CSN6 drives carcinogenesis by positively regulating Myc stability.

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.

journal_name

Nat Commun

journal_title

Nature communications

authors

Chen J,Shin JH,Zhao R,Phan L,Wang H,Xue Y,Post SM,Ho Choi H,Chen JS,Wang E,Zhou Z,Tseng C,Gully C,Velazquez-Torres G,Fuentes-Mattei E,Yeung G,Qiao Y,Chou PC,Su CH,Hsieh YC,Hsu SL,Ohshiro K,Shaikenov T,Wang H

doi

10.1038/ncomms6384

subject

Has Abstract

pub_date

2014-11-14 00:00:00

pages

5384

issn

2041-1723

pii

ncomms6384

journal_volume

5

pub_type

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