Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242706 (hyperoxia)
 5,219 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nitrosamines are carcinogens formed in the mammalian organism from amine precursors contained in food, beverages, cosmetics and drugs. The potent carcinogen, NNK, and the weaker carcinogen, NNN, are nitrosamines formed from nicotine. Metabolites of the nitrosamines react with DNA to form adducts responsible for genotoxic effects. We have identified NNK as a high affinity agonist for the alpha7 nicotinic acetylcholine receptor (alpha7nAChR) whereas NNN bound with high affinity to epibatidine-sensitive nAChRs. Diethylnitrosamine (DEN) bound to both receptors but with lower affinity. High levels of the alpha7nAChR were expressed in human small cell lung cancer (SCLC) cell lines and in hamster pulmonary neuroendocrine cells (PNECs), which serve as a model for the cell of origin of human SCLC. Exposure of SCLC or PNECs to NNK or nicotine increased expression of the alpha7nAChR and caused influx of Ca(2+), activation of PKC, Raf-1, ERK1/2, and c-myc, resulting in the stimulation of cell proliferation. Signaling via the alpha7nAChR was enhanced when cells were maintained in an environment of 10-15% CO(2) similar to that in the diseased lung. Hamsters with hyperoxia-induced pulmonary fibrosis developed neuroendocrine lung carcinomas similar to human SCLC when treated with NNK, DEN, or nicotine. The development of the NNK-induced tumors was prevented by green tea or theophylline. The beta-adrenergic receptor agonist, isoproterenol or theophylline blocked NNK-induced cell proliferation in vitro. NNK and nicotine-induced hyperactivity of the alpha7nAChR/RAF/ERK1/2 pathway thus appears to play a crucial role in the development of SCLC in smokers and could be targeted for cancer prevention.
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PMID:Nitrosamines as nicotinic receptor ligands. 1745 20

The INK4 and CIP cyclin-dependent kinase (Cdk) inhibitors (CKI) activate pocket protein function by suppressing Cdk4 and Cdk2, respectively. Although these inhibitors are lost in tumors, deletion of individual CKIs results in modest proliferation defects in murine models. We have evaluated cooperativity between loss of all INK4 family members (using cdk4r24c mutant alleles that confer resistant to INK4 inhibitors) and p21(Waf1/Cip1) in senescence and transformation of mouse embryo fibroblasts (MEF). We show that mutant cdk4r24c and p21 loss cooperate in pRb inactivation and MEF immortalization. Our studies suggest that cdk4r24c mediates resistance to p15(INK4B)/p16(INK4A) that accumulates over passage, whereas loss of p21 suppresses hyperoxia-induced Cdk2 inhibition and pRb dephosphorylation on MEF explantation in culture. Although cdk4r24c and p21 loss cooperate in H-ras(V12)/c-myc-induced foci formation, they are insufficient for oncogene-induced anchorage-independent growth. Interestingly, p21(-/-); cdk4r24c MEFs expressing H-ras(V12) and c-myc display detachment-induced apoptosis and are transformed by c-myc, H-ras(V12), and Bcl-2. We conclude that the INK4 family and p21 loss cooperate in promoting pRb inactivation, cell immortalization, and H-ras(V12)/c-myc-induced loss of contact inhibition. In addition, absence of pRb function renders H-ras(V12) + c-myc-transduced fibroblasts prone to apoptosis when deprived of the extracellular matrix, and oncogene-induced anchorage-independent growth of pocket protein-deficient cells requires apoptotic suppression.
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PMID:p21 loss cooperates with INK4 inactivation facilitating immortalization and Bcl-2-mediated anchorage-independent growth of oncogene-transduced primary mouse fibroblasts. 1748 23

Treatment of hamsters with nitrosamines and hyperoxia (60% O2) induces neuroendocrine lung tumors. Analysis of 8 different tumors from 7 different hamsters demonstrated 2- to 3.5-fold increases in the expression of c-myc in 4 of 8 tumors, c-fos in 3 tumors, c-jun in 1 tumor, c-raf in 1 tumor, and Ki-ras in 2 tumors. No overexpression of the c-src and Ha-ras gene transcripts were detected. Expression levels of N-myc, p53 and the retinoblastoma gene transcript were too low to be quantitated accurately. In some cases, slightly elevated levels of protooncogene transcripts (less than 2-fold) were detected in normal-appearing tissue isolated from the same tumor bearing hamsters. Hyperoxia alone had little effect on the expression of c-myc or c-fos RNA transcripts compared to untreated hamsters. Reverse transcription of the RNAs and amplification of the cDNA copies by the polymerase chain reaction, followed by selective oligonucleotide hybridization with normal and mutant probes, did not reveal any mutations in the 12th, 13th, or 61st codons of the seven tumors which produced Ki-ras cDNA. An additional 8 tumors were also screened for Ki-ras mutations following amplification of genomic DNA and demonstrated an absence of point mutations at the Ki-ras gene locus. These results indicate that the hamster neuroendocrine lung tumors exhibit slight increases in c-myc and c-fos RNA expression but lack mutations at the Ki-ras gene locus.
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PMID:Molecular characterization of neuroendocrine lung-tumors induced in hamsters by treatment with nitrosamines and hyperoxia. 2156 81