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)

A phenotypic feature of aging is skeletal muscle wasting. It is characterized by a loss of muscle mass and strength. Age-related loss of muscle mass occurs through a reduction in the rate of protein synthesis, an increase in protein degradation or a combination of both. However, the underlying mechanism is still poorly understood. To test the hypothesis that the ubiquitin-proteasome pathway contributes to this phenomenon, we studied MuRF1 and atrogin-1 expression in Tibialis Anterior muscle of aged rats. These two E3 ligases are considered as sensitive markers of muscle protein degradation by the ubiquitin-proteasome system. Our results revealed that, in skeletal muscle of aged rats, the decline in muscle mass is accompanied by an increase in the level of oxidized proteins and ubiquitin conjugates (90%) whereas the functionality of the proteasome remains constant compared to young rats. Furthermore, the level of both MuRF1 and atrogin-1 mRNA is markedly up-regulated in aged muscle (respectively x2 and x2.5). Taken together these data argue for the involvement of the ubiquitin-proteasome pathway in sarcopenia of fast-twitch muscle, in particular through increased expression of MuRF1 and atrogin-1. Moreover, we observed a decrease in the IGF-1/Akt signalling pathways and elevated level of TNFalpha mRNA in aged rat muscle. Therefore, IGF-1/Akt and TNFalpha represent potential mediators implicated in the regulation of MuRF1 and atrogin-1 genes during aging.
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PMID:Atrophy-related ubiquitin ligases, atrogin-1 and MuRF1 are up-regulated in aged rat Tibialis Anterior muscle. 1694 34

Anterior gradient 2 (AGR2), a protein belonging to the protein disulfide isomerase (PDI) family, is overexpressed in multiple cancers and promotes angiogenesis to drive cancer progression. The mechanisms controlling AGR2 abundance in cancer remain largely unknown. Here, we observed that AGR2 expression is significantly suppressed by proteasome inhibitor MG132/bortezomib at mRNA and protein levels in lung cancer cells. MG132-mediated repression of AGR2 transcription was independent of ROS generation and ER stress induction, but partially resulted from the downregulated E2F1. Further investigation revealed that MG132 facilitated polyubiquitinated AGR2 degradation through activation of autophagy, as evidenced by predominant restoration of AGR2 level in cells genetic depletion of Atg5 and Atg7, or by autophagy inhibitors. Activation of autophagy by rapamycin noticeably reduced the AGR2 protein in cells and in the mouse tissue samples administrated with bortezomib. We also provided evidence identifying the K48-linked polyubiquitin chains conjugating onto K89 of AGR2 by an E3 ligase UBR5. In addition, an autophagy receptor NBR1 was demonstrated to be important in polyubiquitinated AGR2 clearance in response to MG132 or bortezomib. Importantly, downregulation of AGR2 by proteasome inhibition significantly enhanced antitumor activity of bevacizumab, highlighting the importance of AGR2 as a predictive marker for selection of subgroup patients in chemotherapy.
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PMID:Proteasome inhibition boosts autophagic degradation of ubiquitinated-AGR2 and enhances the antitumor efficiency of bevacizumab. 3064 55