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Nat Commun. 2014 Nov 14;5:5384. doi: 10.1038/ncomms6384.

CSN6 drives carcinogenesis by positively regulating Myc stability.

Author information

1
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
2
Department of GI Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
3
Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
4
Department of Education and Research, Taichung Veterans General Hospital, No. 160, Section 3, Chung-Gang Road, Taichung, 40705 Taiwan, ROC.
5
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
6
1] Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [2] Department of Emergency Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.

Abstract

Cullin-RING ubiquitin ligases (CRLs) are critical in ubiquitinating Myc, while COP9 signalosome (CSN) controls neddylation of Cullin in CRL. The mechanistic link between Cullin neddylation and Myc ubiquitination/degradation is unclear. Here we show that Myc is a target of the CSN subunit 6 (CSN6)-Cullin signalling axis and that CSN6 is a positive regulator of Myc. CSN6 enhanced neddylation of Cullin-1 and facilitated autoubiquitination/degradation of Fbxw7, a component of CRL involved in Myc ubiquitination, thereby stabilizing Myc. Csn6 haplo-insufficiency decreased Cullin-1 neddylation but increased Fbxw7 stability to compromise Myc stability and activity in an Eμ-Myc mouse model, resulting in decelerated lymphomagenesis. We found that CSN6 overexpression, which leads to aberrant expression of Myc target genes, is frequent in human cancers. Together, these results define a mechanism for the regulation of Myc stability through the CSN-Cullin-Fbxw7 axis and provide insights into the correlation of CSN6 overexpression with Myc stabilization/activation during tumorigenesis.

PMID:
25395170
PMCID:
PMC4234183
DOI:
10.1038/ncomms6384
[Indexed for MEDLINE]
Free PMC Article

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