CI 1.46-2.07). Subgroup analyses by ethnicity and sensitivity analyses both showed associations to remain significant. Conclusion: The present meta-analysis of available data showed a significant association between the MDM2 SNP309 T/G polymorphism and liver cancer risk, the MDM2 SNP309 G allele contributing to increased risk in both Asians and Caucasians in a graded, dose-dependent fashion.

• Asian Pacific Journal of Cancer Prevention
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• 제13권9호
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• pp.4327-4330
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• 2012

The mouse double minute 2 (MDM2) gene plays a key role in the p53 pathway, and the SNP 309T/G single-nucleotide polymorphism in the promoter region of MDM2 has been shown to be associated with increased risk of cancer. However, no consistent results were found concerning the relationships between the polymorphism and prostate cancer risk. This meta-analysis, covering 4 independent case-control studies, was conducted to better understand the association between MDM2-SNP T309G and prostate cancer risk focusing on overall and subgroup aspects. The analysis revealed, no matter what kind of genetic model was used, no significant association between MDM2-SNP T309G and prostate cancer risk in overall analysis (GT/TT: OR = 0.84, 95%CI = 0.60-1.19; GG/TT: OR = 0.69, 95%CI = 0.43-1.11; dominant model: OR = 0.81, 95%CI= 0.58-1.13; recessive model: OR = 1.23, 95%CI = 0.95-1.59). In subgroup analysis, the polymorphism seemed more likely to be a protective factor in Europeans (GG/TT: OR = 0.52, 95%CI = 0.31-0.87; recessive model: OR = 0.58, 95%CI = 0.36-0.95) than in Asian populations, and a protective effect of the polymorphism was also seen in hospital-based studies in all models (GT/TT: OR = 0.74, 95%CI = 0.57-0.97; GG/TT: OR = 0.55, 95%CI = 0.38-0.79; dominant model: OR = 0.69, 95%CI = 0.54-0.89; recessive model: OR = 0.70, 95%CI = 0.51-0.97). However, more primary studies with a larger number of samples are required to confirm our findings.

• Genomics & Informatics
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• 제18권1호
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• pp.9.1-9.5
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• 2020

Ulcerative colitis is a form of inflammatory bowel disease characterized by chronic inflammation of the colon and rectum. The abnormal lesions in the digestive system caused by ulcerative colitis and intermittent colitis are of major clinical importance. MDM2 is a phospho-protein that functions as a ubiquitin ligase for p53. Recently, a T>G substitution in the promoter of the MDM2 gene (rs309) has been identified. In this case-control study, 174 ulcerative colitis biopsy samples and 82 control samples were collected from colonoscopy centers, hospitals, and clinics in Mazandaran and Gilan Provinces in Iran from October 2014 to May 2015. This MDM2 polymorphism was investigated in DNA samples (extracted from biopsy samples) by amplification-refractory mutation system polymerase chain reaction. The mean age of patients with ulcerative colitis was 46.5 years (range, 28 to 69 years) and that of control individuals was 45.3 years (range, 26 to 71 years). Seventy-eight patients (44.82%) were men and 96 (55.18%) were women. The distribution of the TT, TG, and GG genotypes was 17.93%, 27.59%, and 34.48%, respectively, in the ulcerative colitis patients and 31.70%, 24.40%, and 43.90%, respectively, in the control individuals (odds ratio of GG for ulcerative colitis, 7.142; 95% confidence interval, 2.400 to 9.542; p = 0.001). It was found that a single-nucleotide polymorphism at rs309 in the MDM2 gene was associated with ulcerative colitis. A direct relationship was found between age and ulcerative colitis, while no relationship was found with sex. This finding is of note because the occurrence of intestinal inflammation and subsequent ulcers can precede the development of cancer.