17 results on '"TUMOR suppressor proteins"'
Search Results
2. "RB-reactivator screening" as a novel cell-based assay for discoveries of molecular targeting agents including the first-in-class MEK inhibitor trametinib (trade name: Mekinist).
- Author
-
Sakai, Toshiyuki
- Subjects
- *
BUSINESS names , *CYCLIN-dependent kinase inhibitors , *ANAPLASTIC thyroid cancer , *NON-small-cell lung carcinoma , *HISTONE deacetylase inhibitors , *TUMOR suppressor proteins , *CYCLIN-dependent kinases , *ONCOGENES - Abstract
The retinoblastoma gene (RB) was discovered as the first tumor-suppressor gene. It was subsequently shown to be inactivated in most malignant tumors, particularly at the protein level. Therefore, many activated oncogenes as well as inactivated tumor-suppressor genes inactivate the function of the RB protein. I hypothesized that most of the molecular-targeting agents against activated oncogenes may reactivate the function of RB, and proposed screening systems for agents up-regulating the expression of cyclin-dependent kinase inhibitors, such as p15, p27, and p21, which convert the phosphorylated inactive form of the RB protein to the unphosphorylated active form. I termed this screening as "RB-reactivator screening". Using the screening systems for agents that up-regulate the expression of p15, p27, and p21, we discovered the novel MEK inhibitor trametinib, the novel RAF/MEK inhibitor CH5126766/RO5126766/VS-6766, and the histone deacetylase inhibitor YM753/OBP-801, respectively. Trametinib exerted remarkable effects in patients with advanced BRAF mutant melanoma, and was approved in the USA as the first-in-class MEK inhibitor (trade name: Mekinist) in 2013. The British Pharmacological Society selected trametinib as the Drug Discovery of the Year in 2013. The combination of trametinib and the BRAF inhibitor dabrafenib was approved for advanced BRAF mutant melanoma in the USA, EU, Japan, and many other countries. Additionally, the US Food and Drug Administration (FDA) granted Breakthrough Therapy Designation for the combination of trametinib and dabrafenib in the treatment of patients with advanced BRAF mutant non-small cell lung cancer in 2015, and this combination was subsequently approved in the EU, USA, and Japan. In 2018, this combination was also approved for locally advanced or metastatic BRAF V600-mutant anaplastic thyroid cancer in the USA after it had been granted Breakthrough Therapy Designation by the FDA. I describe here the characterization of our original screening system, RB-reactivator screening, by which these three molecular-targeting agents that advanced into clinical trials were identified. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
3. Association of p73 G4C14-to-A4T14 polymorphism at exon 2 and p53 Arg72Pro polymorphism with the risk of endometrial cancer in Japanese subjects.
- Author
-
Niwa Y, Hirose K, Matsuo K, Tajima K, Ikoma Y, Nakanishi T, Nawa A, Kuzuya K, Tamakoshi A, and Hamajima N
- Subjects
- Adult, Aged, Case-Control Studies, Female, Genes, Tumor Suppressor, Humans, Japan, Middle Aged, Polymerase Chain Reaction, Regression Analysis, Risk, Tumor Protein p73, Tumor Suppressor Proteins, Asian People genetics, DNA-Binding Proteins genetics, Endometrial Neoplasms genetics, Genes, p53, Genetic Predisposition to Disease, Nuclear Proteins genetics, Polymorphism, Genetic
- Abstract
To test the association of endometrial cancer with the p73 G4C14-to-A4T14 polymorphism in exon 2 and the p53 Arg72Pro polymorphism, an incident case-control study was performed in Japanese subjects. The cases comprised 114 endometrial cancer patients, and the controls were 320 healthy females and 122 noncancer female outpatients. An unconditional logistic regression model demonstrated a significant association between the p73 AA genotype and an increased risk of endometrial cancer (OR=2.82, 95% CI=1.36-5.82), especially of type-I tumors (OR=3.24, 95% CI=1.53-6.87). In contrast, there was no significant difference in the p53 Arg72Pro genotype frequency between the controls and cases.
- Published
- 2005
- Full Text
- View/download PDF
4. Polymorphisms of p53 Arg72Pro, p73 G4C14-to-A4T14 at exon 2 and p21 Ser31Arg and the risk of non-Hodgkin's lymphoma in Japanese.
- Author
-
Hishida A, Matsuo K, Tajima K, Ogura M, Kagami Y, Taji H, Morishima Y, Emi N, Naoe T, and Hamajima N
- Subjects
- Adult, Aged, Case-Control Studies, Cyclin-Dependent Kinase Inhibitor p21, Female, Genes, Tumor Suppressor physiology, Genetic Predisposition to Disease, Genotype, Humans, Japan epidemiology, Logistic Models, Lymphoma, Non-Hodgkin etiology, Male, Middle Aged, Molecular Epidemiology, Tumor Protein p73, Tumor Suppressor Proteins, Cell Cycle Proteins genetics, DNA-Binding Proteins genetics, Lymphoma, Non-Hodgkin genetics, Mutation, Missense, Nuclear Proteins genetics, Polymorphism, Genetic, Tumor Suppressor Protein p53 genetics
- Abstract
We hypothesized that the polymorphisms in the two p53 family genes (p53 Arg72Pro and p73 G4C14-to-A4T14 at exon 2 (G4A)) and p21 Ser31Arg polymorphism might modulate the risk of non-Hodgkin's lymphoma, and conducted a hospital-based prevalent case control study at Aichi Cancer Center Hospital to clarify the association. Risk estimation for each genotype by the unconditional logistic model demonstrated the possible association between the p53 Pro72 allele and the risk of non-Hodgkin's lymphoma in Japanese population (OR = 1.59; 95% CI, 0.99-2.57, P = 0.057), although no other significant association was observed. The analyses of statistical interactions between these three polymorphisms (p73 G4A, p53 Arg72Pro and p21 Ser31Arg polymorphisms) revealed the marginally significant OR for interaction between p53 Arg72Pro and p73 G4A polymorphisms (OR = 2.54; 95% CI, 0.97 6.62, P = 0.057). When those without p53 Pro72 and p73 A4T14 alleles were defined as a reference, those with p53 Pro72 and p73 A4T14 alleles demonstrated a significantly higher OR (2.08; 95% CI, 1.11-3.90, P = 0.023). Further examination with a sufficiently larger population and other ethnicities are required to confirm our findings.
- Published
- 2004
- Full Text
- View/download PDF
5. Genetic polymorphisms of p73 G4C14-to-A4T14 at exon 2 and p53 Arg72Pro and the risk of cervical cancer in Japanese.
- Author
-
Niwa Y, Hamajima N, Atsuta Y, Yamamoto K, Tamakoshi A, Saito T, Hirose K, Nakanishi T, Nawa A, Kuzuya K, and Tajima K
- Subjects
- Adult, Aged, Aged, 80 and over, Case-Control Studies, Exons genetics, Female, Gene Frequency, Genes, Tumor Suppressor, Genetic Predisposition to Disease, Humans, Japan, Middle Aged, Polymerase Chain Reaction, Risk Factors, Tumor Protein p73, Tumor Suppressor Proteins, DNA-Binding Proteins genetics, Genes, p53 genetics, Nuclear Proteins genetics, Polymorphism, Genetic genetics, Uterine Cervical Neoplasms genetics
- Abstract
To examine the possible association between cervical cancer and p73 G4C14-to-A4T14 in exon 2 and p53 Arg72Pro polymorphisms, an incident case-control study was conducted in Japanese. The cases were 112 cervical cancer patients. Controls were 320 healthy women and 122 non-cancer female outpatients. Risk estimation for each genotype by an unconditional logistic model demonstrated a possible association between the p73 A4T14 variant and the risk of cervical cancer in our Japanese population (OR = 1.57; 95%CI, 0.99-2.48, P = 0.053). There was no significant difference in the p53 Arg72Pro genotype frequency between the controls and cases.
- Published
- 2004
- Full Text
- View/download PDF
6. The relationship between twenty missense ATM variants and breast cancer risk: the Multiethnic Cohort.
- Author
-
Bretsky P, Haiman CA, Gilad S, Yahalom J, Grossman A, Paglin S, Van Den Berg D, Kolonel LN, Skaliter R, and Henderson BE
- Subjects
- Black or African American genetics, Aged, Asian genetics, Ataxia Telangiectasia Mutated Proteins, Cell Cycle Proteins, Cohort Studies, DNA-Binding Proteins, Female, Genetic Variation, Hispanic or Latino genetics, Humans, Japan, Middle Aged, Polymorphism, Genetic, Tumor Suppressor Proteins, White People genetics, Breast Neoplasms genetics, Ethnicity, Mutation, Missense genetics, Protein Serine-Threonine Kinases genetics
- Abstract
Deficiencies in tasks of detecting and repairing DNA damage lead to mutations and chromosomal abnormalities, a hallmark of cancer. The gene mutated in ataxia-telangiectasia (A-T), ATM, is a proximal component in performing such tasks. Studies of A-T families have suggested an increased risk of breast cancer among obligate female heterozygous carriers of ATM mutations. Paradoxically, studies of sporadic and familial breast cancer have failed to demonstrate an elevated prevalence of mutations among breast cancer cases. We characterized the prevalence and distribution of 20 ATM missense mutations/polymorphisms in a population-based case-control study of 854 African-American, Latina, Japanese, and Caucasian women aged >/==" BORDER="0">45 years participating in the Multiethnic Cohort Study. The study population included 428 incident breast cancer cases and 426 controls. The prevalence of variants ranged from 0% to 13.6% among controls and varied by ethnicity (0-32.5%). Overall, these data provide little support for an association of ATM missense mutations with breast cancer among older women. We observed only one sequence variation (L546V), common among African-American women, to be overrepresented among all high-stage breast cancer cases (odds ratio, 3.35; 95% confidence interval, 1.27-8.84). After correction for multiple comparisons, this observed risk modification did not attain statistical significance. The distribution of ATM missense mutations and polymorphisms varied widely across the four ethnic groups studied. Although a single missense variant (L546V) appeared to act as a modest predictor of risk, the remaining variants were no more common in breast cancer cases as compared with controls.
- Published
- 2003
7. EEC syndrome type 3 with a heterozygous germline mutation in the P63 gene and B cell lymphoma.
- Author
-
Akahoshi K, Sakazume S, Kosaki K, Ohashi H, and Fukushima Y
- Subjects
- Adolescent, DNA-Binding Proteins, Ectodermal Dysplasia physiopathology, Female, Genes, Tumor Suppressor, Heterozygote, Humans, Japan, Lymph Nodes pathology, Syndrome, Transcription Factors, Tumor Suppressor Proteins, Ectodermal Dysplasia genetics, Lymphoma, B-Cell genetics, Phosphoproteins genetics, Trans-Activators genetics
- Abstract
Lines of evidence have recently indicated a relationship between mutations in the P63 gene and ectrodactyly-ectodermal dysplasia-clefting (EEC) syndrome type 3 (EEC3). The p63 gene (P63) has homology to P53 known as a tumor-suppressor gene, but biological function of its protein has not yet been known well. There have been two reported patients who had EEC syndrome associated with malignant lymphoma. However, they did not undergo sequencing analysis of P63. Here, we present with a Japanese girl who had EEC3 and developed diffuse large B-cell type non-Hodgkin lymphoma. In this patient, we documented a heterozygous germline mutation, Asp312Gly, in P63. We speculated that p63 may exert a biological function as a tumor suppressor. Malignant lymphoma should be considered as an important complication of EEC3., (Copyright 2003 Wiley-Liss, Inc.)
- Published
- 2003
- Full Text
- View/download PDF
8. Clinical and genetic characteristics of Japanese Burkitt lymphomas with or without leukemic presentation.
- Author
-
Namiki T, Sakashita A, Kobayashi H, Maseki N, Izumo T, Komada Y, Koizumi S, Shikano T, Kikuta A, Watanabe A, Suzumiya J, Kikuchi M, and Kaneko Y
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Burkitt Lymphoma genetics, Burkitt Lymphoma mortality, Cell Cycle Proteins genetics, Child, Child, Preschool, Chromosome Breakage, Cyclin-Dependent Kinase Inhibitor p15, Cyclin-Dependent Kinase Inhibitor p16 genetics, Cytogenetic Analysis, Epstein-Barr Virus Infections epidemiology, Epstein-Barr Virus Infections genetics, Epstein-Barr Virus Infections mortality, Female, Genes, myc, Genes, p16, Genes, p53, Humans, Infant, Japan epidemiology, Male, Middle Aged, Prognosis, Survival Analysis, Translocation, Genetic, Burkitt Lymphoma epidemiology, Tumor Suppressor Proteins
- Abstract
To clarify the clinical and genetic features of Burkitt lymphoma with or without leukemic presentation, we have conducted clinical, cytogenetic, and genetic studies. Of 40 Japanese patients with Burkitt lymphoma examined by cytogenetic and/or fluorescence in situ hybridization analysis or Southern blot analysis using MYC probes, 35 patients had t(8;14) translocations, and 5 had t(8;22). Breakpoints were located far upstream of MYC in 4 (12%) of 33 tumors with t(8;14), and Epstein-Barr virus infection was found in 3 (8%) of 40 tumors. These findings are similar to those reported for non-Japanese patients with the sporadic form of Burkitt lymphoma. Clinical and genetic characteristic were compared for 30 patients presenting with lymphoma and 10 presenting with leukemia. The overall survival was shorter in aggressively treated leukemia patients than in aggressively treated lymphoma patients (P = .003); however, the incidence rates of TP53 mutation, p16INK4a deletion, and p15INK4b deletion that were found in 6 (15%) of 40,3 (9%) of 35, and 2 (6%) of 35 tumors, respectively, were similar between the 2 subtypes. Thus, the present study has shown the different prognoses for the 2 subtypes of Burkitt lymphoma but has failed to clarify the genetic backgrounds that may explain the different outcomes.
- Published
- 2003
- Full Text
- View/download PDF
9. Large-scale search of SNPs for type 2 DM susceptibility genes in a Japanese population.
- Author
-
Daimon M, Ji G, Saitoh T, Oizumi T, Tominaga M, Nakamura T, Ishii K, Matsuura T, Inageda K, Matsumine H, Kido T, Htay L, Kamatani N, Muramatsu M, and Kato T
- Subjects
- Aged, Carrier Proteins genetics, Case-Control Studies, Fatty Acid-Binding Protein 7, Fatty Acid-Binding Proteins, Female, Genetics, Population, Genotype, Humans, Japan, Male, Potassium Channels genetics, Proto-Oncogene Mas, Receptors, Drug genetics, Sulfonylurea Receptors, ATP-Binding Cassette Transporters, Diabetes Mellitus, Type 2 genetics, Genetic Predisposition to Disease, Neoplasm Proteins, Polymorphism, Single Nucleotide, Potassium Channels, Inwardly Rectifying, Tumor Suppressor Proteins
- Abstract
The etiology of type 2 diabetes (DM) is polygenic. We investigated here genes and polymorphisms that associate with DM in the Japanese population. Single-nucleotide polymorphisms (SNPs) of 398 derived from 120 candidate genes were examined for association with DM in a population-based case-control study. The study group consisted of 148 cases and 227 controls recruited from Funagata, Japan. No evident subpopulation structure was detected for the tested population. The association tests were conducted with standard allele positivity tables (chi(2) tests) between SNP genotype frequency and case-control status. The independent association of the SNPs from serum triglyceride levels and body mass index was examined by multiple logistic regression analysis. A value of P<0.01 was accepted as statistically significant. Six genes (met proto-oncogene, ATP-binding cassette transporter A1, fatty acid binding protein 2, LDL receptor defect C complementing, aldolase B, and sulfonylurea receptor) were shown to be associated with DM.
- Published
- 2003
- Full Text
- View/download PDF
10. Smoke exposure, histologic type and geography-related differences in the methylation profiles of non-small cell lung cancer.
- Author
-
Toyooka S, Maruyama R, Toyooka KO, McLerran D, Feng Z, Fukuyama Y, Virmani AK, Zochbauer-Muller S, Tsukuda K, Sugio K, Shimizu N, Shimizu K, Lee H, Chen CY, Fong KM, Gilcrease M, Roth JA, Minna JD, and Gazdar AF
- Subjects
- Adenomatous Polyposis Coli Protein genetics, Adult, Aged, Aged, 80 and over, Australia, Cadherins genetics, Carcinoma, Non-Small-Cell Lung etiology, Cyclin-Dependent Kinase Inhibitor p16 genetics, DNA, Neoplasm, Female, Genes, Tumor Suppressor, Glutathione S-Transferase pi, Glutathione Transferase genetics, Humans, Isoenzymes genetics, Japan, Lung Neoplasms etiology, Male, Middle Aged, Neoplasm Proteins genetics, O(6)-Methylguanine-DNA Methyltransferase genetics, Polymerase Chain Reaction methods, Receptors, Retinoic Acid genetics, Risk Factors, Survival Rate, Taiwan, United States, Carcinoma, Non-Small-Cell Lung genetics, DNA Methylation, Lung Neoplasms genetics, Promoter Regions, Genetic genetics, Smoking adverse effects, Tumor Suppressor Proteins
- Abstract
Aberrant methylation of several known or putative tumor suppressor genes occurs frequently during the pathogenesis of lung cancers. There are major smoke exposure, histology, geography and gender-related changes in non-small cell lung cancer (NSCLC). We investigated smoking-related, histologic, geographic and gender differences in the methylation profiles of resected NSCLCs. We examined 514 cases of NSCLC and 84 corresponding nonmalignant lung tissues from 4 countries (USA, Australia, Japan and Taiwan) for the methylation status of 7 genes known to be frequently methylated in lung cancers [p16, RASSF1A (RAS association domain family 1), APC, RARbeta, CDH13, MGMT and GSTP1]. Multivariate analyses were used for data analysis. Adenocarcinoma was the major histologic type in women and never smokers; analyses that involved smoke exposure and gender were limited to this histology. Our major findings are a) methylation status of any single gene was largely independent of methylation status of other genes; b) the rates of methylation of p16 and APC and the mean Methylation Index (MI), a reflection of the overall methylation status, were significantly higher in ever smokers than in never smokers; c) the mean MI of tumors arising in former smokers was significantly lower than the mean of current smokers; d) the methylation rates of APC, CDH13 and RARbeta were significantly higher in adenocarcinomas than in squamous cell carcinomas; e) methylation rates of MGMT and GSTP1 were significantly higher in the USA and Australian cases than in those from Japan and Taiwan; and (f) no significant gender-related differences in methylation patterns were noted. Our findings demonstrate important smoke exposure, histologic type and geography-related differences in the methylation profiles of NSCLC tumors., (Copyright 2002 Wiley-Liss, Inc.)
- Published
- 2003
- Full Text
- View/download PDF
11. No associations of p73 G4C14-to-A4T14 at exon 2 and p53 Arg72Pro polymorphisms with the risk of digestive tract cancers in Japanese.
- Author
-
Hamajima N, Matsuo K, Suzuki T, Nakamura T, Matsuura A, Hatooka S, Shinoda M, Kodera Y, Yamamura Y, Hirai T, Kato T, and Tajima K
- Subjects
- Adult, Aged, Case-Control Studies, Esophageal Neoplasms genetics, Exons, Female, Gastrointestinal Neoplasms genetics, Gene Frequency, Genes, Tumor Suppressor, Humans, Japan, Male, Middle Aged, Tumor Protein p73, Tumor Suppressor Proteins, DNA-Binding Proteins genetics, Digestive System Neoplasms genetics, Nuclear Proteins genetics, Polymorphism, Genetic, Tumor Suppressor Protein p53 genetics
- Abstract
A case-control study was conducted to examine the possible association between digestive tract cancers and p73 G4C14-to-A4T14 at exon 2 and p53 Arg72Pro polymorphisms in Japanese. Cases were 102 esophageal cancer patients, 144 stomach cancer patients, and 147 colorectal cancer patients, and controls were 241 non-cancer outpatients. The genotype frequencies among controls were 55.3% for p73 GG at position 4, 40.4% for GA, and 4.3% for AA, and 37.7% for p53 ArgArg, 44.4% for ArgPro, and 18.0% for ProPro. No significant differences in the genotype frequencies were observed between the controls and each case group or cases as a whole.
- Published
- 2002
- Full Text
- View/download PDF
12. Molecular genetic analysis and mutation screening of the VHL gene in a Japanese family with von Hippel-Lindau disease.
- Author
-
Wu Y, Nishio H, Lee MJ, Ayaki H, Hayashi A, Ooba T, Ogawa T, and Sumino K
- Subjects
- Adult, Alleles, Base Sequence genetics, Child, Preschool, Female, Heterozygote, Humans, Japan, Male, Molecular Biology, Polymerase Chain Reaction, Von Hippel-Lindau Tumor Suppressor Protein, Asian People genetics, Genetic Testing, Ligases, Mutation, Missense, Proteins genetics, Tumor Suppressor Proteins, Ubiquitin-Protein Ligases, von Hippel-Lindau Disease genetics
- Abstract
Von Hippel-Lindau (VHL) disease is an autosomal dominantly inherited familial cancer syndrome which predisposes individuals to a variety of malignant and benign tumors. Its penetrance is almost 100% by 61-70 years of age. We have identified a germline mutation in the VHL gene of a Japanese male patient with a retinal hemangioma in the left eye, an intracranial hemangioblastoma, a left renal tumor and bilateral pheochromocytomas. Screening for the mutation was performed in all members of the patient's family at risk for VHL disease. The mutation identified in the patient was a missense mutation at codon 238 (CGG to CAG). The elder daughter, who did not show any clinical symptoms, was found to carry the same mutation. In order to detect and treat tumors in VHL patients at an earlier stage, it is necessary to identify and screen for the VHL gene mutation in all family members known at risk.
- Published
- 2000
13. Cell cycle inhibitory protein p27 in esophageal squamous cell carcinoma.
- Author
-
Ohashi Y, Sasano H, Yamaki H, Shizawa S, Shineha R, Akaishi T, Satomi S, and Nagura H
- Subjects
- Adult, Aged, Carcinoma in Situ chemistry, Carcinoma in Situ pathology, Carcinoma, Squamous Cell mortality, Carcinoma, Squamous Cell pathology, Cell Division, Cyclin-Dependent Kinase Inhibitor p27, Disease Progression, Esophageal Neoplasms mortality, Esophageal Neoplasms pathology, Female, Humans, Immunoenzyme Techniques, Japan epidemiology, Ki-67 Antigen analysis, Male, Microtubule-Associated Proteins physiology, Middle Aged, Mitotic Index, Mucous Membrane pathology, Muscle, Smooth pathology, Neoplasm Invasiveness, Neoplasm Proteins physiology, Survival Analysis, Carcinoma, Squamous Cell chemistry, Cell Cycle Proteins, Esophageal Neoplasms chemistry, Microtubule-Associated Proteins analysis, Neoplasm Proteins analysis, Tumor Suppressor Proteins
- Abstract
Background: p27 protein is one of the cdk inhibitors which regulates the progression from G1 to S phase of the cell cycle. Reduced expression of p27 protein has been reported to be correlated with poor clinical outcome in patients with various cancers., Materials and Methods: We performed immunohistochemistry of both p27 and Ki67 in 136 cases of resected human esophageal squamous cell carcinoma, and evaluated the association between p27 immunoreactivity and clinicopathological features including clinical outcome in these patients. We also examined the correlation between labeling index or the percentage of positive tumor cells for p27 and Ki67 in serial tissue sections in these cases., Results: Cases with invasion of the muscularis propria or adventitia had significantly (p < 0.05) higher p27 LI (65.0 +/- 23.7) than those with invasion limited to mucosa or submucosa and those with carcinoma in situ (58.9 +/- 18.3). There were no significant correlations between p27 and other clinicopathological factors such as sex, age, tumor size, differentiation type, nodal status and histological stage. The cases with p27 LI below 40% tended to have a worse prognosis than those with p27 LI above 40%. There was no significant correlation between Ki67 and p27 LIs., Conclusions: Reduced expression of p27 may be correlated with the biological behavior of esophageal squamous cell carcinoma and may play an important role in the early stages of cancer.
- Published
- 1999
14. Variation of the fatty acid binding protein 2 gene is not associated with obesity and insulin resistance in Japanese subjects.
- Author
-
Hayakawa T, Nagai Y, Nohara E, Yamashita H, Takamura T, Abe T, Nomura G, and Kobayashi K
- Subjects
- Adult, Aged, Alleles, Amino Acid Substitution genetics, Asian People genetics, Diabetes Mellitus, Type 2 genetics, Fatty Acid-Binding Protein 7, Fatty Acid-Binding Proteins, Female, Gene Frequency, Glucose Intolerance genetics, Heterozygote, Homozygote, Humans, Japan, Male, Middle Aged, Obesity ethnology, Reference Values, Carrier Proteins genetics, Genetic Variation physiology, Insulin Resistance genetics, Myelin P2 Protein genetics, Neoplasm Proteins, Obesity genetics, Tumor Suppressor Proteins
- Abstract
An alanine to threonine substitution at codon 54 of the fatty acid binding protein 2 (FABP2) gene has been associated with insulin resistance in Pima Indians and with obesity in aboriginal Canadians. We investigated whether this polymorphism contributes to obesity and insulin resistance in 258 Japanese subjects. Thirty-six subjects (13.9%) were homozygous for the Thr54 allele, 106 (41.1%) were heterozygous for the Ala54/Thr54 allele, and 116 (45.0%) were homozygous for the Ala54 allele. The frequency of the Thr54 allele was 0.34 and did not differ significantly between men and women. The incidence of non-insulin-dependent diabetes mellitus (NIDDM) was not different among the three genotypes. The variation at codon 54 of the FABP2 gene was not associated with obesity, hypertension, dyslipidemia, hyperuricemia, or hyperinsulinemia. These results suggest that the polymorphism at codon 54 of the FABP2 gene is not a major contributing factor to obesity and insulin resistance in Japanese subjects.
- Published
- 1999
- Full Text
- View/download PDF
15. Mutations of the ATM gene detected in Japanese ataxia-telangiectasia patients: possible preponderance of the two founder mutations 4612del165 and 7883del5.
- Author
-
Ejima Y and Sasaki MS
- Subjects
- Ataxia Telangiectasia Mutated Proteins, Cell Cycle Proteins, Cell Line, DNA Mutational Analysis, DNA-Binding Proteins, Female, Fibroblasts, Humans, Japan, Male, Microsatellite Repeats, Polymerase Chain Reaction, Tumor Suppressor Proteins, Ataxia Telangiectasia genetics, Founder Effect, Mutation, Protein Serine-Threonine Kinases, Proteins genetics, Sequence Deletion genetics
- Abstract
The ATM (A-T, mutated) gene on human chromosome 11q22.3 has recently been identified as the gene responsible for the human recessive disease ataxia-telangiectasia (A-T). In order to define the types of disease-causing ATM mutations in Japanese A-T patients as well as to look for possible mutational hotspots, reverse-transcribed RNA derived from ten patients belonging to eight unrelated Japanese A-T families was analyzed for mutations by the restriction endonuclease fingerprinting method. As has been reported by others, mutations that lead to exon skipping or premature protein truncation were also predominant in our mutants. Six different mutations were identified on 12 of the 16 alleles examined. Four were deletions involving a loss of a single exon: exon 7, exon 16, exon 33 or exon 35. The others were minute deletions, 4649delA in exon 33 and 7883del5 in exon 55. The mutations 4612del165 and 7883del5 were found in more than two unrelated families; 44% (7 of 16) of the mutant alleles had one of the two mutations. The 4612del165 mutations in three different families were all ascribed to the same T-->A substitution at the splice donor site in intron 33. Microsatellite genotyping around the ATM locus also indicated that a common haplotype was shared by the mutant alleles in both mutations. This suggests that these two founder mutations may be predominant among Japanese ATM mutant alleles.
- Published
- 1998
- Full Text
- View/download PDF
16. Novel exonic mutation (5319 G to A) resulting in two aberrantly spliced transcripts of the ATM gene in a Japanese patient with ataxia-telangiectasia.
- Author
-
Fukao T, Tashita H, Teramoto T, Inoue R, Kaneko H, Komiyama K, Bar-Shira A, Gilad S, Shiloh Y, Nishimura M, and Kondo N
- Subjects
- Adolescent, Adult, Amino Acid Substitution, Ataxia Telangiectasia pathology, Ataxia Telangiectasia Mutated Proteins, Base Sequence, Cell Cycle Proteins, Child, Child, Preschool, DNA Mutational Analysis, DNA, Complementary chemistry, DNA, Complementary genetics, DNA-Binding Proteins, Exons genetics, Family Health, Female, Follow-Up Studies, Humans, Japan, Mutagenesis, Insertional, Mutation, Tumor Suppressor Proteins, Ataxia Telangiectasia genetics, Protein Serine-Threonine Kinases, Proteins genetics, RNA Splicing
- Published
- 1998
- Full Text
- View/download PDF
17. Germline mutations in the Von Hippel-Lindau disease (VHL) gene in families from North America, Europe, and Japan.
- Author
-
Zbar B, Kishida T, Chen F, Schmidt L, Maher ER, Richards FM, Crossey PA, Webster AR, Affara NA, Ferguson-Smith MA, Brauch H, Glavac D, Neumann HP, Tisherman S, Mulvihill JJ, Gross DJ, Shuin T, Whaley J, Seizinger B, Kley N, Olschwang S, Boisson C, Richard S, Lips CH, and Lerman M
- Subjects
- Adrenal Gland Neoplasms genetics, Asian People genetics, Ethnicity genetics, Europe, Family, Genotype, Humans, Introns, Israel, Japan, Kidney Neoplasms genetics, North America, Phenotype, Pheochromocytoma genetics, Point Mutation, Sequence Deletion, Von Hippel-Lindau Tumor Suppressor Protein, White People genetics, Genes, Tumor Suppressor, Ligases, Mutation, Proteins genetics, Tumor Suppressor Proteins, Ubiquitin-Protein Ligases, von Hippel-Lindau Disease genetics
- Abstract
Germline mutation analysis was performed in 469 VHL families from North America, Europe, and Japan. Germline mutations were identified in 300/469 (63%) of the families tested; 137 distinct intragenic germline mutations were detected. Most of the germline VHL mutations (124/137) occurred in 1-2 families; a few occured in four or more families. The common germline VHL mutations were: delPhe76, Asn78Ser, Arg161Stop, Arg167Gln, Arg167Trp, and Leu178Pro. In this large series, it was possible to compare the effects of identical germline mutations in different populations. Germline VHL mutations produced similar cancer phenotypes in Caucasian and Japanese VHL families. Germline VHL mutations were identified that produced three distinct cancer phenotypes: (1) renal carcinoma without pheochromocytoma, (2) renal carcinoma with pheochromocytoma, and (3) pheochromocytoma alone. The catalog of VHL germline mutations with phenotype information should be useful for diagnostic and prognostic studies of VHL and for studies of genotype-phenotype correlations in VHL.
- Published
- 1996
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.