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PubMed2000

Atm and Bax cooperate in ionizing radiation-induced apoptosis in the central nervous system.

Ataxia-telangiectasia is a hereditary multisystemic disease resulting from mutations of ataxia telangiectasia, mutated (ATM) and is characterized by neurodegeneration, cancer, immune defects, and hypersensitivity to ionizing radiation. The molecular details of ATM function in the nervous system are unclear, although the neurological lesion in ataxia-telangiectasia becomes apparent early in life, suggesting a developmental origin. The central nervous system (CNS) of Atm-null mice shows a pronounced defect in apoptosis induced by genotoxic stress, suggesting ATM functions to eliminate neurons with excessive genomic damage. Here, we report that the death effector Bax is required for a large proportion of Atm-dependent apoptosis in the developing CNS after ionizing radiation (IR). Although many of the same regions of the CNS in both Bax-/- and Atm-/- mice were radioresistant, mice nullizygous for both Bax and Atm showed additional reduction in IR-induced apoptosis in the CNS. Therefore, although the major IR-induced apoptotic pathway in the CNS requires Atm and Bax, a p53-dependent collateral pathway exists that has both Atm- and Bax-independent branches. Further, Atm- and Bax-dependent apoptosis in the CNS also required caspase-3 activation. These data implicate Bax and caspase-3 as death effectors in neurodegenerative pathways.

Animals↗

PubMed1996

The product of the ATM gene is a 370-kDa nuclear phosphoprotein.

Neuronal degeneration, gonadal abnormalities, and immune deficiency are some of the major manifestations of the hereditary disease ataxia telangiectasia, which is caused by mutations in a single gene, designated ATM. Here we show that the product of the ATM gene is a 370-kDa nuclear phosphoprotein. Because ATM knockout mice recapitulate the clinical symptoms of the human disease, we have examined ATM gene expression in mice. In mouse embryos at gestation day 13.5, ATM mRNA is expressed ubiquitously, with high levels detected in the nervous system and lung. Elevated ATM mRNA levels were also found in the thymus of mouse embryos at gestation day 18.5, a time when V(D)J recombination is occurring. In adult mice, ATM protein was detected in all tissues examined and was present at elevated levels in the testis, spleen, and thymus. The ATM expression pattern and the nuclear localization of the ATM protein are consistent with the proposed function of ATM in the activation of cell cycle checkpoints, DNA repair, and genetic recombination.

Adult↗

PubMed2000

Regulation of DNA-dependent protein kinase activity by ionizing radiation-activated abl kinase is an ATM-dependent process.

Ionizing radiation (IR) treatment results in activation of the nonreceptor tyrosine kinase c-Abl because of phosphorylation by ATM. In vitro evidence indicates that DNA-dependent protein kinase (DNA-PK) can also phosphorylate and thus potentially activate Abl kinase activity in response to IR exposure. To unravel the role of ATM and DNA-PK in the activation of Abl, we assayed Abl, ATM, and DNA-PK activity in ATM- and DNA-PKcs-deficient cells after irradiation. Our results show that despite the presence of higher than normal levels of DNA-PK kinase activity, c-Abl fails to become activated after IR exposure in ATM-deficient cells. Conversely, normal activation of both ATM and c-Abl occurs in DNA-PKcs-deficient cells, indicating that ATM but not DNA-PK is required for activation of Abl in response to IR treatment. Moreover, activation of Abl kinase activity by IR correlates well with activation of ATM activity in all phases of the cell cycle. These results indicate that ATM is primarily responsible for activation of Abl in response to IR exposure in a cell cycle-independent fashion. Examination of DNA-PK activity in response to IR treatment in Abl-deficient cells expressing mutant forms of Abl or in normal cells exposed to an inhibitor of Abl suggests an in vivo role for Abl in the down-regulation of DNA-PK activity. Collectively, these results suggest a convergence of the ATM and DNA-PK pathways in the cellular response to IR through c-Abl kinase.

Animals↗

PubMed2003

Ataxia-telangiectasia-mutated (ATM) and NBS1-dependent phosphorylation of Chk1 on Ser-317 in response to ionizing radiation.

In mammals, the ATM (ataxia-telangiectasia-mutated) and ATR (ATM and Rad3-related) protein kinases function as critical regulators of the cellular DNA damage response. The checkpoint functions of ATR and ATM are mediated, in part, by a pair of checkpoint effector kinases termed Chk1 and Chk2. In mammalian cells, evidence has been presented that Chk1 is devoted to the ATR signaling pathway and is modified by ATR in response to replication inhibition and UV-induced damage, whereas Chk2 functions primarily through ATM in response to ionizing radiation (IR), suggesting that Chk2 and Chk1 might have evolved to channel the DNA damage signal from ATM and ATR, respectively. We demonstrate here that the ATR-Chk1 and ATM-Chk2 pathways are not parallel branches of the DNA damage response pathway but instead show a high degree of cross-talk and connectivity. ATM does in fact signal to Chk1 in response to IR. Phosphorylation of Chk1 on Ser-317 in response to IR is ATM-dependent. We also show that functional NBS1 is required for phosphorylation of Chk1, indicating that NBS1 might facilitate the access of Chk1 to ATM at the sites of DNA damage. Abrogation of Chk1 expression by RNA interference resulted in defects in IR-induced S and G(2)/M phase checkpoints; however, the overexpression of phosphorylation site mutant (S317A, S345A or S317A/S345A double mutant) Chk1 failed to interfere with these checkpoints. Surprisingly, the kinase-dead Chk1 (D130A) also failed to abrogate the S and G(2) checkpoint through any obvious dominant negative effect toward endogenous Chk1. Therefore, further studies will be required to assess the contribution made by phosphorylation events to Chk1 regulation. Overall, the data presented in the study challenge the model in which Chk1 only functions downstream from ATR and indicate that ATM does signal to Chk1. In addition, this study also demonstrates that Chk1 is essential for IR-induced inhibition of DNA synthesis and the G(2)/M checkpoint.

Ataxia Telangiectasia Mutated Proteins↗

PubMed2001

Extra-chromosomal telomeric DNA in cells from Atm(-/-) mice and patients with ataxia-telangiectasia.

Ataxia-telangiectasia (AT) is an autosomally recessive human genetic disease with pleiotropic defects such as neurological degeneration, immunodeficiency, chromosomal instability, cancer susceptibility and premature aging. Cells derived from AT patients and ataxia-telangiectasia mutated (ATM)-deficient mice show slow growth in culture and premature senescence. ATM, which belongs to the PI3 kinase family along with DNA-PK, plays a major role in signaling the p53 response to DNA strand breaks. Telomere maintenance is perturbed in yeast strains lacking genes homologous to ATM and cells from patients with AT have short telomeres. We examined the length of individual telomeres in cells from ATM(-/-) mice by fluorescence in situ hybridization. Telomeres were extensively shortened in multiple tissues of ATM(-/-) mice. More than the expected number of telomere signals was observed in interphase nuclei of ATM(-/-) mouse fibroblasts. Signals corresponding to 5-25 kb of telomeric DNA that were not associated with chromosomes were also noticed in ATM(-/-) metaphase spreads. Extrachromosomal telomeric DNA was also detected in fibroblasts from AT patients and may represent fragmented telomeres or by-products of defective replication of telomeric DNA. These results suggest a role of ATM in telomere maintenance and replication, which may contribute to the poor growth of ATM(-/-) cells and increased tumor incidence in both AT patients and ATM(-/-) mice.

Animals↗

PubMed2002

Dominant negative ATM mutations in breast cancer families.

BACKGROUND: The ATM gene encoding a putative protein kinase is mutated in ataxia-telangiectasia (A-T), an autosomal recessive disorder with a predisposition for cancer. Studies of A-T families suggest that female heterozygotes have an increased risk of breast cancer compared with noncarriers. However, neither linkage analyses nor mutation studies have provided supporting evidence for a role of ATM in breast cancer predisposition. Nevertheless, two recurrent ATM mutations, T7271G and IVS10-6T-->G, reportedly increase the risk of breast cancer. We examined these two ATM mutations in a population-based, case-control series of breast cancer families and multiple-case breast cancer families. METHODS: Five hundred twenty-five or 262 case patients with breast cancer and 381 or 68 control subjects, respectively, were genotyped for the T7271G and IVS10-6T-->G ATM mutations, as were index patients from 76 non-BRCA1/2 multiple-case breast cancer families. Linkage and penetrance were analyzed. ATM protein expression and kinase activity were analyzed in lymphoblastoid cell lines from mutation carriers. All statistical tests were two-sided. RESULTS: In case and control subjects unselected for family history of breast cancer, one case patient had the T7271G mutation, and none had the IVS10-6T-->G mutation. In three multiple-case families, one of these two mutations segregated with breast cancer. The estimated average penetrance of the mutations was 60% (95% confidence interval [CI] = 32% to 90%) to age 70 years, equivalent to a 15.7-fold (95% CI = 6.4-fold to 38.0-fold) increased relative risk compared with that of the general population. Expression and activity analyses of ATM in heterozygous cell lines indicated that both mutations are dominant negative. CONCLUSION: At least two ATM mutations are associated with a sufficiently high risk of breast cancer to be found in multiple-case breast cancer families. Full mutation analysis of the ATM gene in such families could help clarify the role of ATM in breast cancer susceptibility.

Ataxia Telangiectasia Mutated Proteins↗

PubMed2004

Expression of ATM protein and its relationship with p53 in pancreatic carcinoma with tissue array.

ATM protein anticipates in the initiation of the DNA repair signal pathway and also mediates cell cycle arrest and repair. ATM deficiency predictably results in radiosensitivity, germ cell degeneration, chromosomal instability, immunodeficiency, and an extreme predisposition to tumors. Moreover, studies found that ATM is the upstream gene of the p53 pathway and would phosphorylate p53 directly after DNA damage, which would suppress tumorigenesis. Expression of ATM and p53 in 167 pancreatic cancer and 101 control specimens, benign lesions, and normal pancreata were detected by high-throughput tissue microarray and immunohistochemistry while seeking the role of ATM in the initiation and development of pancreatic carcinoma as well as its relationship with p53. We found that the positive rates of ATM and p53 expression in pancreatic carcinoma and its relative control specimen were 67.7% (113/167) and 82.2% (83/101) (P < 0.05) and 57.5% (96/167) and 5.0% (5/101) (P < 0.01), respectively. ATM positive staining is significantly relative to age and infiltration (P < 0.05), while the expression of p53 was significantly associated with tumor differentiation, lymph node metastasis, and nerve infiltration (P < 0.05). Expression of ATM and p53 was positively correlated. These findings suggest that expression of ATM deficiency may increase the transformative ability of pancreatic cancer cells. ATM may also cooperate with p53 in the repair of cell damage.

Adult↗

PubMed1996

Targeted disruption of ATM leads to growth retardation, chromosomal fragmentation during meiosis, immune defects, and thymic lymphoma.

ATM, the gene mutated in the inherited human disease ataxia-telangiectasia, is a member of a family of kinases involved in DNA metabolism and cell-cycle checkpoint control. To help clarify the physiological roles of the ATM protein, we disrupted the ATM gene in mice through homologous recombination. Initial evaluation of the ATM knockout animals indicates that inactivation of the mouse ATM gene recreates much of the phenotype of ataxia-telangiectasia. The homozygous mutant (ATM-/-) mice are viable, growth-retarded, and infertile. The infertility of ATM-/- mice results from meiotic failure. Meiosis is arrested at the zygotene/pachytene stage of prophase I as a result of abnormal chromosomal synapsis and subsequent chromosome fragmentation. Immune defects also are evident in ATM-/- mice, including reduced numbers of B220+CD43- pre-B cells, thymocytes, and peripheral T cells, as well as functional impairment of T-cell-dependent immune responses. The cerebella of ATM-/- mice appear normal by histologic examination at 3 to 4 months and the mice have no gross behavioral abnormalities. The majority of mutant mice rapidly develop thymic lymphomas and die before 4 months of age. These findings indicate that the ATM gene product plays an essential role in a diverse group of cellular processes, including meiosis, the normal growth of somatic tissues, immune development, and tumor suppression.

Animals↗

PubMed2006

ATM activation by a sulfhydryl-reactive inflammatory cyclopentenone prostaglandin.

ATM (ataxia-telangiectasia mutated) is activated by a variety of noxious agent, including oxidative stress, and ATM deficiency results in an anomalous cellular response to oxidative stress. However, the mechanisms for ATM activation by oxidative stress remain to be established. Furthermore, it is not clear whether ATM responds to oxidative DNA damage or to a change in the intracellular redox state, independent of DNA damage. We found that ATM is activated by N-methyl-N'-nitro-nitrosoguanidine (MNNG) and 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), in NBS1- or MSH6-deficient cells. We further found that ATM is activated by treating chromatin-free immunoprecipitated ATM with MNNG or 15d-PGJ(2), which modifies free sulfhydryl (SH) groups, and that 15d-PGJ(2) binds covalently to ATM. Interestingly, 15d-PGJ(2)-induced ATM activation leads to p53 activation and apoptosis, but not to Chk2 or H2AX phosphorylation. These results indicate that ATM is activated through the direct modification of its SH groups, independent of DNA damage, and this activation leads, downstream, to apoptosis.

Animals↗

PubMed2002

ATM mutations are associated with inactivation of the ARF-TP53 tumor suppressor pathway in diffuse large B-cell lymphoma.

The ATM serine-threonine kinase plays a central role in the cellular response to DNA damage. Germ-line mutations in the ATM gene cause ataxia-telangiectasia (A-T), a multisystem disorder associated with predisposition to lymphoma and acute leukemia. Moreover, somatic ATM mutations have been identified in T-cell prolymphocytic leukemia, mantle cell lymphoma, and B-cell chronic lymphocytic leukemia. In this study, the entire ATM coding sequence was examined in genomic DNA from 120 lymphoid neoplasms. Novel mutations and mutations implicated in cancer and/or A-T were found in 9 of 45 diffuse large B-cell lymphomas (DLBCLs), 2 of 24 follicular lymphomas, and 1 of 27 adult acute lymphoblastic leukemias, whereas no such mutations were detected among 24 peripheral T-cell lymphomas. The mutational spectrum consisted of 2 nonsense mutations, 1 mutation affecting RNA splicing, and 10 missense variants. Most of these mutations were associated with loss or mutation of the paired ATM allele, consistent with biallelic inactivation of ATM. Of the 9 DLBCLs with ATM mutations, 7 also carried TP53 mutations and/or deletions of the INK4a/ARF locus (P =.003). The ATM 735C>T substitution previously considered a rare normal variant was found to be 5.6 times more frequent in individuals with DLBCL than in random individuals (P =.026), suggesting that it may predispose to B-cell lymphoma. Our data suggest that ATM mutations contribute to the development of DLBCL, and that ATM and the ARF-p53 tumor suppressor pathway may cooperate in the pathogenesis of this malignancy.

Adult↗

PubMed2004

Atm heterozygous deficiency enhances development of mammary carcinomas in p53 heterozygous knockout mice.

INTRODUCTION: Ataxia-telangiectasia is an autosomal-recessive disease that affects neuro-immunological functions, associated with increased susceptibility to malignancy, chromosomal instability and hypersensitivity to ionizing radiation. Although ataxia-telangiectasia mutated (ATM) heterozygous deficiency has been proposed to increase susceptibility to breast cancer, some studies have not found excess risk. In experimental animals, increased susceptibility to breast cancer is not observed in the Atm heterozygous deficient mice (Atm+/-) carrying a knockout null allele. In order to determine the effect of Atm heterozygous deficiency on mammary tumourigenesis, we generated a series of Atm+/- mice on the p53+/- background with a certain predisposition to spontaneous development of mammary carcinomas, and we examined the development of the tumours after X-irradiation. METHODS: BALB/cHeA-p53+/- mice were crossed with MSM/Ms-Atm+/- mice, and females of the F1 progeny ([BALB/cHeA x MSM/Ms]F1) with four genotypes were used in the experiments. The mice were exposed to X-rays (5 Gy; 0.5 Gy/min) at age 5 weeks. RESULTS: We tested the effect of haploinsufficiency of the Atm gene on mammary tumourigenesis after X-irradiation in the p53+/- mice of the BALB/cHeA x MSM/Ms background. The singly heterozygous p53+/- mice subjected to X-irradiation developed mammary carcinomas at around 25 weeks of age, and the final incidence of mammary carcinomas at 39 weeks was 31% (19 out of 61). The introduction of the heterozygous Atm knockout alleles into the background of the p53+/- genotype significantly increased the incidence of mammary carcinoma to 58% (32 out of 55) and increased the average number of mammary carcinomas per mouse. However, introduction of Atm alleles did not change the latency of development of mammary carcinoma. CONCLUSION: Our results indicate a strong enhancement in mammary carcinogenesis by Atm heterozygous deficiency in p53+/- mice. Thus, doubly heterozygous mice represent a useful model system with which to analyze the interaction of heterozygous genotypes for p53, Atm and other genes, and their effects on mammary carcinogenesis.

Animals↗

PubMed2000

Rescue of defective T cell development and function in Atm-/- mice by a functional TCR alpha beta transgene.

The Atm-/- mice recapitulate most of the defects observed in ataxia-telangiectasia (A-T) patients, including a high incidence of lymphoid tumors and immune defects characterized by defective T cell differentiation, thymus hypoplasia, and defective T-dependent immune responses. To understand the basis of the T cell developmental defects in Atm-/- mice, a functional TCR alpha beta transgene was introduced into these mutant mice. Analysis of the Atm-/-TCR alpha beta+ mice indicated that the transgenic TCR alpha beta can rescue the defective T cell differentiation and partially rescue the thymus hypoplasia in Atm-/- mice, indicating that thymocyte positive selection is normal in the Atm-/- mice. In addition, cell cycle analysis of the thymocytes derived from Atm-/-TCR alpha beta+ and control mice suggested that Atm is involved in the thymocyte expansion. Finally, evaluation of the T-dependent immune responses in Atm-/-TCR alpha beta+ mice indicated that Atm is dispensable for normal T cell function. Therefore, the defective T-dependent immune responses in Atm-/- mice must be secondary to greatly reduced T cell numbers in these mutant mice.

Animals↗

PubMed2005

The Mre11/Rad50/Nbs1 complex and its role as a DNA double-strand break sensor for ATM.

Double-strand breaks (DSBs) in chromosomal DNA elicit a rapid signaling response through the ATM protein kinase. Recent evidence suggests that the DNA repair complex containing Mre11, Rad50 and Nbs1 (MRN) is important for the activation of ATM by DSBs in cells. Our studies of the effects of MRN on ATM activity in vitro indicated that MRN stimulates ATM through multiple protein-protein contacts, and that this interaction increases the affinity of ATM for its substrates. Recently we isolated dimeric forms of ATM, which require MRN for activity but also require DNA, similar to the requirements for ATM activation and activity in vivo. Here we discuss the distinct characteristics of dimeric ATM, the role of MRN in recruiting ATM to DNA, the importance of DNA unwinding by MRN, and the role of autophosphorylation in ATM activation.

Acid Anhydride Hydrolases↗

PubMed2000

Role for ATM in DNA damage-induced phosphorylation of BRCA1.

The human genetic disorder ataxia-telangiectasia is characterized by immunodeficiency, progressive cerebellar ataxia, radiosensitivity, cell cycle checkpoint defects, and cancer predisposition. The gene product [ataxia-telangiectasia mutation (ATM)] mutated in this syndrome is a component of the DNA damage detection pathway. Loss of ATM function in human and mouse cells causes defects in DNA repair and cell cycle checkpoint control and, not surprisingly, humans and mice with compromised ATM function are prone to cancers. An excess of breast cancer in the relatives of ataxia-telangiectasia patients has also been reported by epidemiological studies. Predisposition to breast and ovarian cancers is also observed in women with germline mutations in BRCA1, a tumor suppressor gene. BRCA1 is a nuclear protein with a cell cycle-regulated expression pattern and is hyperphosphorylated in response to DNA-damaging agents. Here we show that rapid ionizing radiation-induced in vivo phosphorylation of BRCA1 requires the presence of functional ATM protein. Furthermore, we show that ATM interacts with BRCA1, and this association is enhanced by radiation. We also demonstrate that BRCA1 is a substrate of ATM kinase in vitro and in vivo. Using phospho-specific antibodies against serines 1387, 1423, and 1457 of BRCA1, we demonstrate radiation-induced, ATM-dependent phosphorylation of BRCA1 at these sites. These findings show that BRCA1 is regulated by an ATM-dependent mechanism as a part of the cellular response to DNA damage. This interaction between ATM and BRCA1 argues in favor of the involvement of particular aspects of ATM function in breast cancer predisposition.

Ataxia Telangiectasia↗

PubMed2000

Abnormal expression of the ATM and TP53 genes in sporadic breast carcinomas.

The ataxia telangiectasia gene (ATM) has been implicated as a risk factor in the development of sporadic breast carcinomas. ATM protein expression was analyzed by immunohistochemistry in 17 breast carcinomas with two monoclonal antibodies whose immunohistochemical use was first validated by comparing the immunoreactivity observed in spleen samples from ataxia telangiectasia and trauma patients. In normal breast ducts, ATM showed nuclear expression in the epithelial but not in the myoepithelial cells. In contrast, this nuclear expression was absent or low in the epithelial cancer cells in 10 of 17 (59%) of the tumors studied. Allelic imbalance in the ATM gene was found in three of seven tumors examined. Two of these showed reduced ATM protein expression, but this did not correlate with the presence of ATM mutations in the tumor DNA detected by restriction endonuclease fingerprinting screening. These results suggest that the reduced ATM protein expression could be attributable, in certain tumors, to deletions or rearrangements within or close to the ATM gene. Positive p53 immunostaining was found in 10 tumors, with TP53 mutations detected in 8. Three tumors had both low ATM expression and mutated TP53. Our results indicate that in the majority (15 of 17) of the sporadic breast carcinomas examined, not only is the functionality of the ATM-p53-mediated DNA damage response compromised, but also other signaling pathways activated by these two multifunctional proteins are likely to be impaired, which could be a contributing factor to tumor development and progression.

Allelic Imbalance↗

PubMed2002

Rare variants of ATM and risk for Hodgkin's disease and radiation-associated breast cancers.

PURPOSE: In this study, we first sought to evaluate whether individuals heterozygous for ATM mutations may have an increased susceptibility to radiation-induced breast cancer (BC) after treatment for Hodgkin's disease (HD). We next sought to determine the frequency of ATM variants in patients with Hodgkin's lymphoma, regardless of coexisting BC, compared with healthy volunteers. EXPERIMENTAL DESIGN: Full sequence analysis of ATM was performed on cDNA from peripheral blood lymphocytes from 37 cases of BC after therapeutic radiation therapy for HD and 27 comparison cases with HD and no BC treated during the same time period. The frequency of ATM variants was analyzed in the total group of 64 cases of HD and compared to allele frequencies in 128 ethnically matched controls from the same geographical region. RESULTS: No protein-truncating ATM mutations were observed in cases with HD with or without BC. Missense mutations were more frequent in the cohort with HD compared with patients with BC following HD (P = 0.02). The median time from HD to the development of BC was 18 years in patients with ATM variants compared with 16 years in those with no ATM variants (P = 0.04). Multiple ATM variants, including one homozygous mutation, were observed in 9 HD cases. CONCLUSIONS: Heterozygous protein-truncating or missense mutations of ATM were not associated with increased radiation-associated risk of BC after HD. The observation of multiple germ-line mutations and a homozygote suggests that rare ATM variants may constitute cancer-susceptibility alleles in a subset of cases.

Adolescent↗

PubMed2003

[Relationship between ataxia telangiectasia mutant(ATM) expression of HL-60 and SiHA cell lines and their cell cycle arrest after 60Co radiation].

BACKGROUND & OBJECTIVE: Ataxia telangiectasia is caused by ataxia telangiectasia mutant(ATM) gene and it is characterized by hypersensitivity to the radiation. So the ATM expression should be related to the radiation sensitivity. This study was designed to investigate the relationship between ATM expression in two kinds of tumor cell lines and their cell cycle arrest after irradiation of ionization radiation to explore their self-protection function. METHODS: ATM mRNA and protein expression of HL-60 and SiHA cell lines were measured by semi-quantitive reverse transcription polymerase chain reaction (RT-PCR) and flow cytometry. The cells were irradiated at the dose of 6, 10, and 15 Gy by (60)Co and the change of apoptosis and cell cycle arrest phenomenon at the time of 6, 12, 24, 48, and 60 hours after the radiation were observed. RESULTS: The ATM mean protein fluorescent intensity of HL-60 and SiHA cells were 14.11+/-2.38 and 27.74+/-1.16,respectively. The ATM protein abundance in SiHA was two times more than that in HL-60,and consistent with this, the ATM RNA relative expression of HL-60 and SiHA cells were 0.09 and 0.80, respectively. The ATM transcript levels in SiHA are 9 times more than that in HL-60. The G(2)/M phase arrest after the radiation was observed in both cell lines, whereas SiHA exhibits a much strong cell cycle arrest than HL-60. CONCLUSION: The cell cycle arrest of HL-60 and SiHA cell lines to the irradiation corresponds to their ATM expression levels. The lower ATM expression, the weaker response for cell cycle arrest induced by radiation.

Apoptosis↗

PubMed1997

Genetic interactions between atm and p53 influence cellular proliferation and irradiation-induced cell cycle checkpoints.

Ataxia-telangiectasia and Li-Fraumeni syndrome, pleiotropic disorders caused by mutations in the genes atm and p53, share a marked increase in cancer rates. A number of studies have argued for an interaction between these two genes (for comprehensive reviews, see M. S. Meyn, Cancer Res., 55: 5991-6001, 1995, and M. F. Lavin and Y. Shiloh, Annu. Rev., Immunol., 15: 177-202, 1996). Specifically, atm is placed upstream of p53 in mediating G1-S cell cycle checkpoint control, and both atm and p53 are believed to influence cellular proliferation. To analyze the genetic interactions of atm and p53, mouse embryonic fibroblasts (MEFs) homozygously deficient for both atm and p53 were used to assess cell cycle and growth control. These double-null fibroblasts proliferate rapidly and fail to exhibit the premature growth arrest seen with atm-null MEFs. MEFs null for both atm and p53 do not express any p21(cipl/wafl), showing that p53 is required for p21(cipl/wafl) expression in an atm-null background. By contrast, homozygous loss of either atm, p53, or both results in similar abnormalities of the irradiation-induced G1-S cell cycle checkpoint. Our results suggest two separate pathways of interaction between atm and p53, one linear, involving G1-S cell cycle control, and another more complex, involving aspects of growth regulation.

Animals↗