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)

Glioblastoma is a very aggressive form of brain tumor with limited therapeutic options. Usually, glioblastoma is treated with ionizing radiation (IR) and chemotherapy after surgical removal. However, radiotherapy is frequently unsuccessful, among others owing to resistance mechanisms the tumor cells have developed. Antiapoptotic B-cell leukemia (Bcl)-2 family members can contribute to radioresistance by interfering with apoptosis induction in response to IR. Bcl-2 and the closely related Bcl-xL and Mcl-1 are often overexpressed in glioblastoma cells. In contrast to Bcl-2 and Bcl-xL, Mcl-1 is a short-lived protein whose stability is closely regulated by ubiquitylation-dependent proteasomal degradation. Although ubiquitin ligases facilitate degradation, the deubiquitylating enzyme ubiquitin-specific protease 9x (USP9x) interferes with degradation by removing polyubiquitin chains from Mcl-1, thereby stabilizing this protein. Thus, an inability to downregulate Mcl-1 by enhanced USP9x activity might contribute to radioresistance. Here we analyzed the impact of USP9x on Mcl-1 levels and radiosensitivity in glioblastoma cells. Correlating Mcl-1 and USP9x expressions were significantly higher in human glioblastoma than in astrocytoma. Downregulation of Mcl-1 correlated with apoptosis induction in established glioblastoma cell lines. Although Mcl-1 knockdown by siRNA increased apoptosis induction after irradiation in all glioblastoma cell lines, USP9x knockdown significantly improved radiation-induced apoptosis in one of four cell lines and slightly increased apoptosis in another cell line. In the latter two cell lines, USP9x knockdown also increased radiation-induced clonogenic death. The massive downregulation of Mcl-1 and apoptosis induction in A172 cells transfected with USP9x siRNA shows that the deubiquitinase regulates cell survival by regulating Mcl-1 levels. In contrast, USP9x regulated radiosensitivity in Ln229 cells without affecting Mcl-1 levels. We conclude that USP9x can control survival and radiosensitivity in glioblastoma cells by Mcl-1-dependent and Mcl-1-independent mechanisms.
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PMID:Deubiquitylating enzyme USP9x regulates radiosensitivity in glioblastoma cells by Mcl-1-dependent and -independent mechanisms. 2677 94

Glioblastoma is a malignant primary brain tumor with poor prognosis with a median survival of only 12-15 months. The high mortality rate of this disease is mainly due to the chemoresistance resulting from various reasons. Ubiquitin-specific protease 4 (USP4) has recently been found to be elevated in various types of cancer through regulating P53 activity. However, whether USP4 is responsible for chemoresistance in glioblastoma is not clear. In the present study, the expression of USP4 in glioblastoma tissues and cell lines, as well as its association with temozolomide (TMZ) chemoresistance was analyzed. The results demonstrated that USP4 was significantly upregulated in glioblastoma tissues and cell lines at the mRNA and protein levels. Notably, USP4 knockdown alone did not affect glioblastoma cell viability; however, when USP4 knockdown cells were treated with TMZ, the cell viability was decreased significantly. In addition, the results revealed that cleaved poly(ADP-ribose) polymerase level increased when USP4 was knocked down in glioblastoma cells treated with TMZ. It was also observed that P53 was increased in U251 and U87 cells with USP4 knockdown. Following treatment with a P53 specific inhibitor, the results suggested that USP4 mediated chemoresistance through inhibiting apoptosis in a P53-dependent manner. In conclusion, the data revealed the critical role of USP4 in TMZ resistance in glioblastoma and provided new insight for future drug development for the treatment of this disease.
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PMID:Deubiquitinating enzyme 4 facilitates chemoresistance in glioblastoma by inhibiting P53 activity. 3065 54