Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mitogen-activated protein kinase (MAPK) pathways regulate many cellular functions including cell proliferation, differentiation, migration and apoptosis. We evaluate genetic variation in the c-Jun-N-terminal kinases, p38, and extracellular regulated kinases 1/2 MAPK-signaling pathways and colon and rectal cancer risk using data from population-based case-control studies (colon: n = 1555 cases, 1956 controls; rectal: n = 754 cases, 959 controls). We assess 19 genes (DUSP1, DUSP2, DUSP4, DUSP6, DUSP7, MAP2K1, MAP3K1, MAP3K2, MAP3K3, MAP3K7, MAP3K9, MAP3K10, MAP3K11, MAPK1, MAPK3, MAPK8, MAPK12, MAPK14 and RAF1). MAP2K1 rs8039880 [odds ratio (OR) = 0.57, 95% confidence interval (CI) = 0.38, 0.83; GG versus AA genotype] and MAP3K9 rs11625206 (OR = 1.41, 95% CI = 1.14, 1.76; recessive model) were associated with colon cancer (P (adj) value < 0.05). DUSP1 rs322351 (OR = 1.43, 95% CI = 1.09, 1.88; TT versus CC) and MAPK8 rs10857561 (OR = 1.48, 95% CI 1.08, 2.03; AA versus GG/GA) were associated with rectal cancer (P (adj) < 0.05). Aspirin/non-steroidal anti-inflammatory drug, cigarette smoking and body mass index interacted with several genes to alter cancer risk. Genetic variants had unique associations with KRAS, TP53 and CIMP+ tumors. DUSP2 rs1724120 [hazard rate ratio (HRR) = 0.72, 95%CI = 0.54, 0.96; AA versus GG/GA), MAP3K10 rs112956 (HRR = 1.40, 95% CI = 1.10, 1.76; CT/TT versus CC) and MAP3K11 (HRR = 1.76, 95% CI 1.18, 2.62 TT versus GG/GT) influenced survival after diagnosis with colon cancer; MAP2K1 rs8039880 (HRR = 2.53, 95% CI 1.34, 4.79 GG versus AG/GG) and Raf1 rs11923427 (HRR = 0.59 95% CI = 0.40, 0.86; AA versus TT/TA) were associated with rectal cancer survival. These data suggest that genetic variation in the MAPK-signaling pathway influences colorectal cancer risk and survival after diagnosis. Associations may be modified by lifestyle factors that influence inflammation and oxidative stress.
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PMID:MAP kinase genes and colon and rectal cancer. 2302 23

Earlier work from this laboratory showed that autocrine generation of angiotensin II and c-Jun-NH2-terminal kinase phosphorylation (p-JNK) are both required events in alveolar epithelial cell (AEC) apoptosis. Although earlier data showed that angiotensin-(1-7) [ANG-(1-7)] protects against AEC apoptosis, the pathways by which ANG-(1-7)/mas activation prevent JNK phosphorylation and apoptosis are poorly understood. Therefore, in the current study, it was theorized that ANG-(1-7) activates a mitogen-activated protein kinase phosphatase (MKP) and thereby reduces JNK phosphorylation to inhibit apoptosis and promote cell survival. This hypothesis was evaluated in the human A549 and mouse MLE12 AEC lines and primary cultures of human AECs. Cells were transfected with small-interfering RNAs, antisense oligonucleotides, or inhibitors specific for MKP-2 or mas, and were then assayed for phospho-JNK, caspase-9, loss of mitochondrial membrane potential, and nuclear fragmentation. Silencing of MKP-2 significantly prevented the blockade of all apoptotic markers by ANG-(1-7). Knockdown or blockade of mas receptor by antisense oligonucleotides or by the receptor antagonist A779, respectively, caused significant decreases in MKP-2, and simultaneously increased the apoptotic markers of caspase-9 activation and nuclear fragmentation. These data show that the ANG-(1-7)/mas pathway constitutively prevents JNK phosphorylation and apoptosis of AECs by maintaining activation of the JNK-selective phosphatase MKP-2, and further demonstrate the critical role of the ANG-(1-7) receptor mas in AEC survival.
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PMID:Angiotensin-(1-7)/mas inhibits apoptosis in alveolar epithelial cells through upregulation of MAP kinase phosphatase-2. 2663 35


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