Abstract
The COP9 signalosome (CSN) is an evolutionarily conserved multi-protein complex found in plants and animals. In mammals, the CSN consists of eight subunits (CSN1-CSN8). It has been suggested to play a key role in tumorigenesis, because its subunits are frequently overexpressed in human cancers and because the CSN is involved in the regulation of a number of processes that are relevant to carcinogenesis and cancer progression, e.g. cell cycle control, signal transduction, and apoptosis. The best-studied biochemical function of the CSN is the control of cellular protein stability via the ubiquitin-proteasome system through regulation of cullin-RING E3 ligase (CRL) activity by deNEDDylation of cullins or by the deubiquitination function of the CSN. Through these activities, the CSN regulates the degradation of several tumor suppressors and oncogenes that are degraded by the 26S proteasome. This review summarizes recent findings that support CSN’s role as a potential key player in tumorigenesis in general, but particularly focuses on evidence on the role of the CSN in gastrointestinal cancers. We cover links to tumorigenesis in the liver, stomach, pancreas, and colon, gathering and discussing findings about CSN’s expression and its functional impact on cancer development and progression.
Highlights
The constitutive photomorphogenesis 9 (COP9) signalosome (CSN) and its Potential Role in CancerCancer diseases still belong to the most challenging human diseases that are associated with high mortality rates and that are difficult to cure with still only limited knowledge about the mechanisms of their development
USP15, a deubiquitinase (DUB) involved in NF-κB signaling [27]
It has been suggested to play a key role in tumorigenesis, because its subunits are frequently overexpressed in human cancers and because the constitutive photomorphogenesis 9 (COP9) signalosome (CSN) is involved in the regulation of a number of processes that are relevant to carcinogenesis and cancer progression, e.g. cell cycle control, signal transduction, and apoptosis
Summary
Cancer diseases still belong to the most challenging human diseases that are associated with high mortality rates and that are difficult to cure with still only limited knowledge about the mechanisms of their development. The CSN5 gene is rarely mutated, but its amplification was identified in hepatocellular carcinoma and breast tumors [39,43]. Protein and mRNA analysis in tumor lysates showed that CSN4 is overexpressed in prostate tumors [44]. An amplification of the CSN6 gene was identified in human breast cancer samples and in 17 breast cancer cell lines, and CSN6 protein levels were higher in human breast tumors compared to normal breast tissue [45]. Higher CSN6 levels were detected in malignant follicular thyroid carcinomas compared to benign thyroid lesions or normal thyroid tissue [45]. CSN5 and CSN6 mRNA levels were shown to be higher in tumors compared to normal tissue for most myelomas as well as in breast cancer and glioblastoma patients [46]. We here focus on the CSN and its role in gastrointestinal cancers
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