The deubiquitination enzyme USP46 functions as a tumor suppressor by controlling PHLPP-dependent attenuation of Akt signaling in colon cancer
| Autor: | B. M. Evers, W. Wang, Prateek gulhati, Xin Li, Payton D. Stevens, H. Yang, Tianyan Gao |
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| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Male
Cancer Research USP46 medicine.disease_cause Deubiquitinating enzyme Mice 0302 clinical medicine Ubiquitin Phosphoprotein Phosphatases Protein Isoforms Genes Tumor Suppressor deubiquitination 0303 health sciences Mice Inbred BALB C biology Nuclear Proteins Up-Regulation Cell Transformation Neoplastic 030220 oncology & carcinogenesis Colonic Neoplasms Signal transduction Protein Binding Signal Transduction tumor suppressor Mice Nude Article 03 medical and health sciences Downregulation and upregulation Cell Line Tumor Endopeptidases Genetics medicine Animals Humans Protein Interaction Domains and Motifs PHLPP Molecular Biology Protein kinase B 030304 developmental biology Cell Proliferation Akt Ubiquitination HCT116 Cells HEK293 Cells Proteasome biology.protein Cancer research Carcinogenesis Proto-Oncogene Proteins c-akt |
| Zdroj: | Oncogene |
| ISSN: | 1476-5594 0950-9232 |
| Popis: | PH domain leucine-rich-repeats protein phosphatase (PHLPP) is a family of Ser/Thr protein phosphatases that serve as tumor suppressors by negatively regulating Akt. Our recent studies have demonstrated that the ubiquitin proteasome pathway has an important role in the downregulation of PHLPP in colorectal cancer. In this study, we show that the deubiquitinase USP46 stabilizes the expression of both PHLPP isoforms by reducing the rate of PHLPP degradation. USP46 binds to PHLPP and directly removes the polyubiquitin chains from PHLPP in vitro and in cells. Increased USP46 expression correlates with decreased ubiquitination and upregulation of PHLPP proteins in colon cancer cells, whereas knockdown of USP46 has the opposite effect. Functionally, USP46-mediated stabilization of PHLPP and the subsequent inhibition of Akt result in a decrease in cell proliferation and tumorigenesis of colon cancer cells in vivo. Moreover, reduced USP46 protein level is found associated with poor PHLPP expression in colorectal cancer patient specimens. Taken together, these results indentify a tumor suppressor role of USP46 in promoting PHLPP expression and inhibiting Akt signaling in colon cancer. |
| Databáze: | OpenAIRE |
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