Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.25.1 (proteasome)
 28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The promyelocytic leukemia (PML) protein, also known as TRIM19, functions as a major organizer of PML nuclear bodies (NBs) in most mammalian cells and plays important roles in antiviral activities against both DNA and RNA viruses. In this study, we found that the downregulation of PML rendered HeLa cells more susceptible to infection by enterovirus 71 (EV71), and the overexpression of the PMLIII or PMLIV isoforms inhibited viral protein expression and resulted in viral titers that were 2-3 log units lower than those in the control. Using short interfering RNAs, the downregulation of either the PMLIII or PMLIV isoform increased both viral protein VP1 expression and viral production. The PML repression of EV71 replication was partially mediated by the inhibition of autophagy, and PML deficiency triggered autophagy. Furthermore, the EV71 infection resulted in a reduction in PML independent of the proteasome pathway. Instead, PML degradation was mediated by virus protease 3Cpro. In conclusion, PML contributes to a cellular antiviral effect by inhibiting autophagy, which is countered by a disruption of promyelocytic leukemia protein-nuclear bodies mediated by viral protease 3Cpro.
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PMID:Promyelocytic Leukemia Restricts Enterovirus 71 Replication by Inhibiting Autophagy. 2992 92

Hepatitis B virus (HBV) is causally linked to hepatocellular injury and cell death, which are followed by hepatocellular carcinoma (HCC) after a long latent period. The HBV derived X protein (HBX) is the most potent carcinogenic factor for HCC, however, the molecular mechanism of HBX-induced transformation of hepatic cells in HCC is poorly understood. We have shown that nuclear receptor co-repressor (NCoR) is essential for the spatial repression of global transcription by the promyelocytic leukemia oncogenic domains (PODs), a frequent target of viral oncoproteins like HBX and that disintegration of PODs due to misfolded conformation dependent loss (MCDL) of NCoR is linked to promyelocytic and monocytic acute myeloid leukemia (AML). Given the key role of NCoR in cellular homeostasis across various tissue subtypes, we hypothesized that HBX-induced MCDL of NCoR might be linked to HCC through similar mechanism. Based on this hypothesis, the conformation of NCoR in HCC derived tumor cells and primary human tissue sections were analyzed and a selective MCDL of NCoR in HBX positive HCC cells was identified. HBX triggered the misfolding of NCoR through ubiquitination, followed by its degradation by autophagy, thus suggesting a cross talk between ubiquitin proteasome system (UPS) and autophagy lysosomal pathway (ALP) in MCDL of NCoR in HBX positive HCC cells. SiRNA-induced NCoR ablation selectively impaired the growth and survival of HBX positive HCC cells, suggesting a role of MCDL in the growth and survival of HBX positive HCC cells. These finding identify a possible crosstalk between UPS and ALP in the misfolding and loss of NCoR in HBX positive HCC cells and suggest a role of autophagic recycling of misfolded NCoR in the activation of oncogenic metabolic signaling in HCC. The misfolded NCoR reported in this study represents a novel conformation based molecular target which could be valuable in the design and development of tumor cell specific diagnostic and therapeutic approach for HBX positive HCC.
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PMID:Autophagic Degradation of Misfolded Nuclear Receptor Co-repressor (NCoR) Is Linked to the Growth of Tumor Cells in HBX Positive Hepatocellular Carcinoma (HCC). 3185 Feb 20


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