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Chromosome Instability (chromosome + instability)
Selected AbstractsChromosome instability in Candida albicansFEMS YEAST RESEARCH, Issue 1 2007Elena Rustchenko Abstract Candida albicans maintains genetic diversity by random chromosome alterations, and this diversity allows utilization of various nutrients. Although the alterations seem to occur spontaneously, their frequencies clearly depend on environmental factors. In addition, this microorganism survives in adverse environments, which cause lethality or inhibit growth, by altering specific chromosomes. A reversible loss or gain of one homolog of a specific chromosome in this diploid organism was found to be a prevalent means of adaptation. We found that loss of an entire chromosome is required because it carries multiple functionally redundant negative regulatory genes. The unusual mode of gene regulation in Candida albicans implies that genes in this organism are distributed nonrandomly over chromosomes. [source] Analysis of Aurora-A and hMPS1 mitotic kinases in mantle cell lymphomaINTERNATIONAL JOURNAL OF CANCER, Issue 2 2006Emma Camacho Abstract Aurora-A and hMPS1 are kinases involved in spindle checkpoint and centrosome duplication regulation and whose alterations have been associated with cell transformation and chromosome instability in different tumor models. In this study, we have examined the possible alterations of these genes in 58 mantle cell lymphomas (MCLs) and 4 MCL-related cell lines. Aurora-A was also examined in 46 diffuse large B-cell lymphomas (DLBCLs). Aurora-A and hMPS1 mRNA expression levels were related to tumor proliferative activity. Interestingly, a MCL case with the highest number or chromosomal imbalances also showed an extremely high value of Aurora-A mRNA expression. No Aurora-A gene amplifications were detected in any tumor or cell line, whereas hemizygous hMPS1 gene deletions were observed in 23% of MCLs and 3 of the 4 cell lines. However, no expression alterations or gene mutations were detected in these cases. The Aurora-A proposed cancer susceptibility polymorphic variant (P31I) was observed with a similar frequency in MCL, DLBCL, chronic lymphocytic leukemia and in the 431 healthy controls. However, the 3 MCLs and 4 DLBCLs with the homozygous variant of this polymorphism had particular clinical characteristics with an unusual early-age presentation and second epithelial malignancies in MCL and extranodal origin in DLBCL. These findings indicate that Aurora-A and hMPS1 aberrations are uncommon in aggressive lymphomas but Aurora-A overexpression may contribute to numerical chromosomal alterations in occasional MCL. Although the Aurora-A P31I polymorphic variant is not directly involved in a genetic predisposition to these lymphomas, it may modulate the clinical presentation of these tumors. © 2005 Wiley-Liss, Inc. [source] Sister chromatid exchange and micronucleus studies in patients with Behçet's diseaseJOURNAL OF CUTANEOUS PATHOLOGY, Issue 8 2009Ali Karaman Background:, Genetic factors that predispose individuals to Behçet's disease (BD) are considered to play important roles in the development of the disease. The aim of this study was to determine, by counting sister chromatid exchange (SCE) and micronucleus (MN) frequencies, whether DNA damage have an effect on the pathogenesis of BD. Furthermore, our aim was to show if there is an association between oxidative stress and chromosome instability in BD. Methods:, We analyzed lymphocytes from patients with BD (16 in active and 14 in inactive periods) and 20 healthy controls for SCE and MN frequencies. In addition, malondialdehyde (MDA) level, superoxide dismutase (SOD) level, glutathione peroxidase (GSH-Px) activity, erythrocyte sedimentation rate (ESR) and polymorphonuclear leukocyte (PMNL) count were determined in the all subjects. Results:, The SCE and MN frequencies were significantly higher in both the active and inactive period patients than in the controls (p < 0.00001, p < 0.0001, p < 0.01 and p < 0.05, respectively), and the MDA level was significantly higher in both the active and inactive period patients than in the controls (p < 0.01 and p < 0.05, respectively). In contrast, the SOD and GSH-Px levels were significantly lower in both the active and inactive period patients than in the controls (p < 0.01, p < 0.05, p < 0.01 and p < 0.05, respectively). Conclusions:, Our results suggest that increased plasma MDA level and decreased plasma GSH-Px and SOD levels reflect the increased levels of oxidative stress in BD patients, and this situation may impair genetic stability in BD patients. [source] Combined BubR1 protein down-regulation and RASSF1A hypermethylation in Wilms tumors with diverse cytogenetic changesMOLECULAR CARCINOGENESIS, Issue 9 2008Masayuki Haruta Abstract BUB1B and RASSF1A genes play specific roles in the mitotic checkpoint, and their defects may cause chromosome instability or aneuploidy in mouse fibroblasts and human cancer cell lines; however, few studies have reported a correlation between defects in these genes and chromosome changes in human tumor samples. We examined chromosome abnormalities in 25 Wilms tumors by metaphase comparative genomic hybridization, and classified them into 14 hyperdiploid (50,,,chromosomes), 2 near-or-pseudodiploid, and 9 diploid tumors. We also examined various molecular aspects of BUB1B and RASSF1A, and evaluated the relationship between chromosome changes and the status of both genes. No tumors showed BUB1B mutation. BubR1 protein (BUB1B gene product) expression was undetectable or decreased in five of six hyperdiploid or near-or-pseudodiploid tumors and increased in four of five diploid tumors, whereas all seven tumors examined showed BUB1B mRNA expression irrespective of their chromosome pattern. Furthermore, while complete promoter methylation of RASSF1A was found in 13 of 16 hyperdiploid or near-or-pseudodiploid tumors, unmethylated RASSF1A was found in 5 of 9 diploid tumors. Partial RASSF1A methylation was found in three hyperdiploid or near-or-pseudodiploid tumors and in four diploid tumors. Thus, BubR1 protein expression decreased, and the promoter region of RASSF1A was completely methylated in the great majority of hyperdiploid or near-or-pseudodiploid tumors, BubR1 protein expression increased and RASSF1A was unmethylated in the majority of diploid tumors. These findings suggest that the combined BubR1 protein down-regulation and RASSF1A hypermethylation might be implicated in the formation of chromosomal changes found in Wilms tumors. © 2008 Wiley-Liss, Inc. [source] Frequency of sister chromatid exchanges in the lymphocytes of patients with atopic dermatitisTHE JOURNAL OF DERMATOLOGY, Issue 9 2006Ali KARAMAN ABSTRACT The combination of genetic susceptibility and environmental factors can induce allergic sensitization and subsequent local inflammation, resulting in atopic dermatitis (AD). Sister chromatid exchange (SCE) is a sensitive method that may reflect an instability in DNA or a deficiency in DNA repair. The aim of the present study was to investigate whether patients with AD have defects in DNA repair and whether SCE frequency can be used as a genetic marker in the pathogenesis of AD. Between September 2004 and July 2005, SCE was analyzed in the peripheral blood lymphocyte chromosomes of 32 patients with AD and 28 control subjects at the Dermatology Unit of Erzurum State Hospital. This study found that the SCE frequency was significantly increased in patients with AD (P < 0.00001). The prevalence of SCE was not correlated with patient age, sex, disease duration or AD disease severity. Our results indicate that increased chromosome instability may play an important role in the etiology of AD. [source] Induction of centrosome amplification and chromosome instability in p53 -deficient lung cancer cells exposed to benzo[a]pyrene diol epoxide (B[a]PDE),THE JOURNAL OF PATHOLOGY, Issue 3 2008K Shinmura Abstract Benzo[a]pyrene diol epoxide (B[a]PDE), the ultimate carcinogenic metabolite of benzo[a] pyrene, has been implicated in the mutagenesis of the p53 gene involved in smoking-associated lung cancer. To further understand the role of B[a]PDE in lung tumour progression, we investigated its effect on the numerical integrity of centrosomes and chromosome stability in lung cancer cells lacking p53. Exposure of p53 -deficient H1299 lung cancer cells to B[a]PDE resulted in S-phase arrest, leading to abnormal centrosome amplification. Analysis of H1299 cells stably expressing fluorescence-tagged centrin (a known centriolar marker) revealed that the centrosome amplification was primarily attributable to excessive centrosome duplication rather than to centriole splitting. Forced expression of POLK DNA polymerase, which has the ability to bypass B[a]PDE,guanine lesions in an error-free manner, suppressed the B[a]PDE-induced centrosome amplification. Fluorescence in situ hybridization analyses with probes specific for chromosomes 2, 3, and 16 revealed that B[a]PDE exposure also led to chromosome instability, which was likely to have resulted from centrosome amplification. We extended these findings to primary lung carcinomas containing non-functional p53, and found a strong association between centrosome amplification and a high level of B[a]PDE,DNA accumulation. Therefore B[a]PDE contributes to neoplasia by inducing centrosome amplification and consequent chromosome destabilization as well as its mutagenic activity. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [source] Strong HLA-DR antigen expression on cancer cells relates to better prognosis of colorectal cancer patients: Possible involvement of c-myc suppression by interferon-,in situCANCER SCIENCE, Issue 1 2006Kazuyuki Matsushita Strong HLA-DR antigen expression on cancer cells relates to better prognosis of colorectal cancer patients, although the precise mechanism is controversial. From an immunological point of view, HLA-DR antigen, induced by interferon (IFN)-,, is required for tumor-associated antigen recognition by CD4+ T cells. For instance, as reported previously, the expression of HLA-DR antigen in normal colorectal epithelium immediately adjacent to cancer coincided significantly with the existence of IFN-, mRNA in the tissue. From another aspect, IFN-, has been revealed to suppress c-myc expression in vivo through a stat1-dependent mechanism, which is important for cell growth, cell cycle and chromosome instability. In the present study, strong HLA-DR-positive expression on cancer cells was significantly related to better prognosis for colorectal cancer patients. High IFN-, mRNA expression in situ indicated significantly less activation of c-myc mRNA expression. Further, HLA-DR antigen expression in cancer cells, as well as Dukes stages, was an independent factor for better long-term survival by multivariate analysis. Taken together, IFN-,, which induces HLA-DR antigens on the cell surface, also suppresses c-myc expression in situ, and is a possible non-immunological mechanism involved in the better long-term survival of colorectal cancer patients. (Cancer Sci 2006; 97: 57, 63) [source] Human ovarian surface epithelial cells immortalized with hTERT maintain functional pRb and p53 expressionCELL PROLIFERATION, Issue 5 2007N. F. Li Normal human ovarian surface epithelial (OSE) cells, which are thought to be the origin of most of human ovarian carcinomas, have a very limited lifespan in culture. Establishment of immortalized OSE cell lines has, in the past, required inactivation of pRb and p53 functions. However, this often leads to increased chromosome instability during prolonged culture. Materials and Methods:,In this study, we have used a retroviral infection method to overexpress human telomerase reverse transcriptase (hTERT) gene, in primary normal OSE cells, under optimized culture conditions. Results:,In vitro and in vivo analysis of hTERT-immortalized cell lines confirmed their normal epithelial characteristics. Gene expression profiles and functional analysis of p16INK4A, p15INK4B, pRb and p53 confirmed the presence of their intact functions. Our study suggests that inactivation of pRb and p53 is not necessary for OSE immortalization. Furthermore, down-regulation of p15INK4B in the immortalized cells may indicate a functional role for this protein in them. Conclusion:,These immortal OSE cell lines are likely to be an important tool for studying human OSE biology and carcinogenesis. [source] Cornelia de Lange syndrome, cohesin, and beyondCLINICAL GENETICS, Issue 4 2009J Liu Cornelia de Lange syndrome (CdLS) (OMIM #122470, #300590 and #610759) is a dominant genetic disorder with multiple organ system abnormalities which is classically characterized by typical facial features, growth and mental retardation, upper limb defects, hirsutism, gastrointestinal and other visceral system involvement. Mutations in three cohesin proteins, a key regulator of cohesin, NIPBL, and two structural components of the cohesin ring SMC1A and SMC3, etiologically account for about 65% of individuals with CdLS. Cohesin controls faithful chromosome segregation during the mitotic and meiotic cell cycles. Multiple proteins in the cohesin pathway are also involved in additional fundamental biological events such as double-strand DNA break repair and long-range regulation of transcription. Moreover, chromosome instability was recently associated with defective sister chromatid cohesion in several cancer studies, and an increasing number of human developmental disorders is being reported to result from disruption of this pathway. Here, we will discuss the human disorders caused by alterations of cohesin function (termed ,cohesinopathies'), with an emphasis on the clinical manifestations of CdLS and mechanistic studies of the CdLS-related proteins. [source] | |||||||||||||||||||||||||