Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0001486 (Adenovirus)
 3,125 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

IFI16 is a member of the PYRIN superfamily that has been implicated in BRCA1-mediated apoptosis and inflammation signaling pathways. Here we report that most breast cancer cell lines examined expressed decreased mRNA and protein levels of IFI16, although IFI16 is expressed in human primary normal mammary epithelial cells. Significantly, immunohistochemical analysis of tissues from 25 breast cancer patients demonstrated that carcinoma cells showed negative or weaker staining of IFI16 compared with positive nuclear staining in normal mammary duct epithelium. si-RNA-mediated reduction of IFI16 resulted in perturbation of p53 activation when treated with ionizing radiation (IR). Expression of IFI16 enhanced p53 transcriptional activity in cells exposed to IR. Adenovirus expression of IFI16 in IFI16-deficient MCF7 induced apoptosis, which was enhanced by radiomimetic neocarcinostatin treatment. Tetracycline-regulated IFI16 also induced apoptosis when coexpressed with p53 in p53-deficient EJ cells subjected to IR, suggesting that IFI16 is involved in p53-mediated transmission of apoptosis signaling. Consistent with these results, expression of IFI16 enhanced activation of the known p53 target genes, including p21, Hdm2, and bax in MCF7 cells. These results suggest that loss of IFI16 results in deregulation of p53-mediated apoptosis, leading to cancer development.
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PMID:Requirement of IFI16 for the maximal activation of p53 induced by ionizing radiation. 1499 May 79

Loss of retinal pericytes is one of the distinctive features of diabetic retinopathy (DR), which is characterized by retinal capillary obliteration. The matricellular proteins, cysteine-rich protein 61 (Cyr61) and connective tissue growth factor (CTGF), are aberrantly expressed in the retinal vasculature from the early stages of DR, but their effects on retinal pericytes are unknown. We show herein that rat retinal pericytes (RRPs) exposed to advanced glycosylation-end products, an important injurious stimulus of diabetes, express increased levels of both Cyr61 and CTGF, and concomitantly undergo anoikis, a form of apoptosis by loss of cell-matrix interactions. Adenovirus-mediated expression of Cyr61 and/or CTGF conferred an anoikis-prone phenotype to rat retinal pericytes, including decreased phosphotyrosine protein levels at focal adhesion points and formation of cortical actin rings. When used as substrates for pericyte attachment and compared with other matrix proteins (e.g. type IV collagen), recombinant Cyr61 and CTGF proteins exhibited antiadhesive and apoptogenic activities. Phosphatase inhibitors reversed these effects, suggesting that Cyr61 and CTGF promote dephosphorylation events. Furthermore, Cyr61- and CTGF-induced apoptosis was mediated through the intrinsic pathway and involved the expression of genes that have been functionally grouped as p53 target genes. Expression of the matrix metalloproteinase-2 gene, a known target of p53, was increased in pericytes overexpressing either Cyr61 or CTGF. Inhibition of matrix metalloproteinase-2 had, at least in part, a protective effect against Cyr61- and CTGF-induced apoptosis. Taken together, these findings support the involvement of Cyr61 and CTGF in pericyte detachment and anoikis, implicating these proteins in the pathogenesis of DR.
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PMID:Cysteine-rich protein 61 and connective tissue growth factor induce deadhesion and anoikis of retinal pericytes. 1818 44

Adenovirus E1B-55K represses p53-mediated transcription. However, the phenotypic consequence of p53 inhibition by E1B-55K for cell cycle regulation and drug sensitivity in tumor cells has not been examined. In HCT116 cells with constitutive E1B-55K expression, the activation of p53 target genes such as the p21, Mdm2, and Puma genes was attenuated, despite markedly elevated p53 protein levels. HCT116 cells with E1B-55K expression displayed a cell cycle profile similar to that of the isogenic HCT116p53(-/-) cells, including unhindered S-phase entry despite DNA damage. Surprisingly, E1B-55K-expressing cells were more sensitive to drug treatment than parental cells. Compared to HCT116 cells, HCT116p53(-/-) cells were more susceptible to both doxorubicin and etoposide, and E1B-55K expression had no effects on drug treatment. E1B-55K expression increased the rate of cell proliferation in HCT116 but not in HCT116p53(-/-) cells. Thus, deregulation of p53-mediated cell cycle control by E1B-55K probably underlies sensitization of HCT116 cells to anticancer drugs. Consistently, E1B-55K expression in A549, A172, and HepG2 cells, all containing wild-type (wt) p53, also enhanced etoposide-induced cytotoxicity, whereas in p53-null H1299 cells, E1B-55K had no effects. We generated several E1B-55K mutants with mutations at positions occupied by the conserved Phe/Trp/His residues. Most of these mutants showed no or reduced binding to p53, although some of them could still stabilize p53, suggesting that binding might not be essential for E1B-55K-induced p53 stabilization. Despite heightened p53 protein levels in cells expressing certain E1B-55K mutants, p53 activity was largely suppressed. Furthermore, most of these E1B-55K mutants could sensitize HCT116 cells to etoposide and doxorubicin. These results indicate that E1B-55K might have utility for enhancing chemotherapy.
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PMID:Inhibition of p53 by adenovirus type 12 E1B-55K deregulates cell cycle control and sensitizes tumor cells to genotoxic agents. 2168 May 22

Background: There is no curative therapy for severe acute pancreatitis (SAP) due to poor understanding of its molecular mechanisms. Endoplasmic reticulum (ER) stress is involved in SAP and increased expression of ATF6 has been detected in SAP patients. Here, we aimed to investigate the role of ATF6 in a preclinical SAP mouse model and characterize its regulatory mechanism. Methods: Pancreatic tissues of healthy and SAP patients were collected during surgery. Humanized PRSS1 transgenic mice were treated with caerulein to mimic the SAP development, which was crossed to an ATF6 knockout mouse line, and pancreatic tissues from the resulting pups were screened by proteomics. Adenovirus-mediated delivery to the pancreas of SAP mice was used for shRNA-based knockdown or overexpression. The potential functions and mechanisms of ATF6 were clarified by immunofluorescence, immunoelectron microscopy, Western blotting, qRT-PCR, ChIP-qPCR and luciferase reporter assay. Results: Increased expression of ATF6 was associated with elevated apoptosis, ER and mitochondrial disorder in pancreatic tissues from SAP patients and PRSS1 mice. Knockout of ATF6 in SAP mice attenuated acinar injury, apoptosis and ER disorder. AIFM2, known as a p53 target gene, was identified as a downstream regulatory partner of ATF6, whose expression was increased in SAP. Functionally, AIFM2 could reestablish the pathological disorder in SAP tissues in the absence of ATF6. p53 expression was also increased in SAP mice, which was downregulated by ATF6 knockout. p53 knockout significantly suppressed acinar apoptosis and injury in SAP model. Mechanistically, ATF6 promoted AIFM2 transcription by binding to p53 and AIFM2 promoters. Conclusion: These results reveal that ATF6/p53/AIFM2 pathway plays a critical role in acinar apoptosis during SAP progression, highlighting novel therapeutic target molecules for SAP.
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PMID:ATF6 aggravates acinar cell apoptosis and injury by regulating p53/AIFM2 transcription in Severe Acute Pancreatitis. 3272 72