Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P62988 (Ubiquitin)
 4,326 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cell cycle progression requires the E3 ubiquitin ligase anaphase-promoting complex (APC/C), which uses the substrate adaptors CDC20 and CDH1 to target proteins for proteasomal degradation. The APC(CDH1) substrate cyclin A is critical for the G1/S transition and, paradoxically, accumulates even when APC(CDH1) is active. We show that the deubiquitinase USP37 binds CDH1 and removes degradative polyubiquitin from cyclin A. USP37 was induced by E2F transcription factors in G1, peaked at G1/S, and was degraded in late mitosis. Phosphorylation of USP37 by CDK2 stimulated its full activity. USP37 overexpression caused premature cyclin A accumulation in G1 and accelerated S phase entry, whereas USP37 knockdown delayed these events. USP37 was inactive in mitosis because it was no longer phosphorylated by CDK2. Indeed, it switched from an antagonist to a substrate of APC(CDH1) and was modified with degradative K11-linked polyubiquitin.
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PMID:Deubiquitinase USP37 is activated by CDK2 to antagonize APC(CDH1) and promote S phase entry. 2159 6

p21WAF1/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 SCFSKP2, CRL4CDT2, and APC/CCDC20 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.
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PMID:Deubiquitylation and stabilization of p21 by USP11 is critical for cell-cycle progression and DNA damage responses. 2966 78

Endometrial carcinoma(EC) is the most common cancer of female reproductive system, thus requiring for new effective biomarkers which could predict the onset of EC and poor prognosis. Our study integrated two GEO datasets(i.e.GSE63678, GSE17025) and TCGA(The Cancer Genome Atlas ) UCEC data to screen out 344 common differentially expressed genes(DEGs), which were further analyzed by GO(gene ontology) functions and KEGG(Kyoto Encyclopedia of Gene and Genome) pathways. KEGG analysis results showed these DEGs were mainly enriched in cell cycle, oocyte meiosis, cellular senescence, carbon metabolism and p53 signaling pathway. Top 20 hub genes with higher degree were selected from PPI(protein-protein interaction) network and 15 of them were associated with the prognosis of EC, that is, CCNB2, CDC20, BUB1B, UBE2C, AURKB, FOXM1, NCAPG, RRM2, TPX2, DLGAP5, CDCA8, CDC45, MKI67, BUB1, KIF2C. UBE2C(Ubiquitin Conjugating Enzyme E2 C) was chosen for further validation in TCGA cohort on mRNA level and in our patient samples on protein level by immunohistochemistry. UBE2C was significantly highly expressed in endometrial carcinoma, and its expression level was associated with advanced FIGO staging and poor prognosis. Cox risk model demonstrated high UBE2C expression was an independent risk factor. Somatic mutations, elevated copy number, DNA hypomethylation all contributed to its overexpression. Therefore, by combination of bioinformatics and experiment, our study provided a unique insight into the pathogenesis and molecular mechanisms underlying EC and discovered new biomarkers for early diagnosis and prognostic prediction. UBE2C could serve as a potential marker to predict poor prognosis and as a therapeutic target.
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PMID:Combining Bioinformatics and Experiments to Identify and Verify Key Genes with Prognostic Values in Endometrial Carcinoma. 3194 95

Ubiquitin-dependent proteolysis of cyclin B and securin initiates sister chromatid segregation and anaphase. The anaphase-promoting complex/cyclosome and its coactivator CDC20 (APC/CCDC20) form the main ubiquitin E3 ligase for these two proteins. APC/CCDC20 is regulated by CDK1-cyclin B and counteracting PP1 and PP2A family phosphatases through modulation of both activating and inhibitory phosphorylation. Here, we report that PP1 promotes cyclin B destruction at the onset of anaphase by removing specific inhibitory phosphorylation in the N-terminus of CDC20. Depletion or chemical inhibition of PP1 stabilizes cyclin B and results in a pronounced delay at the metaphase-to-anaphase transition after chromosome alignment. This requirement for PP1 is lost in cells expressing CDK1 phosphorylation-defective CDC206A mutants. These CDC206A cells show a normal spindle checkpoint response and rapidly destroy cyclin B once all chromosomes have aligned and enter into anaphase in the absence of PP1 activity. PP1 therefore facilitates the metaphase-to-anaphase transition by promoting APC/CCDC20-dependent destruction of cyclin B in human cells.
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PMID:PP1 promotes cyclin B destruction and the metaphase-anaphase transition by dephosphorylating CDC20. 3275 77