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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Premature ovarian failure (POF) is an heterogeneous syndrome. Among genetic causes, X monosomy as in Turner syndrome or X deletions and translocations are known to be responsible for POF. The genes involved in ovarian function, located on the X chromosome are still unknown. On the other hand, autosomal abnormalities have been identified in POF patients such as mutations of the FSH gene, the LH and FSH receptor genes, chromosome 3q containing the blepharophimosis gene, the ATM gene (Ataxia-telangiectasia gene). Mutations in the AIRE gene (responsible for APECED syndrome) can involve ovarian insufficiency. It is likely that studies on the function of the protein AIRE might improve our knowledge on follicular development. Furthermore, different mouse models of ovarian failure such as mouse lacking connexins or mice lacking GDF9 (growth derived factor 9), might increase our knowledge of ovarian failure. In the future, a better knowledge of the cellular and biochemical components involved in folliculogenesis and apoptosis should elucidate the mechanisms of POF.
Mol Cell Endocrinol 1998 Oct 25
PMID:Genes and premature ovarian failure. 992 2

In this report, the frequency of the G-->A transition polymorphism at nucleotide 5557 in exon 39 of the coding sequence of the gene mutated in ataxia-telangiectasia (ATM) was analysed. The frequency of the A and G alleles was estimated in the general population at 0. 15 and 0.85, respectively. This polymorphism can be identified by single-strand conformation polymorphism (SSCP) and by a simple and rapid Dde I digestion after polymerase chain reaction (PCR)-mediated site directed mutagenesis (PSDM).
Mol Cell Probes 1999 Feb
PMID:PCR-mediated detection of a polymorphism in the ATM gene. 1002 35

Microinjection of the restriction endonuclease HaeIII, which causes DNA double-strand breaks with blunt ends, induces nuclear accumulation of p53 protein in normal and xeroderma pigmentosum (XP) primary fibroblasts. In contrast, this induction of p53 accumulation is not observed in ataxia telangiectasia (AT) fibroblasts. HaeIII-induced p53 protein in normal fibroblasts is phosphorylated at serine 15, as determined by immunostaining with an antibody specific for phosphorylated serine 15 of p53. This phosphorylation correlates well with p53 accumulation. Treatment with lactacystin (an inhibitor of the proteasome) or heat shock leads to similar levels of p53 accumulation in normal and AT fibroblasts, but the p53 protein lacks a phosphorylated serine 15. Following microinjection of HaeIII into lactacystin-treated normal fibroblasts, lactacystin-induced p53 protein is phosphorylated at serine 15 and stabilized even in the presence of cycloheximide. However, neither stabilization nor phosphorylation at serine 15 is observed in AT fibroblasts under the same conditions. These results indicate the significance of serine 15 phosphorylation for p53 stabilization after DNA double-strand breaks and an absolute requirement for ATM in this phosphorylation process.
Mol Cell Biol 1999 Apr
PMID:Requirement of ATM in phosphorylation of the human p53 protein at serine 15 following DNA double-strand breaks. 1008 48

Both p53 and ATM are checkpoint regulators with roles in genetic stabilization and cancer susceptibility. ATM appears to function in the same DNA damage checkpoint pathway as p53. However, ATM's role in p53-dependent apoptosis and tumor suppression in response to cell cycle dysregulation is unknown. In this study, we tested the role of murine ataxia telangiectasia protein (Atm) in a transgenic mouse brain tumor model in which p53-mediated apoptosis results in tumor suppression. These p53-mediated activities are induced by tissue-specific inactivation of pRb family proteins by a truncated simian virus 40 large T antigen in brain epithelium. We show that p53-dependent apoptosis, transactivation, and tumor suppression are unaffected by Atm deficiency, suggesting that signaling in the DNA damage pathway is distinct from that in the oncogene-induced pathway. In addition, we show that Atm deficiency has no overall effect on tumor growth and progression in this model.
Mol Cell Biol 1999 Apr
PMID:Atm is dispensable for p53 apoptosis and tumor suppression triggered by cell cycle dysfunction. 1008 76

ATM, the gene mutated in ataxia-telangiectasia (A-T), mediates multiple cellular responses to DNA damage. A-T homozygotes have a high risk of cancer and exhibit spontaneous chromosomal instability, and cultured A-T cells react abnormally to ionizing radiation. We have developed an ATM antisense vector that confers an A-T phenotype on normal cells. An episomal antisense vector was created that contained a 1.3 kb segment of the ATM cDNA, and was transfected into normal human fibroblasts. Intracellular levels of ATM protein were typically reduced 10-fold in antisense-expressing (GM639-46alpha) clones. GM639-46alpha clones exhibited the low threshold for radiation-induced apoptosis, low clonogenic survival, and cell cycle defects normally seen in A-T cells. Transfection with the corresponding ATM sense strand vector had no effect on the behavior of normal cells, and neither vector affected the behavior of A-T cells. Our results demonstrate that interference with ATM gene expression recreates the A-T phenotype in normal cells, and provide functional evidence linking the ATM gene to cellular DNA damage responses. The ATM antisense vector should prove a useful tool for studying ATM function in a variety of normal, mutant, and malignant cell lines.
Int J Mol Med 1999 Jul
PMID:Human fibroblasts transfected with an ATM antisense vector respond abnormally to ionizing radiation. 1037 36

In complex with FKBP12, the immunosuppressant rapamycin binds to and inhibits the yeast TOR1 and TOR2 proteins and the mammalian homologue mTOR/FRAP/RAFT1. The TOR proteins promote cell cycle progression in yeast and human cells by regulating translation and polarization of the actin cytoskeleton. A C-terminal domain of the TOR proteins shares identity with protein and lipid kinases, but only one substrate (PHAS-I), and no regulators of the TOR-signaling cascade have been identified. We report here that yeast TOR1 has an intrinsic protein kinase activity capable of phosphorylating PHAS-1, and this activity is abolished by an active site mutation and inhibited by FKBP12-rapamycin or wortmannin. We find that an intact TOR1 kinase domain is essential for TOR1 functions in yeast. Overexpression of a TOR1 kinase-inactive mutant, or of a central region of the TOR proteins distinct from the FRB and kinase domains, was toxic in yeast, and overexpression of wild-type TOR1 suppressed this toxic effect. Expression of the TOR-toxic domain leads to a G1 cell cycle arrest, consistent with an inhibition of TOR function in translation. Overexpression of the PLC1 gene, which encodes the yeast phospholipase C homologue, suppressed growth inhibition by the TOR-toxic domains. In conclusion, our findings identify a toxic effector domain of the TOR proteins that may interact with substrates or regulators of the TOR kinase cascade and that shares sequence identity with other PIK family members, including ATR, Rad3, Mei-41, and ATM.
Mol Biol Cell 1999 Aug
PMID:Protein kinase activity and identification of a toxic effector domain of the target of rapamycin TOR proteins in yeast. 1043 10

The activation of the cysteine proteases with aspartate specificity, termed caspases, is of fundamental importance for the execution of programmed cell death. These proteases are highly specific in their action and activate or inhibit a variety of key protein molecules in the cell. Here, we study the effect of apoptosis on the integrity of two proteins that have critical roles in DNA damage signalling, cell cycle checkpoint controls, and genome maintenance-the product of the gene defective in ataxia telangiectasia, ATM, and the related protein ATR. We find that ATM but not ATR is specifically cleaved in cells induced to undergo apoptosis by a variety of stimuli. We establish that ATM cleavage in vivo is dependent on caspases, reveal that ATM is an efficient substrate for caspase 3 but not caspase 6 in vitro, and show that the in vitro caspase 3 cleavage pattern mirrors that in cells undergoing apoptosis. Strikingly, apoptotic cleavage of ATM in vivo abrogates its protein kinase activity against p53 but has no apparent effect on the DNA binding properties of ATM. These data suggest that the cleavage of ATM during apoptosis generates a kinase-inactive protein that acts, through its DNA binding ability, in a trans-dominant-negative fashion to prevent DNA repair and DNA damage signalling.
Mol Cell Biol 1999 Sep
PMID:Cleavage and inactivation of ATM during apoptosis. 1045 55

Cells derived from ataxia telangiectasia (A-T) patients show a prominent defect at chromosome ends in the form of chromosome end-to-end associations, also known as telomeric associations, seen at G(1), G(2), and metaphase. Recently, we have shown that the ATM gene product, which is defective in the cancer-prone disorder A-T, influences chromosome end associations and telomere length. A possible hypothesis explaining these results is that the defective telomere metabolism in A-T cells are due to altered interactions between the telomeres and the nuclear matrix. We examined these interactions in nuclear matrix halos before and after radiation treatment. A difference was observed in the ratio of soluble versus matrix-associated telomeric DNA between cells derived from A-T and normal individuals. Ionizing radiation treatment affected the ratio of soluble versus matrix-associated telomeric DNA only in the A-T cells. To test the hypothesis that the ATM gene product is involved in interactions between telomeres and the nuclear matrix, we examined such interactions in human cells expressing either a dominant-negative effect or complementation of the ATM gene. The phenotype of RKO colorectal tumor cells expressing ATM fragments containing a leucine zipper motif mimics the altered interactions of telomere and nuclear matrix similar to that of A-T cells. A-T fibroblasts transfected with wild-type ATM gene had corrected telomere-nuclear matrix interactions. Further, we found that A-T cells had different micrococcal nuclease digestion patterns compared to normal cells before and after irradiation, indicating differences in nucleosomal periodicity in telomeres. These results suggest that the ATM gene influences the interactions between telomeres and the nuclear matrix, and alterations in telomere chromatin could be at least partly responsible for the pleiotropic phenotypes of the ATM gene.
Mol Cell Biol 1999 Oct
PMID:Altered telomere nuclear matrix interactions and nucleosomal periodicity in ataxia telangiectasia cells before and after ionizing radiation treatment. 1049 Jun 33

The fission yeast Rad3p checkpoint protein is a member of the phosphatidylinositol 3-kinase-related family of protein kinases, which includes human ATMp. Mutation of the ATM gene is responsible for the disease ataxia-telangiectasia. The kinase domain of Rad3p has previously been shown to be essential for function. Here, we show that although this domain is necessary, it is not sufficient, because the isolated kinase domain does not have kinase activity in vitro and cannot complement a rad3 deletion strain. Using dominant negative alleles of rad3, we have identified two sites N-terminal to the conserved kinase domain that are essential for Rad3p function. One of these sites is the putative leucine zipper, which is conserved in other phosphatidylinositol 3-kinase-related family members. The other is a novel motif, which may also mediate Rad3p protein-protein interactions.
Mol Biol Cell 1999 Oct
PMID:Requirement of sequences outside the conserved kinase domain of fission yeast Rad3p for checkpoint control. 1051 62

The identification of breast cancer susceptibility genes, such as BRCA1, BRCA2, ATM, and p53, has been accompanied by the examination of the effects of radiation in combination with genetic mutations at these loci. Women at high risk for developing breast cancer may respond differently than the general population to low- and high-dose radiation exposures associated with screening and treatment. Epidemiologic studies are being performed to investigate the effects of radiation on subsequent breast cancer development in genetically predisposed individuals. Mouse strains with specific genetic modifications are being created to study the consequence of both inherited mutations and radiation on mammary gland carcinogenesis. Finally, studies investigating DNA damage-response pathways after radiation exposure are being performed. Recent work on the effects of several known or suspected breast cancer susceptibility genes, alone or in combination with radiation, is presented here, and directions for future research are considered.
Mol Carcinog 1999 Nov
PMID:Breast cancer: genetic predisposition and exposure to radiation. 1055 88


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