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: EC:3.4.25.1 (
proteasome
)
28,817
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
C53/LZAP (also named as Cdk5rap3) is a putative tumor suppressor that plays important roles in multiple cell signaling pathways, including DNA damage response and NF-kappaB signaling. Yet how its function is regulated remains largely unclear. Here we report the isolation and characterization of two novel C53/LZAP-interacting proteins, RCAD (Regulator of C53/LZAP and
DDRGK1
) and
DDRGK1
(
DDRGK domain-containing protein 1
). Our co-immunoprecipitation assays confirmed their interactions, while gel filtration assay indicated that C53/LZAP and RCAD may form a large protein complex. Intriguingly, we found that RCAD knockdown led to dramatic reduction of C53/LZAP and
DDRGK1
proteins. We also found that C53/LZAP and
DDRGK1
became more susceptible to the
proteasome
-mediated degradation in RCAD knockdown cells, whereas their ubiquitination was significantly attenuated by RCAD overexpression. In addition, we found that RCAD, like C53/LZAP, also plays an important role in regulation of NF-kappaB signaling and cell invasion. Taken together, our findings strongly suggest that RCAD is a novel regulator of C53/LZAP tumor suppressor and NF-kappaB signaling.
...
PMID:A novel C53/LZAP-interacting protein regulates stability of C53/LZAP and DDRGK domain-containing Protein 1 (DDRGK1) and modulates NF-kappaB signaling. 2022 63
p53 is the most intensively studied tumour suppressor
1
. The regulation of p53 homeostasis is essential for its tumour-suppressive function
2,3
. Although p53 is regulated by an array of post-translational modifications, both during normal homeostasis and in stress-induced responses
2-4
, how p53 maintains its homeostasis remains unclear. UFMylation is a recently identified ubiquitin-like modification with essential biological functions
5-7
. Deficiency in this modification leads to embryonic lethality in mice and disease in humans
8-12
. Here, we report that p53 can be covalently modified by UFM1 and that this modification stabilizes p53 by antagonizing its ubiquitination and
proteasome
degradation. Mechanistically, UFL1, the UFM1 ligase
6
, competes with MDM2 to bind to p53 for its stabilization. Depletion of UFL1 or
DDRGK1
, the critical regulator of UFMylation
6,13
, decreases p53 stability and in turn promotes cell growth and tumour formation in vivo. Clinically, UFL1 and
DDRGK1
expression are downregulated and positively correlated with levels of p53 in a high percentage of renal cell carcinomas. Our results identify UFMylation as a crucial post-translational modification for maintenance of p53 stability and tumour-suppressive function, and point to UFMylation as a promising therapeutic target in cancer.
...
PMID:UFMylation maintains tumour suppressor p53 stability by antagonizing its ubiquitination. 3280 1
