Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angiotensin II (Ang II) and insulin-like growth factor I (IGF I) stimulate intracellular signaling events through binding to their respective G-protein-coupled and growth factor receptors. In rat aortic vascular smooth muscle cells, IGF I (20 ng/ml) induced a sustained (>30 min) increase in the tyrosine phosphorylation of both Src-homology 2 domain-docking insulin receptor substrate 1 (IRS-1) and Src-homology 2-binding tyrosine phosphatase 1D (PTP-1D). In addition, IGF I stimulated PTP-1D phosphatase activity. Ang II (10(-7) M) also increased the tyrosine phosphorylation of IRS-1 (4-fold), PTP-1D (5-fold), and PTP-1D activity (3-4-fold), but with a more transient time course. Ang II also induced PTP-1D.IRS-1 complex formation. These Ang II-induced events were not affected by preincubation with an anti-IGF I antibody, suggesting that Ang II's actions were not mediated via the autocrine secretion of IGF I. Anti-PTP-1D antibody electroporation attenuated Ang II-induced PTP-1D.IRS-1 complex formation and PTP-1D tyrosine phosphorylation and activation. Our findings show that the tyrosine phosphorylation of IRS-1 and PTP-1D represents a convergent intracellular signaling cascade stimulated by both growth factor (i.e. IGF I) and G-protein-coupled (i.e. AT1) receptors.
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PMID:Angiotensin II stimulates tyrosine phosphorylation and activation of insulin receptor substrate 1 and protein-tyrosine phosphatase 1D in vascular smooth muscle cells. 913 82

The hypothesis, based on previous in vivo data, that angiotensin AT1 receptors are regulated by GH or insulin-like growth factor I (IGF-I) has been investigated in this study using primary cultures of rat astrocytes as a model of AT1 receptor expression. At a dose of 1 ng/ml GH, there was an increase in AT1 density within 4 h and a maximum increase of 361 +/- 57% of the control value at 12 h. At 24 h, receptor density was still 176 +/- 23% that in the control. Astrocytes incubated with 1 ng/ml rat IGF-I for 24 h showed no change in AT1 receptor density. Reverse transcriptase-PCR was used to show that astrocytes express both the AT1a receptor subtype and, to a much lesser extent, the AT1b subtype. Treatment with 1 ng/ml recombinant bovine GH for 12 h increased the messenger RNA of the AT1a receptor by 170%, without affecting the AT1b receptor. Inhibition of protein synthesis by cycloheximide and of transcription by the adenosine analog dichlororibofuranosylbenzimidazole both prevented the increase in AT1 receptor density following GH treatment, indicating that the action of GH is transcriptional. In summary, we have shown that GH up-regulates, directly and not via IGF-I, angiotensin receptors of the AT1a subtype in astrocytes by a transcriptional mechanism. The long latency of the response and the dependency on transcription relegate the AT1a gene to the class of GH-regulated genes identified as delayed stable genes. This mechanism of AT1 activation may be one way in which GH activates the renin-angiotensin system and initiates consequential cardiovascular and angiogenic effects.
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PMID:Growth hormone regulates AT-1a angiotensin receptors in astrocytes. 932 27

In the present work we review evidence supporting the use of insulin-like growth factor I (IGF-I) for treatment of cerebellar ataxia, a heterogeneous group of neurodegenerative diseases of low incidence but high societal impact. Most types of ataxia display not only motor discoordination, but also additional neurological problems including peripheral nerve dysfunctions. Therefore, a feasible therapy should combine different strategies aimed to correct the various disturbances specific for each type of ataxia. For cerebellar deficits, and most probably also for other types of brain deficits, the use of a wide-spectrum neuroprotective factor such as IGF-I may prove beneficial. Intriguingly, both ataxic animals as well as human patients show altered serum IGF-I levels. While the pathogenic significance of IGF-I, if any, in this varied group of diseases is difficult to envisage, disrupted IGF-I neuroprotective signaling may constitute a common stage in the pathological cascade associated to neuronal death. Indeed, treatment with IGF-I has proven effective in animal models of ataxia. Based on this pre-clinical evidence we propose that IGF-I should be tested in clinical trials of cerebellar ataxia in those cases where either serum IGF-I deficiency (as in primary cerebellar atrophy) or loss of sensitivity to IGF-I (as in ataxia telangiectasia) has been reported. Taking advantage of the widely protective and anabolic actions of IGF-I on peripheral tissues, this neurotrophic factor may provide additional therapeutic advantages for many of the disturbances commonly associated to ataxia such as cardiopathy, muscle wasting, or immune dysfunction.
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PMID:Insulin-like growth factor I treatment for cerebellar ataxia: addressing a common pathway in the pathological cascade? 1595 Feb 89

Aberrant activation of Akt plays a pivotal role in cancer development. ATM, a protein deficient in patients with ataxia-telangiectasia disease, is traditionally considered as a nuclear protein kinase that functions as a signal transducer in response to DNA damage. It has recently been shown that ATM is also a cytoplasmic protein that mediates the full activation of Akt in response to insulin. Our study shows that a specific ATM inhibitor, KU-55933, blocks the phosphorylation of Akt induced by insulin and insulin-like growth factor I in cancer cells that exhibit abnormal Akt activity. Moreover, KU-55933 inhibits cancer cell proliferation by inducing G(1) cell cycle arrest. It does so through the downregulation of the synthesis of cyclin D1, a protein known to be elevated in a variety of tumors. In addition, KU-55933 treatment during serum starvation triggers apoptosis in these cancer cells. Our results suggest that KU-55933 may be a novel chemotherapeutic agent targeting cancer resistant to traditional chemotherapy or immunotherapy due to aberrant activation of Akt. Furthermore, KU-55933 completely abrogates rapamycin-induced feedback activation of Akt. Combination of KU-55933 and rapamycin not only induces apoptosis, which is not seen in cancer cells treated only with rapamycin, but also shows better efficacy in inhibiting cancer cell proliferation than each drug alone. Therefore, combining KU-55933 with rapamycin may provide a highly effective approach for improving mammalian target of rapamycin-targeted anticancer therapy that is currently hindered by rapamycin-induced feedback activation of Akt.
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PMID:The ATM inhibitor KU-55933 suppresses cell proliferation and induces apoptosis by blocking Akt in cancer cells with overactivated Akt. 2005 81

Hellebrigenin, one of bufadienolides belonging to cardioactive steroids, was found in skin secretions of toads and plants of Helleborus and Kalanchoe genera. In searching for natural constituents with anti-hepatoma activities, we found that hellebrigenin, isolated from traditional Chinese medicine Venenum Bufonis, potently reduced the viability and colony formation of human hepatocellular carcinoma cells HepG2, and went on to explore the underlying molecular mechanisms. Our results demonstrated that hellebrigenin triggered DNA damage through DNA double-stranded breaks and subsequently induced cell cycle G2/M arrest associated with up-regulation of p-ATM (Ser(1981)), p-Chk2 (Tyr(68)), p-CDK1 (Tyr(15)) and Cyclin B1, and down-regulation of p-CDC25C (Ser(216)). It was also found that hellebrigenin induced mitochondrial apoptosis, characterized by Bax translocation to mitochondria, disruption of mitochondrial membrane potential, release of cytochrome c into cytosol and sequential activation of caspases and PARP. In addition, Akt expression and phosphorylation were inhibited by hellebrigenin, whereas Akt silencing with siRNA significantly blocked cell cycle arrest but enhanced apoptosis induced by hellebrigenin. Activation of Akt by human insulin-like growth factor I (hIGF-I) could obviously attenuate hellebrigenin-induced cell death. In summary, our study is the first to report the efficacy of hellebrigenin against HepG2 and elucidated its molecular mechanisms including DNA damage, mitochondria collapse, cell cycle arrest and apoptosis, which will contribute to the development of hellebrigenin into a chemotherapeutic agent in the treatment of liver cancer.
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PMID:Hellebrigenin induces cell cycle arrest and apoptosis in human hepatocellular carcinoma HepG2 cells through inhibition of Akt. 2495 31