Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Protein phosphorylation at tyrosine residues is believed to be involved in several important cellular processes because tyrosine-specific protein kinase activation is associated with stimulation of cellular proliferation by hormones and growth factors, embryogenesis, and retroviral cell transformation. Because cell proliferation is thought to be an essential component of chemical carcinogenesis, liver tyrosine-specific protein kinase activity was examined during the early stages of the Solt and Farber chemical hepatocarcinogenesis model. Rats were given diethylnitrosamine in one dose (200 mg/kg, IP) followed by 2 weeks of dietary 0.02% 2-acetylamino-fluorene starting at day 14 after diethylnitrosamine, followed by partial hepatectomy on day 21. By day 32 this regimen produces a relatively synchronized population of hyperplastic liver nodules up to 1.5 mm in diameter. Rats were sacrificed on day 32, their livers were perfused with cold normal saline, homogenized, and centrifuged at 1,000g for 10 min. The resulting supernatant was centrifuged at 30,000g for 30 min and the pellet was assayed for tyrosine kinase activity using the synthetic peptide [Val5]angiotensin II as substrate. Rats that received the complete regimen had a 2.6-fold increase in their liver tyrosine kinase activity as compared to sham controls (2.4 pmoles/min/mg protein vs 6.4 pmoles/min/mg protein, P less than .05). In contrast, rats that received a partial regimen (ie, partial hepatectomy, or 2-acetylaminofluorene + partial hepatectomy, or diethylnitrosamine + 2-acetylaminofluorene) did not have elevated tyrosine kinase activity nor did they have hyperplastic nodules. These preliminary data suggest that activation of liver tyrosine kinase is associated with the very early stages of chemical hepatocarcinogenesis.
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PMID:Liver tyrosine kinase activation during early stages of chemical hepatocarcinogenesis. 403 31

The cyclin-dependent kinase (CDK) inhibitor p27(KIP1) exerts its growth suppressive effects by targeting the cyclin-CDK complexes. Reduced protein levels of p27(KIP1) have been reported in numerous human cancers and this has been attributed to increased degradation. However, few reports have addressed the significance of p27(KIP1) expression in chemical carcinogenesis of rodents. In a rat two-stage urinary bladder carcinogenesis model, with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) initiation followed by promotion with sodium L-ascorbate (Na-AsA), we evaluated the expression of p27(KIP1) protein using immunohistochemistry during various stages of urinary bladder carcinogenesis. In addition, we evaluated the mRNA expression profiles for p27(KIP1), p21(WAF1/Cip1) and p53 in tumors. Fisher 344 rats were initiated with 0.05% BBN in the drinking water for 4 weeks and then administered 5% Na-AsA in the diet. Immunohistochemical examination revealed p27(KIP1) protein to be constitutively expressed in normal urothelium, simple hyperplasia and in most papillary and nodular (PN) hyperplasias and small papillomas, but diminished or absent in large papillomas and in transitional cell carcinomas. An inverse correlation between expression of p27(KIP1) and cell proliferation was generally observed. Quantitation of mRNA by multiplex reverse transcription-PCR showed a significant downregulaton of p27(KIP1), p21(WAF1/Cip1) and p53 mRNA in tumors. More than 50% reduction in p27(KIP1) mRNA expression was observed in 42 and 47% of tumors at weeks 18 and 24, respectively; similar reduction in p21(WAF1/Cip1) mRNA expression was observed in 58 and 73% of tumors at weeks 18 and 24, and in p53 mRNA expression in 50 and 73% of tumors at weeks 18 and 24, respectively. None of the 25 tumors we examined by PCR-single-strand conformational polymorphism analysis had p53 mutations. These data imply that abnormal down-regulation of p27(KIP1), p21(WAF1/Cip1) and/or p53 in tumor cells may contribute to the malignant progression of tumors during rat two-stage bladder carcinogenesis.
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PMID:Reduced expression of the CDK inhibitor p27(KIP1) in rat two-stage bladder carcinogenesis and its association with expression profiles of p21(WAF1/Cip1) and p53. 1046 13

Dietary energy restriction (DER) has long been known to strikingly inhibit carcinogenesis in many animal models. The animal data has been corroborated by recent and ongoing epidemiological studies demonstrating the importance of energy balance, physical exercise and obesity in human cancer. Dr. Edward Bresnick provided key insights into this important area of research and pivotal direction for the author's research while he served as Director of the Eppley Institute for Research in Cancer, Omaha, NE. These insights moved this research toward demonstrating that DER reduced the expression of key protein kinase C isoforms in mouse skin. More recent studies have uncovered downstream events that are inhibited by DER including blockage of tumor promoter activation of Raf-1, ERK 1,2 and AP-1 expression. Parallel studies have demonstrated the DER inhibition of these key cellular signaling events in mouse skin carcinogenesis are dependent upon an intact adrenal gland because adrenalectomized mice fed DER diet did not have reduced tumor burden or inhibited signaling and blocked AP-1 activation as was observed in DER mice with intact adrenal glands. In addition, the DER inhibition of tumorigenesis and AP-1 signaling was restored in adrenalectomized mice that were given corticosterone in the drinking water. This showed that in mice in the chemical carcinogenesis protocol glucocorticoid hormone plays a major role in mediating DER prevention of cancer. Studies are ongoing to further assess the mechanism of DER modulation of skin cancer by assessing impacts on transcriptional regulation and expression of genes that are critical in skin carcinogenesis.
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PMID:Identification of molecular targets for dietary energy restriction prevention of skin carcinogenesis: an idea cultivated by Edward Bresnick. 1474 86

The association between inflammation and tumorigenesis is well recognized. Mitogen-activated protein kinase-activated protein kinase-2 (MK2) is known to play a pivotal role in inflammatory processes. Here, we studied the effect of MK2-deficiency and tumor necrosis factor (TNF)-alpha-deficiency on skin tumor development in mice using the two-stage chemical carcinogenesis model. We found that MK2(-/-) mice developed significantly fewer skin tumors compared with both TNF-alpha(-/-) and wild-type mice when induced by initiation with 7,12-dimethylbenz[a]anthracene (DMBA) and by promotion with 12-O-tetradecanoylphorbol-13-acetate (TPA). The TPA-induced inflammatory response was reduced in both, TNF-alpha(-/-) mice and MK2(-/-) mice, but most pronounced in TNF-alpha(-/-) mice, indicating that a reduced inflammatory response was not the only explanation for the inhibited tumorigenesis seen in MK2(-/-) mice. Interestingly, increased numbers of apoptotic cells were detected in the epidermis of MK2(-/-) mice compared with TNF-alpha(-/-) and wild-type mice, suggesting an additional role of MK2 in the regulation of apoptosis. This was further supported by: (i) increased levels of the tumor suppressor protein p53 in MK2(-/-) mice after DMBA/TPA treatment compared with controls, (ii) reduced phosphorylation (activation) of the negative p53 regulator, murine double minute 2 in MK2(-)(/-) mouse keratinocytes in vitro and (iii) a significant decrease in the DMBA/TPA induced apoptosis in cultured MK2(-/-) keratinocytes transfected with p53 small interfering RNA. Taken together, these findings demonstrate a dual role of MK2 in the early stages of tumor promotion through regulation of both the inflammatory response and apoptosis of DNA-damaged cells. These results also identify MK2 as a putative target for future skin carcinoma therapy.
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PMID:MK2 regulates the early stages of skin tumor promotion. 1980 57

Transcriptomic, proteomic, phosphoproteomic, and metabolomic analyses were combined to determine the role of pregnane X receptor (PXR) in nongenotoxic signaling and energy homeostasis in liver after rats were repeatedly orally dosed with the PXR agonist pregnenolone carbonitrile (PCN) for 7 days. Analyses of mRNAs and proteins in the supernatant, membrane, and cytosolic fractions of enlarged liver homogenates showed diverse expression profiles. Gene set enrichment analysis showed that the synchronous increase in mRNAs and proteins involved in chemical carcinogenesis and the response to drug was possibly mediated by the PXR pathway and proteasome core complex assembly was possibly mediated by the Nrf2 pathway. In addition, levels of proteins in the endoplasmic reticulum lumen and involved in the acute-phase response showed specific increase with no change in mRNA level, and those composed of the mitochondrial inner membrane showed specific decrease. The analysis of phosphorylated peptides of poly(A) RNA binding proteins showed a decrease in phosphorylation, possibly by casein kinase 2, which may be related to the regulation of protein expression. Proteins involved in insulin signaling pathways showed an increase in phosphorylation, possibly by protein kinase A, and those involved in apoptosis showed a decrease. Metabolomic analysis suggested the activation of the pentose phosphate and anaerobic glycolysis pathways and the increase of amino acid and fatty acid levels, as occurs in the Warburg effect. In conclusion, the results of combined analyses suggest that PXR's effects are due to transcriptional and post-transcriptional regulation with alteration of nongenotoxic signaling pathways and energy homeostasis.
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PMID:Combining Genomics To Identify the Pathways of Post-Transcriptional Nongenotoxic Signaling and Energy Homeostasis in Livers of Rats Treated with the Pregnane X Receptor Agonist, Pregnenolone Carbonitrile. 2882 34