期刊
MOLECULAR CELL
卷 12, 期 6, 页码 1413-1426出版社
CELL PRESS
DOI: 10.1016/S1097-2765(03)00490-8
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资金
- NATIONAL CANCER INSTITUTE [K08CA093655] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM058556, R01GM056230] Funding Source: NIH RePORTER
- NCI NIH HHS [K08CA093655] Funding Source: Medline
- NIGMS NIH HHS [GM58556, R01GM56230] Funding Source: Medline
The transcription factor NF-kappaB is activated by the degradation of its inhibitor IB, resulting in its nuclear translocation. However, the mechanism by which nuclear NF-kappaB is subsequently regulated is not clear. Here we demonstrate that NF-kappaB function is regulated by Pin1-mediated prolyl isomerization and ubiquitin-mediated proteolysis of its p65/RelA subunit. Upon cytokine treatment, Pin1 binds to the pThr254-Pro motif in p65 and inhibits p65 binding to IkappaBalpha, resulting in increased nuclear accumulation and protein stability of p65 and enhanced NF-kappaB activity. Significantly, Pin1-deficient mice and cells are refractory to NF-kappaB activation by cytokine signals. Moreover, the stability of p65 is controlled by ubiquitin-mediated proteolysis, facilitated by a cytokine signal inhibitor, SOCS-1, acting as a ubiquitin ligase. These findings uncover two important mechanisms of regulating NF-kappaB signaling and offer new insight into the pathogenesis and treatment of some human diseases such as cancers.
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