Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UNIPROT:P62988 (
Ubiquitin
)
4,326
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Amplification of
squamous cell carcinoma-related oncogene
(
SCCRO
) activates its function as an oncogene in a wide range of human cancers. The oncogenic activity of
SCCRO
requires its potentiating neddylation domain, which regulates its E3 activity for neddylation. The contribution of the N-terminal ubiquitin-associated (UBA) domain to
SCCRO
function remains to be defined. We found that the UBA domain of
SCCRO
preferentially binds to
polyubiquitin
chains in a linkage-independent manner. Binding of
polyubiquitin
chains to the UBA domain inhibits the neddylation activity of
SCCRO
in vivo by inhibiting
SCCRO
-promoted nuclear translocation of neddylation components and results in a corresponding decrease in cullin-RING-ligase-promoted ubiquitination. The results of colony formation and xenograft assays showed a mutation in the UBA domain of
SCCRO
that reduces binding to
polyubiquitin
chains, significantly enhancing its oncogenic activity. Analysis of 47 lung and head and neck squamous cell carcinomas identified a case with a frameshift mutation in
SCCRO
that putatively codes for a protein that lacks a UBA domain. Analysis of data from The Cancer Genome Atlas showed that recurrent mutations cluster in the UBA domains of
SCCRO
, lose the ability to bind to polyubiquitinated proteins, and have increased neddylation and transformation activities. Combined, these data suggest that the UBA domain functions as a negative regulator of
SCCRO
function. Mutations in the UBA domain lead to loss of inhibitory control, which results in increased biochemical and oncogenic activity. The clustering of mutations in the UBA domain of
SCCRO
suggests that mutations may be a mechanism of oncogene activation in human cancers.
...
PMID:The ubiquitin-associated (UBA) domain of SCCRO/DCUN1D1 protein serves as a feedback regulator of biochemical and oncogenic activity. 2541 Dec 43
