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:3.4.21.69 (
APC
)
16,337
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
p21
WAF1/CIP1
is a broad-acting cyclin-dependent kinase inhibitor. Its stability is essential for proper cell-cycle progression and cell fate decision. Ubiquitylation by the multiple E3 ubiquitin ligase complexes is the major regulatory mechanism of p21, which induces p21 degradation. However, it is unclear whether ubiquitylated p21 can be recycled. In this study, we report
USP11
as a deubiquitylase of p21. In the nucleus,
USP11
binds to p21, catalyzes the removal of polyubiquitin chains conjugated onto p21, and stabilizes p21 protein. As a result,
USP11
reverses p21 polyubiquitylation and degradation mediated by SCF
SKP2
, CRL4
CDT2
, and
APC
/C
CDC20
in a cell-cycle-independent manner. Loss of
USP11
causes the destabilization of p21 and induces the G1/S transition in unperturbed cells. Furthermore, p21 accumulation mediated by DNA damage is completely abolished in cells depleted of
USP11
, which results in abrogation of the G2 checkpoint and induction of apoptosis. Functionally,
USP11
-mediated stabilization of p21 inhibits cell proliferation and tumorigenesis in vivo. These findings reveal an important mechanism by which p21 can be stabilized by direct deubiquitylation, and they pinpoint a crucial role of the
USP11
-p21 axis in regulating cell-cycle progression and DNA damage responses.
...
PMID:Deubiquitylation and stabilization of p21 by USP11 is critical for cell-cycle progression and DNA damage responses. 2966 78
