| Status | 已發表Published |
| Maturity of p100:NFkB Complex Determines p100 processing vs. Complete Degradation in Response to Non-Canonical NF-kB Signaling | |
Wang, V. Y.-F.  ; Fusco, A.; Mazumder, A.; Basak, S.; Ware, C.; Ghosh, G.
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| 2017-06-21 | |
| Source Publication | The 4th Macau Symposium on Biomedical Sciences Abstract Book
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| Abstract | NF-κB transcription factors are critical mediators of a diverse array of physiological processes through transcriptional regulation of hundreds of target genes. Inhibitor IκB proteins ensure appropriate NF-κB activation in stimulus- and cell-specific manners. Two proteins, p105 (NF-κB1) and p100 (NF-κB2) reside at the interface of both NF-κB and IκB activities by virtue of having both NF-κB and IκB domains. p100 and p105 are processed into NF-κB p52 and p50, respectively. Processing is carried out by the proteasome, which completely degrades the C-terminal IκB region. Unlike constitutive processing of p105, p100 undergoes inducible processing. NF-κB inhibitory activity of unprocessed p100, which is referred to as IκBδ, has been demonstrated to be critical in different cellular settings. Lack of IκBδ activity in osteoclast progenitor cells blocks osteoclast differentiation whereas p100 deficiency sensitizes differentiation. Similarly, cells devoid of p100 is defective in terminating pathogen-triggered NF-κB responses generated through sustained TLR. TLR stimulated expression of p100 through canonical pathway dampens NF-κB responses and IL-2 production in T cells. These observations suggest that like IκBα, IκBδ functions both pre- and post- stimulations. The processing of p100 into p52 is induced by a distinct class of stimuli such as LTβ, BAFF and CD40; and this NF-κB activation pathway is known as the non-canonical signaling pathway. The predominant NF-κB dimer that is activated from these stimuli is the p52:RelB heterodimer. The non-canonical NF-κB signaling pathway induces p100 processing through the activation of NF-κB inducing kinase (NIK) and IKKα/IKK1. Unregulated p100 processing has been reported to link to cancers. Recent reports have shown that hyper-activation of p100 processing in multiple myeloma patients is due to aberrant stabilization of NIK caused by mutations of different components in the NIK degradation pathway underscoring the importance of non-canonical NF-κB activation pathway. Previous experiments revealed that p100 processing is blocked in the presence of protein synthesis inhibitor cycloheximide. Although it was thought that new p100 synthesis is required for processing, in light of recent reports on NIK, it is unclear if continuous synthesis of NIK or p100 or both are essential for processing. Previous reports suggested that in addition to signal induced processing of p100 to p52, p100 might undergo complete degradation releasing other NF-κB subunits. However, there has been no clear experimental evidence to support the complete degradation or the consequence of complete p100 degradation. Here we investigate mechanism of p100 processing, and activation of p52:RelB and p50:RelA heterodimers. We will determine if p100 undergoes complete degradation; and if and how RelB influences p100 life cycle during signaling. |
| Keyword | NF-kB Non-canonical Signaling |
| Language | 英語English |
| The Source to Article | PB_Publication |
| PUB ID | 57349 |
| Document Type | Conference paper |
| Collection | DEPARTMENT OF BIOMEDICAL SCIENCES |
| Corresponding Author | Wang, V. Y.-F. |
| Recommended Citation GB/T 7714 | Wang, V. Y.-F.,Fusco, A.,Mazumder, A.,et al. Maturity of p100:NFkB Complex Determines p100 processing vs. Complete Degradation in Response to Non-Canonical NF-kB Signaling[C], 2017. |
| APA | Wang, V. Y.-F.., Fusco, A.., Mazumder, A.., Basak, S.., Ware, C.., & Ghosh, G. (2017). Maturity of p100:NFkB Complex Determines p100 processing vs. Complete Degradation in Response to Non-Canonical NF-kB Signaling. The 4th Macau Symposium on Biomedical Sciences Abstract Book. |
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