|CDCB164386||Chicken ATM ORF Clone (NM_001162400)||Inquiry|
|CDCB188279||Rabbit ATM ORF clone (XM_008261832.1)||Inquiry|
|CDCR243755||Mouse Atm ORF Clone(NM_007499.2)||Inquiry|
|CDCR277773||Human ATM ORF Clone(NM_000051.3)||Inquiry|
|CDCR373559||Rat Atm ORF Clone(NM_001106821.1)||Inquiry|
|CDCS405381||Human ATM ORF Clone (BC061584)||Inquiry|
|CDCS405382||Human ATM ORF Clone (BC022307)||Inquiry|
|CDFH001375||Human ATM cDNA Clone(NM_000051.3)||Inquiry|
|CDFR006548||Rat Atm cDNA Clone(NM_001106821.1)||Inquiry|
|MiUTR1H-00668||ATM miRNA 3'UTR clone||Inquiry|
|MiUTR1M-01788||ATM miRNA 3'UTR clone||Inquiry|
|SHG079111||shRNA set against Human ATM(NM_000051.3)||Inquiry|
|SHG080529||shRNA set against Mouse Atm(NM_007499.2)||Inquiry|
|SHH242282||shRNA set against Human ATM (NM_000051.3)||Inquiry|
|SHH242286||shRNA set against Mouse ATM (NM_007499.2)||Inquiry|
|SHH242290||shRNA set against Rat ATM (NM_001106821.1)||Inquiry|
|SHW002911||shRNA set against Chicken ATM (NM_001162400)||Inquiry|
The ataxia-telangiectasia mutated gene (ATM) protein is a member of the phosphatidylinositol 3-kinase family. Its C-terminal region contains about 400 amino acids, which has a high degree of similarity to the catalytic subunit of phosphatidylinositol 3-kinases (PI3K). The ATM protein is an autophosphorylated protein that is distributed in the nucleus and cytoplasm and is dominated by the nucleus.
ATM is ubiquitous in higher eukaryotic tissue cells and is highly expressed in some tissue cells such as testis, spleen, thymus, human cervical cancer cells (HeLa cells), human osteosarcoma cells (U2OS), and fibroblasts. Typically, ATM protein kinases exist as inactive dimers. Some scholars believe that there is no significant change in ATM protein levels and their distribution in subcellular organs after ionizing radiation or during different periods of the cell cycle. This feature may be associated with high fidelity of DNA repair and cell cycle regulation after genomic injury.
ATM protein kinases play an important role in maintaining the stability of the entire genome. In response to DNA damage, ATM kinase activates different effector substrates and plays a role in cell cycle regulation, DNA repair, and apoptosis.
Figure 1. ATM controls cellular survival in response to DNA damage through multiple pathways. (Stracker, et al. 2013).
ATM protein kinases are key regulators in DNA repair processes. It recognizes DNA damage and participates in the recruitment of the RAD50/MRE11/NBS1 complex to the breakpoint. And ATM phosphorylates downstream substrate molecules such as histone H2AX, chromosomal structural maintenance protein-1 (SMC-1), checkpoint kinase 1, 2 (CHK1, 2), p53, etc., and then mediates Multiple signaling pathways involved in DNA damage repair. The researchers applied the restriction endonuclease of different sites to the study of DNA double strands and found that ATM-dependent DNA damage repair is also related to the structural specificity of DNA double-strand breaks. DNA damage caused by oxygen free radicals also activates ATM kinase. Activated ATM kinase acts on glucose hexose phosphate dehydrogenase to regulate the pentose phosphate pathway, resulting in increased nucleotide synthesis, which facilitates the repair of DNA duplexes.
When the DNA double-strand breaks, the ATM protein recognizes the breakpoint and rapidly autophosphorylates, and then activates its downstream substrates p53, Chk2, and Chk1 through phosphorylation. Some anti-tumor drugs related to DNA also induce tumor cell cycle arrest. In one study, four types of myeloma cell lines were treated with bendamustine, and cell cycle assays and Western blotting were used to detect ATM kinase and its downstream substrates. Studies have confirmed that bendamustine is associated with G2 arrest and phosphorylation of ATM kinase.
Apoptosis induced by DNA double-strand injury is associated with activation of ATM kinase. In the in vitro experiment, the researchers applied the nitrogen mustard drug BO-1051 to the liver epithelial cell line and found that DNA double-strand break caused by BO-1051 can activate ATM kinase, and then activate the caspase signaling pathway to cause tumor cell apoptosis. Thus, ATM kinases mediate tumor cell apoptosis by modulating the interaction between DNA damage and death receptor signaling.
ATM and Tumor
ATM is a DNA damage repair gene whose germline mutation is associated with the susceptibility of A-T patients to various tumors. Since the ATM gene undergoes a mutation in the germ cells, the probability of the second attack of alleles in the somatic cells by environmental factors will increase significantly, leading to patients susceptible to lymphoma, leukemia and epithelial tumors such as gastric cancer and ovarian cancer.
ATM has the dual functions of tumor suppression and cancer promotion. Velimezi et al. found that the tumor suppressor gene NKX3.1 protein may achieve tumor suppressor function in prostate cancer by initiating ATM. In cancer cells transformed with human oncogenes, ATM inhibits ARF protein levels and activity in a transcription-independent manner to exert a tumor suppressor effect. In ER-negative breast cancer tissues, the expression of ATM kinase is abnormally up-regulated. Guo et al. found that at the cellular level, ERα initiated MiR-18a and MiR-106a down-regulated ATM expression. MIR-18A and MIR-106A were significantly down-regulated in ER-negative breast cancer tissues. Hesse et al. found that ATM can regulate a variety of MiRNAs to affect the expression of mRNA associated with tumorigenesis and progression, such as SOCS1 and MAF.
In recent years, many studies have shown that single nucleotide polymorphisms in the ATM gene are associated with an increased incidence of lung cancer. At the same time, the ATM gene and its encoded product ATM protein predict the response to lung cancer radiotherapy, chemotherapy, and prognosis, suggesting that the ATM gene may become a new potential target for the diagnosis and treatment of lung cancer. Petersen et al. used a quantitative fluorescence immunohistochemistry to analyze tissue microarrays of 165 excised NSCLC tumors in order to investigate the frequency and effect of ATM deficiency in early resected non-small cell lung cancer (NSCLC). The ratio of ATM expression in malignant tumor cells and ATM expression in the surrounding tumor stroma (defined as ATM expression index (ATM-EI)) was determined and it was correlated with clinical outcome. ATM was found to be lost in 21.8% of patients and was not affected by clinical pathology variables. Patients with low ATM-EI tumors had worse survival outcomes than patients with high ATM-EI (p < 0.01).
Weber et al. evaluated the radiosensitivity and functional phenotypic consequences of ATM missense changes reported in seven NSCLC cell lines for ATM signaling. The results showed that only 2/7 NSCLC cell lines (H1395 and H23) containing ATM missense mutations showed the impaired function of ATM signaling after IR exposure. In both cell lines, missense mutations result in a significant decrease in ATM protein levels, impaired ATM signaling, and significant radiosensitivity.
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