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)

Our previous study has shown that angiotensin II induces the rapid tyrosine phosphorylation and activation of phospholipase C-gamma 1 in cultured rat aortic smooth muscle (RASM) cells (Marrero, M.B., Paxton, W.G., Duff, J. L., Berk, B. C., and Bernstein, K. E. (1994) J. Biol. Chem, 269, 10935-10939). This signaling pathway is initiated by ligand binding to the AT1 receptor, a cell surface G protein-coupled receptor. Antibodies to pp60c-src were introduced into RASM cells by electroporation. Angiotensin II-stimulated tyrosine phosphorylation of phospholipase C-gamma 1 was eliminated by the anti-pp60c-src antibodies but not by anti-mouse IgG or bovine serum albumin. Angiotensin II also induced the rapid tyrosine phosphorylation of pp120, a known pp60c-src kinase substrate, and this phosphorylation was also specifically inhibited by anti-pp60c-src antibodies. Electroporation of RASM cells with anti-pp60c-src antibodies had no effect on platelet-derived growth factor-stimulated tyrosine phosphorylation of PLC-gamma 1. Anti-pp60c-src also reduced the angiotensin II-stimulated inositol 1,4,5-trisphosphate production by 78%, while it had no effect on the platelet-derived growth factor-stimulated inositol 1,4,5-trisphosphate production. These data provide the first evidence for a direct involvement of pp60c-src kinase in angiotensin II-mediated PLC-gamma 1 phosphorylation and activation. Furthermore, it also describes a pathway in which a seven-transmembrane receptor can stimulate an intracellular tyrosine kinase.
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PMID:Electroporation of pp60c-src antibodies inhibits the angiotensin II activation of phospholipase C-gamma 1 in rat aortic smooth muscle cells. 754 Oct 47

Most cell types, including vascular smooth muscle cells and rat kidney mesangial cells, are controlled mainly by two types of cell surface receptors: (a) single membrane-spanning tyrosine kinase receptors for growth factors and (b) seven-transmembrane G-protein linked receptors for vasoactive peptides such as angiotensin II, vasopressin, and endothelin. These vasoactive peptide hormones also act as growth factors in normal and abnormal cell development. However, in contrast to the growth factor receptors (e.g., epidermal growth factor receptor and platelet-derived growth factor receptor), the G-protein linked receptors, such as the angiotensin II AT1 receptor, lack cytoplasmic tyrosine kinase domains. Nevertheless, angiotensin II has recently been demonstrated to cause increased tyrosine phosphorylation of numerous proteins in several cellular systems. For example, angiotensin II has been reported to induce the tyrosine phosphorylation of the gamma-isoform of phospholipase C, pp120, pp125FAK, and members of the janus kinase/signal transducer and activator of transcription pathway. Furthermore, angiotensin II seems to modulate the activity of the soluble cytoplasmic tyrosine kinase pp60c-src, and this tyrosine kinase has been implicated in the phosphorylation of some of the above proteins. Understanding the biochemistry of tyrosine phosphorylation involved in G-protein coupled receptors, such as the AT1 receptor, may therefore lead to the development of new pharmacological interventions important in cardiovascular diseases.
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PMID:The role of tyrosine phosphorylation in angiotensin II mediated intracellular signaling and cell growth. 882 Apr 3

Glioblastoma multiforme (GBM) is an aggressive brain tumor that is resistant to all known therapies. Within these tumors, a CD133-positive cancer-initiating neural stem cell (NSC) population was shown to be resistant to gamma radiation through preferential activation of the DNA double-strand break (DSB) response machinery, including the ataxia-telangiectasia-mutated (ATM) kinase. The polycomb group protein BMI1 is enriched in CD133-positive GBM cells and required for their self-renewal in an INK4A/ARF-independent manner through transcriptional repression of alternate tumor suppressor pathways. We report here that BMI1 copurifies with DNA DSB response and nonhomologous end joining (NHEJ) repair proteins in GBM cells. BMI1 was enriched at the chromatin after irradiation and colocalized and copurified with ATM and the histone gammaH2AX. BMI1 also preferentially copurified with NHEJ proteins DNA-PK, PARP-1, hnRNP U, and histone H1 in CD133-positive GBM cells. BMI1 deficiency in GBM cells severely impaired DNA DSB response, resulting in increased sensitivity to radiation. In turn, BMI1 overexpression in normal NSCs enhanced ATM recruitment to the chromatin, the rate of gammaH2AX foci resolution, and resistance to radiation. BMI1 thus displays a previously uncharacterized function in controlling DNA DSB response and repair. Pharmacological inhibition of BMI1 combined with radiation therapy may provide an effective mean to target GBM stem cells.
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PMID:BMI1 confers radioresistance to normal and cancerous neural stem cells through recruitment of the DNA damage response machinery. 2066 94

We previously identified the heterogeneous ribonucleoprotein SAF-A/hnRNP U as a substrate for DNA-PK, a protein kinase involved in DNA damage response (DDR). Using laser micro-irradiation in human cells, we report here that SAF-A exhibits a two-phase dynamics at sites of DNA damage, with a rapid and transient recruitment followed by a prolonged exclusion. SAF-A recruitment corresponds to its binding to Poly(ADP-ribose) while its exclusion is dependent on the activity of ATM, ATR and DNA-PK and reflects the dissociation from chromatin of SAF-A associated with ongoing transcription. Having established that SAF-A RNA-binding domain recapitulates SAF-A dynamics, we show that this domain is part of a complex comprising several mRNA biogenesis proteins of which at least two, FUS/TLS and TAFII68/TAF15, exhibit similar biphasic dynamics at sites of damage. Using an original reporter for live imaging of DNA:RNA hybrids (R-loops), we show a transient transcription-dependent accumulation of R-loops at sites of DNA damage that is prolonged upon inhibition of RNA biogenesis factors exclusion. We propose that a new component of the DDR is an active anti-R-loop mechanism operating at damaged transcribed sites which includes the exclusion of mRNA biogenesis factors such as SAF-A, FUS and TAF15.
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PMID:DNA damage triggers SAF-A and RNA biogenesis factors exclusion from chromatin coupled to R-loops removal. 2503 Sep 5