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PubMed2005

The TP53 mutational spectrum and frequency of CHEK2*1100delC in Li-Fraumeni-like kindreds.

Li-Fraumeni syndrome (LFS) is a dominantly inherited cancer predisposition syndrome characterized by a wide spectrum of neoplasms occurring at young age. Germline mutations in the TP53 tumor suppressor gene have been identified in approximately 71 of LFS patients and 22 of Li-Fraumeni-like (LFL) patients. Mutations within the cell cycle checkpoint gene CHEK2 have also been reported in some patients with LFS, LFL, and phenotypically suggestive of LFS (PS-LFS) not carrying a TP53 mutation. In this study, we show that 7 of the 23 patients with LFS/LFL tested positive for deleterious mutations in p53. Fifteen of the remaining sixteen were not found to carry the CHEK2* 1100delCmutation. These results indicate that CHEK2*1100delC is not a common cause of LFS, LFL, or PS-LFS in North American kindreds not carrying a TP53 mutation. Of note, two patients were found to carry p53* R72P, which is of unknown clinical significance. Lack of segregation of this allele in one of these kindreds provides strong evidence that the R72P allele is not disease-causing. While mutations in p53 account for a proportion of patients with LFS/LFL, future studies are needed to determine if other genes are responsible for LFS/LFL families not carrying germline p53 mutations.

Adolescent↗
PubMed2005

The CHEK2 1100delC allele is not relevant for risk assessment in HNPCC and HBCC Spanish families.

The frame-shift mutation 1100delC in the cell-cycle-checkpoint kinase 2 gene (CHEK2) has been reported to be a low penetrance breast cancer gene in Northern European populations. However, the variant may be relevant for breast cancer risk in other populations, due to its low prevalence. Recent studies have proposed a role for the mutation in colorectal cancer, finding a strong association between the CHEK21100delC mutation and hereditary breast and colorectal cancer (HBCC). A previous study suggested that the CHEK21100delC variant was not of clinical relevance in Spanish breast/ovarian cancer families. Here, we demonstrate that this genetic variant is not of clinical relevance for HNPCC and HBCC Spanish families.

Adult↗
PubMed2006

Effects of trichostatin A on HDAC8 expression, proliferation and cell cycle of Molt-4 cells.

The effects of Trichostatin A (TSA) on histone deacetylase 8 (HDAC8) expression, proliferation and cell cycle arrest in T-lymphoblastic leukemia cell line Molt-4 cells in vitro were investigated. The effect of TSA on the growth of Molt-4 cells was studied by MTT assay. Flow cytometry was used to examine the cell cycle. The expression of HDAC8 was detected by using immunocytochemistry and Western blot. The results showed that proliferation of Molt-4 cells was inhibited in TSA-treated group in a time- and dose-dependent manner. The IC50 of TSA exposures for 24 h and 36 h were 254.3236 and 199.257 microg/L respectively. The cell cycle analysis revealed that Molt-4 was mostly in G0/G1 phase, and after treatment with TSA from 50 to 400 microg/L for 24 h, the percents of G0/G1 cells were decreased and cells were arrested in G2/M phase. Treatment of TSA for 24 h could significantly inhibit the expression of HDAC8 protein in Molt-4 cells (P<0.01). It was concluded that TSA could decrease the expression of HDAC8 in Molt-4 cells, which contributed to the inhibition of proliferation and induction of cell cycle arrest in Molt-4 cells.

Cell Cycle Checkpoints↗
PubMed2006

The inhibitory action of long-chain fatty acids on the DNA binding activity of p53.

The in vitro relationship between human p53 DNA binding domain (p53 DBD) and FA was investigated. We found that saturated and monounsaturated long-chain FA inhibited the double-stranded DNA (dsDNA) binding activity of p53 DBD. The strongest inhibitors of saturated and unsaturated FA were docosanoic acid (22:0) and cis-12-heneicosenoic acid (21:1n-9), respectively. n-Octadecane, trans-unsaturated FA, and FAME had no influence on the binding activity of p53 DBD, showing that the FA structures such as one or no double bond of cis configuration, hydrocarbon chain of length C20 to C22, and free carboxyl groups are important for the inhibition. The inhibitory effect of the R248A mutant of p53 DBD by saturated FA was as strong as that for wild-type p53 DBD. On the other hand, the inhibition of dsDNA binding activity of the same mutant by the cis-configuration of monounsaturated FA was weaker than that for the wild type. These results suggest that R248 in p53 DBD is important for binding to monounsaturated FA. This is the first report that long-chain FA act as a dsDNA binding inhibitor of p53, and it could be considered that FA in the cell membrane might regulate the activity of p53 for cell division, cell-cycle checkpoint, and tumor suppression.

Computer Simulation↗
PubMed1996

The Saccharomyces cerevisiae kinetochore.

Accurate chromosome segregation is dependent on a specialized chromosomal structure, the kinetochore/centromere. The only essential constituent of the S. cerevisiae kinetochore established today is CBF3, a multisubunit complex that binds to S. cerevisiae centromere DNA. Therefore CBF3 and its four components, Cbf3a, Cbf3b, Cbf3c and Cbf3d, will form the centerpiece of this review. In addition, we will describe proteins that are putatively involved in kinetochore function specifically in the context with CBF3 interaction. Furthermore, we discuss the role of the S. cerevisiae kinetochores in a putative cell cycle checkpoint control and in microtubule attachment.

Base Sequence↗
PubMed1993

Lack of mutations in the P53 gene exons 5 to 8 in ataxia-telangiectasia.

Alterations of the TP53 tumor suppressor gene are present in various human malignancies and in the dominantly inherited Li-Fraumeni syndrome. Recently, a cell cycle checkpoint pathway involving p53 and GADD45 has been identified as defective in ataxia-telangiectasia. Using single strand conformation polymorphism analysis of PCR products, we looked for TP53 mutations in DNA of patients with AT. We did not find any mutation in 6 patients, suggesting that TP53 mutations are not directly involved in the cancer susceptibility observed in AT.

Ataxia Telangiectasia↗
PubMed2004

Analysis of familial male breast cancer for germline mutations in CHEK2.

We have previously shown that the1100delC variant of the cell-cycle-checkpoint kinase gene CHEK2, which is carried by approximately 1% of the population confers a two-fold increase in female breast cancer and a 10-fold increase in male breast cancer. To extend our knowledge on the role of CHEK2 in susceptibility to male breast cancer we have screened a series of 26 breast cancer cases with male representation for germline sequence variation in the CHEK2 gene. One individual was found to harbour the 1100delC variant. No other mutations were identified. Variants other than 1100delC are rare in male breast cancer.

Breast Neoplasms, Male↗
PubMed2004

DNA damage tumor suppressor genes and genomic instability.

Disruption of the mechanisms that regulate cell-cycle checkpoints, DNA repair, and apoptosis results in genomic instability and the development of cancer in multicellular organisms. The protein kinases ATM and ATR, as well as their downstream substrates Chk1 and Chk2, are central players in checkpoint activation in response to DNA damage. Histone H2AX, ATRIP, as well as the BRCT-motif-containing molecules 53BP1, MDC1, and BRCA1 function as molecular adapters or mediators in the recruitment of ATM or ATR and their targets to sites of DNA damage. The increased chromosomal instability and tumor susceptibility apparent in mutant mice deficient in both p53 and either histone H2AX or proteins that contribute to the nonhomologous end-joining mechanism of DNA repair indicate that DNA damage checkpoints play a pivotal role in tumor suppression.

Animals↗
PubMed2005

DNA repair disorders causing malformations.

DNA damage contributes significantly to the abnormal development or demise of the conceptus. The widely differing phenotypes that result from mutations in DNA repair genes suggest that these genes play critical roles during development, even in the absence of exogenous DNA-damaging agents. Molecules that sense DNA damage and regulate DNA repair, cell cycle checkpoints and apoptosis act as teratogen suppressor genes, protecting the conceptus against insult from DNA damaging teratogens.

Adenosine Diphosphate Ribose↗
PubMed2005

Mathematical modelling of radiotherapy strategies for early breast cancer.

Targeted intraoperative radiotherapy (Targit) is a new concept of partial breast irradiation where single fraction radiotherapy is delivered directly to the tumour bed. Apart from logistic advantages, this strategy minimizes the risk of missing the tumour bed and avoids delay between surgery and radiotherapy. It is presently being compared with the standard fractionated external beam radiotherapy (EBRT) in randomized trials. In this paper we present a mathematical model for the growth and invasion of a solid tumour into a domain of tissue (in this case breast tissue), and then a model for surgery and radiation treatment of this tumour. We use the established linear-quadratic (LQ) model to compute the survival probabilities for both tumour cells and irradiated breast tissue and then simulate the effects of conventional EBRT and Targit. True local recurrence of the tumour could arise either from stray tumour cells, or the tumour bed that harbours morphologically normal cells having a predisposition to genetic changes, such as a loss of heterozygosity (LOH) in genes that are crucial for tumourigenesis, e.g. tumour suppressor genes (TSGs). Our mathematical model predicts that the single high dose of radiotherapy delivered by Targit would result in eliminating all these sources of recurrence, whereas the fractionated EBRT would eliminate stray tumour cells, but allow (by virtue of its very schedule) the cells with LOH in TSGs or cell-cycle checkpoint genes to pass on low-dose radiation-induced DNA damage and consequently mutations that may favour the development of a new tumour. The mathematical model presented here is an initial attempt to model a biologically complex phenomenon that has until now received little attention in the literature and provides a 'proof of principle' that it is possible to produce clinically testable hypotheses on the effects of different approaches of radiotherapy for breast cancer.

Brachytherapy↗
PubMed2005

Solar ultraviolet radiation-induced DNA damage in aquatic organisms: potential environmental impact.

Continuing depletion of stratospheric ozone and subsequent increases in deleterious ultraviolet (UV) radiation at the Earth's surface have fueled the interest in its ecological consequences for aquatic ecosystems. The DNA is certainly one of the key targets for UV-induced damage in a variety of aquatic organisms. UV radiation induces two of the most abundant mutagenic and cytotoxic DNA lesions, cyclobutane pyrimidine dimers (CPDs) and pyrimidine pyrimidone photoproducts (6-4PPs) and their Dewar valence isomers. However, aquatic organisms have developed a number of repair and tolerance mechanisms to counteract the damaging effects of UV on DNA. Photoreactivation with the help of the enzyme photolyase is one of the most important and frequently occurring repair mechanisms in a variety of organisms. Excision repair, which can be distinguished into base excision repair (BER) and nucleotide excision repair (NER), also play an important role in DNA repair in several organisms with the help of a number of glycosylases and polymerases, respectively. In addition, mechanisms such as mutagenic repair or dimer bypass, recombinational repair, cell-cycle checkpoints, apoptosis and certain alternative repair pathways are also operative in various organisms. This review deals with the UV-induced DNA damage and repair in a number of aquatic organisms as well as methods of detecting DNA damage.

Animals↗
PubMed2005

Regulation of DNA damage recognition and nucleotide excision repair: another role for p53.

In response to DNA damage, the p53 tumor suppressor gene product is activated leading to the induction of several downstream cellular processes including cell cycle checkpoints, DNA repair or apoptosis. Experiments first performed in the Hanawalt laboratory identified a p53-dependent pathway affecting global genomic nucleotide excision repair. The mechanisms involved in this process include both transcriptional and post-translational regulation by p53 of the DDB2 and XPC gene products, two critical DNA damage recognition proteins required for GGR. A historical review of this work is presented.

DNA Damage↗
PubMed2004

p53's double life: transactivation-independent repression of homologous recombination.

The tumor suppressor protein p53 controls cell cycle checkpoints and apoptosis via the transactivation of several genes. However, data from various laboratories suggest an additional role for p53: transcription-independent suppression of homologous recombination (HR). Genetic and physical interactions among p53, HR proteins (e.g. RAD51 and RAD54) and HR-DNA intermediates show that p53 acts directly on HR during the early and late steps of recombination. Complementary to the MSH2 mismatch-repair system, p53 appears to impair excess HR by controlling the minimal efficiency processing segment and by reversing recombination intermediates. By controlling the balance between the BLM and the RAD51 pathways, this direct role of p53 could maintain genome stability when replication forks are stalled at regions of DNA damage. In this article, we discuss the direct role of p53 on HR and the consequences for genome stability, tumor protection and speciation.

Animals↗
PubMed2002

Recombinational DNA repair and human disease.

We review the genes and proteins related to the homologous recombinational repair (HRR) pathway that are implicated in cancer through either genetic disorders that predispose to cancer through chromosome instability or the occurrence of somatic mutations that contribute to carcinogenesis. Ataxia telangiectasia (AT), Nijmegen breakage syndrome (NBS), and an ataxia-like disorder (ATLD), are chromosome instability disorders that are defective in the ataxia telangiectasia mutated (ATM), NBS, and Mre11 genes, respectively. These genes are critical in maintaining cellular resistance to ionizing radiation (IR), which kills largely by the production of double-strand breaks (DSBs). Bloom syndrome involves a defect in the BLM helicase, which seems to play a role in restarting DNA replication forks that are blocked at lesions, thereby promoting chromosome stability. The Werner syndrome gene (WRN) helicase, another member of the RecQ family like BLM, has very recently been found to help mediate homologous recombination. Fanconi anemia (FA) is a genetically complex chromosomal instability disorder involving seven or more genes, one of which is BRCA2. FA may be at least partially caused by the aberrant production of reactive oxidative species. The breast cancer-associated BRCA1 and BRCA2 proteins are strongly implicated in HRR; BRCA2 associates with Rad51 and appears to regulate its activity. We discuss in detail the phenotypes of the various mutant cell lines and the signaling pathways mediated by the ATM kinase. ATM's phosphorylation targets can be grouped into oxidative stress-mediated transcriptional changes, cell cycle checkpoints, and recombinational repair. We present the DNA damage response pathways by using the DSB as the prototype lesion, whose incorrect repair can initiate and augment karyotypic abnormalities.

Ataxia Telangiectasia↗
PubMed2000

Incidence of p14ARF gene deletion in high-grade adult and pediatric astrocytomas.

The INK4a-ARF locus encodes 2 separate proteins through differential splicing of alternative first exons to produce p16INK4a (exon 1alpha) and p14ARF (exon 1beta) products in human cells. The p16INK4a protein inhibits the cyclin D-dependent kinases (CDK) that control the phosphorylation of the Rb protein and cell proliferation. The p14ARF gene product can complex with and sequester the MDM2 protein within the nucleus, thus modulating the activity of the p53 protein. Loss of p16INK4a expression would disrupt the retinoblastoma (Rb)/p16INK4a/cyclin D-dependent kinase (CDK4) pathway, whereas loss of p14ARF expression would inactivate both the Rb and p53/ MDM2/p14ARF pathways through MDM2, which can complex with either Rb or p53. Loss of the p16INK4a gene on 9p21 has been documented in a wide range of human tumors, including one third of glioblastomas. However, in tumors showing homozygous loss of exon 2 of the p16INK4a gene, loss of exon 1beta of the p14ARF gene has not been established. In this study, we have assessed deletion of the p14ARF gene in 29 pediatric and 107 adult high-grade astrocytomas and 9 glioma cell lines, using multiplex PCR analysis for exon 1beta. We found homozygous deletions for exon 1alpha and exon 1beta in 3 of 29 (10%) of the pediatric cases (2 grade III, 1 grade IV), 25 of 107 (23%) of the adult cases (6 grade III and 19 grade IV), and 8 of 9 (89%) of the glioma cell lines. Therefore, loss of the INK4a-ARF locus in high-grade astrocytomas may contribute to the highly malignant behavior and treatment resistance of these tumors through elimination of multiple checkpoint cell cycle control proteins.

Adult↗
PubMed2001

BRCA1-associated tumorigenesis: what have we learned from knockout mice?

A series of allelic mutations in the tumor suppressor Brca1 have been created to study mechanisms underlying BRCA1-associated tumorigenesis. Brca1 is essential in maintaining genome integrity through its involvement in DNA damage repair, G(2)-M cell-cycle checkpoint and centrosome duplication. The loss of Brca1 is not sufficient for malignant transformation, rather, it triggers multiple genetic alterations, including the inactivation of p53 and activation of a number of oncogenes, that ultimately result in mammary tumorigenesis.

Alleles↗
PubMed1997

Preimplantation genetic diagnosis: strategies and surprises.

Several inherited diseases can now be diagnosed by genetic analysis of single cells biopsied from human eggs and preimplantation embryos following in vitro fertilization (IVF). 'At risk' couples can, therefore, have only unaffected embryos replaced in the uterus and avoid the possibility of terminating a pregnancy that might only be diagnosed as affected later is gestation. Single-cell genetic analysis has also provided powerful tools for studying genetic defects arising during early human development. Recent studies of cleavage-stage human embryos have revealed an unexpectedly high incidence of postzygotic chromosomal abnormalities, which might arise because of a lack of cell-cycle checkpoints before the embryonic genome is activated. These genetic abnormalities are likely to contribute to early pregnancy loss and have important implications for improving pregnancy rates in infertile couples by assisted reproduction.

Chromosome Aberrations↗
PubMed2000

Accumulation of tumor suppressor p53 in rat muscle after a space flight.

Tumor suppressor p53 functions as a cell cycle checkpoint under stressful conditions. Early studies have shown that genotoxic stress activates p53 pathway. Recently, many kinds of non-genotoxic stress such as heat shock, cold shock, and low pH also have been found to activate p53 pathway. The effects on living organism remains to be explored. Here, we show that an 18-day space flight induced a 3.6 fold accumulation of p53 in rat skeletal muscle. This results suggests that the p53 pathway plays a role in safeguarding genomic stability against the stressful space environments and supports our previous observation of p53 accumulation in rat skin after a space flight.

Animals↗