Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Macrophage migration inhibitory factor (MIF) binds to c-Jun activation domain binding protein-1 (JAB1)/subunit 5 of COP9 signalosome (CSN5) and modulates cell signaling and the cell cycle through JAB1. The binding domain of JAB1 responsible for binding to MIF is unknown. We hypothesized that the conserved Mpr1p Pad1p N-terminal (MPN) domain of JAB1 may mediate binding to MIF. In fact, yeast two hybrid (YTH) and in vitro translation/coimmunoprecipitation (CoIP) analysis showed that a core MPN domain, which did not cover the functional JAB1/MPN/Mov34 metalloenzyme (JAMM) deneddylase sequence, binds to MIF comparable to full-length JAB1. YTH and pull-down analysis in conjunction with nanobead affinity matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry demonstrated that MIF(50-65) and MPN are sufficient to mediate MIF-JAB1 interaction, respectively. Finally, endogenous CoIP of MIF-CSN6 complexes from mammalian cells demonstrated that MPN is responsible for MIF-JAB1 binding in vivo, and, as CSN6 does not contain a functional JAMM motif, confirmed that the interaction does not require JAMM.
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PMID:Binding of JAB1/CSN5 to MIF is mediated by the MPN domain but is independent of the JAMM motif. 1575 63

CSN6, a critical subunit of the constitutive photomorphogenesis 9 (COP9) signalosome (CSN), has received attention as a regulator of the degradation of cancer-related proteins such as p53, c-myc and c-Jun, through the ubiquitin-proteasome system, suggesting its importance in cancerogenesis. However, the biological functions and molecular mechanisms of CSN6 in glioblastoma (GBM) remain poorly understood. Here, we report that GBM tumors overexpressed CSN6 compared with normal brain tissues and that CSN6 promoted GBM cell proliferation, migration, invasion and tumorigenesis. Erlotinib, a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, was used to reveal that the proliferative and metastatic effects of CSN6 on GBM cells were EGFR dependent. We also found that CSN6 positively regulated EGFR stability via reduced levels of EGFR ubiquitination, thereby elevating steady expression of EGFR. In addition, this study is the first description of a novel role for the CSN6-interacting E3 ligase, CHIP (carboxyl terminus of heat-shock protein 70-interacting protein), regulating EGFR ubiquitination in cancer cells. We showed that CSN6 associated with CHIP and led to CHIP destabilization by increasing CHIP self-ubiquitination. Moreover, CSN6 decreased CHIP expression and increased EGFR expression in the tumor samples. Deregulation of this axis promoted GBM cell's proliferation and metastasis. Thus, our study provides insights into the applicability of using the CSN6-CHIP-EGFR axis as a potential therapeutic target in cancer.
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PMID:CSN6 controls the proliferation and metastasis of glioblastoma by CHIP-mediated degradation of EGFR. 2754 21