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)

Although tyrosine kinases are critically involved in the angiotensin II (Ang II) type 1 (AT1) receptor signaling, how AT1 receptors activate tyrosine kinases is not fully understood. We examined the structural requirements of the AT1 receptor for transactivation of the epidermal growth factor (EGF) receptor (EGFR). Studies using carboxyl terminal-truncated AT1 receptors indicated that the amino acid sequence between 312 and 337 is required for activation of EGFR. The role of the conserved YIPP motif in this sequence in transactivation of EGFR was investigated by mutating tyrosine 319. Ang II failed to activate EGFR in cells expressing AT1-Y319F, whereas EGFR was activated even without Ang II in cells expressing AT1-Y319E, which mimics the AT1 receptor phosphorylated at Tyr-319. Immunoblot analyses using anti-phospho Tyr-319-specific antibody showed that Ang II increased phosphorylation of Tyr-319. EGFR interacted with the AT1 receptor but not with AT1-Y319F in response to Ang II stimulation, whereas the EGFR-AT1 receptor interaction was inhibited in the presence of dominant negative SHP-2. The requirement of Tyr-319 seems specific for EGFR because Ang II-induced activation of other tyrosine kinases, including Src and JAK2, was preserved in cells expressing AT1-Y319F. Extracellular signal-regulated kinase activation was also maintained in AT1-Y319F through activation of Src. Overexpression of wild type AT1 receptor in cardiac fibroblasts enhanced Ang II-induced proliferation. By contrast, overexpression of AT1-Y319F failed to enhance cell proliferation. In summary, Tyr-319 of the AT1 receptor is phosphorylated in response to Ang II and plays a key role in mediating Ang II-induced transactivation of EGFR and cell proliferation, possibly through its interaction with SHP-2 and EGFR.
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PMID:Phosphorylation of tyrosine 319 of the angiotensin II type 1 receptor mediates angiotensin II-induced trans-activation of the epidermal growth factor receptor. 1252 32

Angiotensin II (Ang II) receptor subtype 1, AT1, is expressed by the rat thyroid. A relationship between thyroid function and several components of the renin-angiotensin system has also been established, but the Ang II cellular effects in thyrocytes and its transduction signalling remain undefined. The aim of the present paper was to investigate the modulation of the activity of the Na(+)-K(+)ATPase by Ang II and its intracellular transduction pathway in PC-Cl3 cells, an established epithelial cell line derived from rat thyroid. Here we have demonstrated, by RT-PCR analysis, the expression of mRNA for the Ang II AT1 receptor in PC-Cl3 cells; mRNA for the Ang II AT2 receptor was not detected. Ang II was not able to affect the intracellular Ca(2+) concentration in fura-2-loaded cells, but it stimulated the translocation from the cytosol to the plasma membrane of atypical protein kinase C-zeta (PKC-zeta) and -iota (PKC-) isoforms with subsequent phosphorylation of the extracellular signal-regulated kinases 1 and 2 (ERK1 and 2). Translocated atypical PKCs displayed temporally different activations, the activation of PKC-zeta being the fastest. PC-Cl3 cells stimulated with increasing Ang II concentrations showed dose- and time-dependent activation of the Na(+)-K(+)ATPase activity, which paralleled the PKC-zeta translocation time course. Na(+)-K(+)ATPase activity modulation was dependent on PKC activation since the PKC antagonist staurosporine abolished the stimulatory effect of Ang II. The inhibition of the ERK kinases 1 and 2 (MEK1 and 2) by PD098059 (2'-amino-3'-methoxyflavone) failed to block the effect of Ang II on the Na(+)-K(+)ATPase activity. In conclusion, our results suggest that Ang II modulates Na(+)-K(+)ATPase activity in PC-Cl3 cells through the AT1 receptor via activation of atypical PKC-zeta while the Ang II-activated PKC- appears to have other as yet unknown functions.
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PMID:Angiotensin II AT1 receptor stimulates Na+ -K+ATPase activity through a pathway involving PKC-zeta in rat thyroid cells. 1252 32

Vascular endothelial growth factor (VEGF), produced predominantly by endothelial cells, is involved in angiogenesis and mitogenesis. Myofibroblasts (myoFb) are phenotypically transformed fibroblast-like cells found at the site of myocardial infarction. Since myoFb play a role in tissue repair/remodeling at the site of infarction, and express endothelin and angiotensin II (AngII), it was interesting to investigate whether myoFb express VEGF and its receptors de novo, and if the expression is influenced by vasoactive peptides. Primary cultures of myoFb were isolated from 4-week-old adult rat heart infarct were used in this study. Semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR), utilizing primers designed to amplify known isoforms of VEGF revealed expression of two predominant forms, VEGF120 and VEGF164 and northern blot hybridization detected VEGF mRNA of 4.5 kb. VEGF actions are mediated via two major receptors, Flt-1 and KDR, and hence the expression of these receptors was investigated. Flt-1 and KDR expression in myoFb was detected by RT-PCR, RNA transcripts were confirmed by northern blot hybridization while western blot confirmed the presence of VEGF, Flt-1 and KDR proteins in myoFb. In this study AngII upregulated VEGF and Flt-1 expression in myoFb, but not KDR; this was mediated predominantly by AT1-receptor. We report for the first time that cardiac myoFb, isolated from the site of infarction express VEGF, its receptors, Flt-1 and KDR, with modulation of VEGF and Flt-1 expression by AngII. Thus, VEGF may contribute to tissue remodeling and angiogenesis at the site of infarction in an autocrine manner.
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PMID:Cardiac myofibroblasts: a novel source of vascular endothelial growth factor (VEGF) and its receptors Flt-1 and KDR. 1267 42

We examined the signalling pathways responsible for the Ang II induction of growth in MCF-7 human breast cancer cells. Ang II in MCF-7 cells induced: (a) the translocation from the cytosol to membrane and nucleus of atypical protein kinase C-zeta (PKC-zeta) but not of PKC-alpha, -delta, - epsilon and -eta; (b) the expression of c-fos mRNA and protein; (c) the phosphorylation of the extracellular signal-regulated protein kinases 1 and 2 (ERK1/2). All these effects were due to the activation of the Ang II type I receptor (AT1) since they were blocked by the AT1 antagonist losartan. The Ang II-stimulated ERK1/2 phosphorylation was blocked by (a) high doses of staurosporine, inhibitor of PKC-zeta, and by a synthetic myristoylated peptide with sequences based on the endogenous PKC-zeta pseudosubstrate region (zeta-PS); (b) PD098059, a mitogen-activated protein kinase kinase inhibitor (MAPKK/MEK); and, moreover, (c) the inhibitors of phosphoinositide 3-kinases (PI3K), LY294002 and wortmannin, thus indicating that PI3K may act upstream of ERK1/2. The Ang II-evoked c-fos induction was blocked only by high doses of staurosporine and by zeta-PS whilst PD098059, LY294002 and wortmannin were ineffective, thus indicating that c-fos induction is not due to ERK1/2 activity. When the epidermal growth factor-receptor (EGFR) tyrosine kinase activity was inhibited by the use of its inhibitor AG1478, Ang II was still able to induce ERK1/2 phosphorylation and c-fos expression, therefore proving that the transactivation of EGFR was not required for these Ang II effects in MCF-7 cells. The previously reported proliferation of MCF-7 cells induced by Ang II was blocked by PD098059 and by wortmannin in a dose-dependent manner, thereby indicating that in MCF-7 cells the PI3K and ERK pathways mediate the mitogenic signalling of AT1. Our results suggest that in MCF-7 cells Ang II activates multiple signalling pathways involving PKC-zeta, PI3K and MAPK; of these pathways only PKC-zeta appears responsible for the induction of c-fos.
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PMID:PKC-zeta is required for angiotensin II-induced activation of ERK and synthesis of C-FOS in MCF-7 cells. 1294 41

Angiotensin II (Ang II) stimulates hypertrophy of glomerular mesangial cells. The signalling mechanism by which Ang II exerts this effect is not precisely known. Downstream potential targets of Ang II are the extracellular-signal-regulated kinases 1 and 2 (ERK1/ERK2). We demonstrate that Ang II activates ERK1/ERK2 via the AT1 receptor. Arachidonic acid (AA) mimics the action of Ang II on ERK1/ERK2 and phospholipase A2 inhibitors blocked Ang II-induced ERK1/ERK2 activation. The antioxidant N-acetylcysteine as well as the NAD(P)H oxidase inhibitors diphenylene iodonium and phenylarsine oxide abolished both Ang II- and AA-induced ERK1/ERK2 activation. Moreover, dominant-negative Rac1 (N17Rac1) blocks activation of ERK1/ERK2 in response to Ang II and AA, whereas constitutively active Rac1 resulted in an increase in ERK1/ERK2 activity. Antisense oligonucleotides for Nox4 NAD(P)H oxidase significantly reduce activation of ERK1/ERK2 by Ang II and AA. We also show that protein synthesis in response to Ang II and AA is inhibited by N17Rac1 or MEK (mitogen-activated protein kinase/ERK kinase) inhibitor. These results demonstrate that Ang II stimulates ERK1/ERK2 by AA and Nox4-derived reactive oxygen species, suggesting that these molecules act as downstream signal transducers of Ang II in the signalling pathway linking the Ang II receptor AT1 to ERK1/ERK2 activation. This pathway involving AA, Rac1, Nox4, reactive oxygen species and ERK1/ERK2 may play an important role in Ang II-induced mesangial cell hypertrophy.
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PMID:Angiotensin II-induced ERK1/ERK2 activation and protein synthesis are redox-dependent in glomerular mesangial cells. 1502 96

Angiotensin II (Ang II) is known to modulate tyrosine kinases (PTKs) activity in pituitary tumor cells. It is known that AngII is acting via AT1 receptors in many tissues. The aim of this study was to see whether 3-8 fragment of AngII, called angiotensin IV (AngIV) has a similar effect on tyrosine kinase activity in normal pituitary gland and what type of angiotensin receptor is involved in this process. The homogenates of normal rat pituitaries was a source of enzymes. The PTKs activity was determined using the synthetic substrate poly GluTyr and gamma-(32)P-ATP. Ang IV was found to increase the PTK activity in the rat anterior pituitary tissue, with the maximal effect at concentration of 10(-10) M. AngII was ineffective at all concentrations studied. Losartan, a selective AT1 receptor blocker, added together with Ang IV abolished the effect of the latter, however losartan diminished also the PTK activity when applied together with Ang II, but only when it was added immediately before, but not after, the addition of Ang II. The involvement of a non-classic AT1-like receptor is suggested.
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PMID:Angiotensin IV stimulates the activity of tyrosine kinases in rat anterior pituitary gland acting via AT1-like receptors? 1508 71

We recently found that a small molecule 2[[3-(2,3-dichlorophenoxy)propyl]amino]ethanol (2,3-DCPE) could induce apoptosis and downregulate Bcl-XL expression in various cancer cells. Here, we found that 2,3-DCPE suppressed the proliferation of Bcl-XL-overexpressing cancer cells without inducing apoptosis. Subsequently, we found that 2,3-DCPE could induce S-phase arrest and upregulate p21 but not p27 at a time- and dose-dependent but p53-dispensable manner in DLD-1 human colon cancer cells. Activation of ERK was also detected after treatment with 2,3-DCPE. Moreover, p21 induction was dramatically attenuated by ERK inhibitors PD98059 and U0126. Induction of p21 and S-phase arrest and corresponding activation of ERK were also observed in ATM-defective cells, suggesting that 2,3-DCPE-induced these events were ATM-dispensable. Furthermore, ERK inhibitors dramatically attenuated 2,3-DCPE-induced S-phase arrest. Together, our data indicate that ERK activation correlated with the 2,3-DCPE-mediated induction of p21 expression and S-phase arrest. This finding may have implication for cancer therapy.
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PMID:Induction of S-phase arrest and p21 overexpression by a small molecule 2[[3-(2,3-dichlorophenoxy)propyl] amino]ethanol in correlation with activation of ERK. 1512 44

Array-based comparative genomic hybridization (aCGH) allows the identification of DNA sequence copy number changes at high resolution by co-hybridizing differentially labelled test and control DNAs to a micro-array of genomic clones. The present study has analysed a series of 23 formalin-fixed, paraffin wax-embedded tissue samples of Barrett's adenocarcinoma (BCA, n = 18) and non-neoplastic squamous oesophageal (n = 2) and gastric cardia mucosa (n = 3) by aCGH. The micro-arrays used contained 287 genomic targets covering oncogenes, tumour suppressor genes, and DNA sequences localized within chromosomal regions previously reported to be altered in BCA. DNA sequence copy number changes for a panel of approximately 50 genes were identified, most of which have not been previously described in BCA. DNA sequence copy number gains (mean 41 +/- 25/BCA) were more frequent than DNA sequence copy number losses (mean 20 +/- 15/BCA). The highest frequencies for DNA sequence copy number gains were detected for SNRPN (61%); GNLY (44%); NME1 (44%); DDX15, ABCB1 (MDR), ATM, LAMA3, MYBL2, ZNF217, and TNFRSF6B (39% each); and MSH2, TERC, SERPINE1, AFM137XA11, IGF1R, and PTPN1 (33% each). DNA sequence copy number losses were identified for PDGFB (44%); D17S125 (39%); AKT3 (28%); and RASSFI, FHIT, CDKN2A (p16), and SAS (CDK4) (28% each). In all non-neoplastic tissue samples of squamous oesophageal and gastric cardia mucosa, the measured mean ratios were 1.00 (squamous oesophageal mucosa) or 1.01 (gastric mucosa), indicating that no DNA sequence copy number chances were present. For validation, the DNA sequence copy number changes of selected clones (SNRPN, CMYC, HER2, ZNF217) detected by aCGH were confirmed by fluorescence in situ hybridization (FISH). These data show the sensitivity of aCGH for the identification of DNA sequence copy number changes at high resolution in BCA. The newly identified genes may include so far unknown biomarkers in BCA and are therefore a starting point for further studies elucidating their possible role in Barrett's carcinogenesis.
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PMID:Array-based comparative genomic hybridization for the detection of DNA sequence copy number changes in Barrett's adenocarcinoma. 1522 37

Genetic interventions that accelerate or retard aging in mice are crucial in advancing our knowledge over mammalian aging. Yet determining if a given intervention affects the aging process is not straightforward since, for instance, many disease-causing mutations may decrease life span without affecting aging. In this work, we employed the Gompertz model to determine whether several published interventions previously claimed to affect aging in mice do indeed alter the aging process. First, we constructed age-specific mortality tables for a number of mouse cohorts used in longevity experiments and calculated the rate at which mortality increases with age. Estimates of age-independent mortality were also calculated. We found no statistical evidence that GHRHR, IGF1R, INSR, PROP1, or TRX delay or that ATM + TERC, BubR1, klotho, LMNA, PRDX1, p53, WRN + TERC, or TOP3B accelerate mouse aging. Often, changes in the expression of these genes affected age-independent mortality and so they may prove useful to other aspects of medicine. We found statistical evidence that C/EBP, MSRA, SHC1, growth hormone, GHR, PIT1, and PolgA may influence aging in mice. These results were interpreted together with age-related physiological and pathological changes and provide novel insights regarding the role of several genes in the mammalian aging process.
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PMID:The influence of genes on the aging process of mice: a statistical assessment of the genetics of aging. 1546 29

The type 1 insulin-like growth factor receptor (IGF-1R) is overexpressed by many tumours and mediates proliferation, motility and apoptosis protection. Tumour growth and metastasis can be blocked by agents that inhibit IGF-1R expression or function, suggesting the IGF-1R as a promising treatment target. We showed that antisense-IGF-1R expression in melanoma cells leads to enhanced radiosensitivity and impaired activation of ATM, required for DNA double-strand break repair. Antisense and dominant negative strategies also enhance tumour cell chemosensitivity, and remarkably, immune protection can be induced by tumour cells killed in vivo by IGF-1R-antisense. However, antisense agents cause only modest IGF1R down-regulation, and can affect the insulin receptor. Specificity is an important issue for development of both kinase inhibitors and molecular reagents. Using an array-based screen to identify accessible regions of IGF1R mRNA, we designed small interfering RNAs (siRNAs) that induce potent IGF1R gene silencing without affecting the insulin receptor. These siRNAs block IGF signalling, enhance radio- and chemosensitivity, and show genuine therapeutic potential. The clinical efficacy of IGF-1R targeting will be determined by key factors including the role of the receptor in established tumours, the potency of inhibition achieved in vivo, and the extent to which other signalling pathways compensate for IGF-1R loss.
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PMID:The IGF receptor as anticancer treatment target. 1556 33


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