Degradation of the Tumor Suppressor PDCD4 Is Impaired by the Suppression of p62/SQSTM1 and Autophagy
PDCD4 (programmed cell death 4) is a tumor suppressor that plays a crucial role in multiple cellular functions, such as the control of protein synthesis and transcriptional control of some genes, the inhibition of cancer invasion and metastasis. The expression of this protein is controlled by synthe...
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MDPI AG
2020-01-01
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| author | M. Manirujjaman Iwata Ozaki Yuzo Murata Jing Guo Jinghe Xia Kenichi Nishioka Rasheda Perveen Hirokazu Takahashi Keizo Anzai Sachiko Matsuhashi |
| author_facet | M. Manirujjaman Iwata Ozaki Yuzo Murata Jing Guo Jinghe Xia Kenichi Nishioka Rasheda Perveen Hirokazu Takahashi Keizo Anzai Sachiko Matsuhashi |
| author_sort | M. Manirujjaman |
| collection | DOAJ |
| description | PDCD4 (programmed cell death 4) is a tumor suppressor that plays a crucial role in multiple cellular functions, such as the control of protein synthesis and transcriptional control of some genes, the inhibition of cancer invasion and metastasis. The expression of this protein is controlled by synthesis, such as via transcription and translation, and degradation by the ubiquitin-proteasome system. The mitogens, known as tumor promotors, EGF (epidermal growth factor) and TPA (12-<i>O</i>-tetradecanoylphorbol-13-acetate) stimulate the degradation of PDCD4 protein. However, the whole picture of PDCD4 degradation mechanisms is still unclear, we therefore investigated the relationship between PDCD4 and autophagy. The proteasome inhibitor MG132 and the autophagy inhibitor bafilomycin A1 were found to upregulate the PDCD4 levels. PDCD4 protein levels increased synergistically in the presence of both inhibitors. Knockdown of p62/SQSTM1 (sequestosome-1), a polyubiquitin binding partner, also upregulated the PDCD4 levels. P62 and LC3 (microtubule-associated protein 1A/1B-light chain 3)-II were co-immunoprecipitated by an anti-PDCD4 antibody. Colocalization particles of PDCD4, p62 and the autophagosome marker LC3 were observed and the colocalization areas increased in the presence of autophagy and/or proteasome inhibitor(s) in Huh7 cells. In ATG (autophagy related) 5-deficient Huh7 cells in which autophagy was impaired, the PDCD4 levels were increased at the basal levels and upregulated in the presence of autophagy inhibitors. Based on the above findings, we concluded that after phosphorylation in the degron and ubiquitination, PDCD4 is degraded by both the proteasome and autophagy systems. |
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| language | English |
| last_indexed | 2024-03-12T08:01:30Z |
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| spelling | doaj.art-04295055b69b4424b06f9e025cdd9ef72023-09-02T19:50:26ZengMDPI AGCells2073-44092020-01-019121810.3390/cells9010218cells9010218Degradation of the Tumor Suppressor PDCD4 Is Impaired by the Suppression of p62/SQSTM1 and AutophagyM. Manirujjaman0Iwata Ozaki1Yuzo Murata2Jing Guo3Jinghe Xia4Kenichi Nishioka5Rasheda Perveen6Hirokazu Takahashi7Keizo Anzai8Sachiko Matsuhashi9Department of Internal Medicine, Saga Medical School, Saga University, 5-1-1 Nabeshima, Saga 849-8501, JapanDepartment of Internal Medicine, Saga Medical School, Saga University, 5-1-1 Nabeshima, Saga 849-8501, JapanDivision of Histology and Neuroanatomy, Department of Anatomy and Physiology, Saga Medical School, Saga University, 5-1-1 Nabeshima, Saga 849-8501, JapanDepartment of Internal Medicine, Saga Medical School, Saga University, 5-1-1 Nabeshima, Saga 849-8501, JapanDepartment of Internal Medicine, Saga Medical School, Saga University, 5-1-1 Nabeshima, Saga 849-8501, JapanDivision of Molecular Genetics and Epigenetics, Department of Biomolecular Sciences, Saga Medical School, Saga University, 5-1-1 Nabeshima, Saga 849-8501, JapanDepartment of Internal Medicine, Saga Medical School, Saga University, 5-1-1 Nabeshima, Saga 849-8501, JapanDepartment of Internal Medicine, Saga Medical School, Saga University, 5-1-1 Nabeshima, Saga 849-8501, JapanDepartment of Internal Medicine, Saga Medical School, Saga University, 5-1-1 Nabeshima, Saga 849-8501, JapanDepartment of Internal Medicine, Saga Medical School, Saga University, 5-1-1 Nabeshima, Saga 849-8501, JapanPDCD4 (programmed cell death 4) is a tumor suppressor that plays a crucial role in multiple cellular functions, such as the control of protein synthesis and transcriptional control of some genes, the inhibition of cancer invasion and metastasis. The expression of this protein is controlled by synthesis, such as via transcription and translation, and degradation by the ubiquitin-proteasome system. The mitogens, known as tumor promotors, EGF (epidermal growth factor) and TPA (12-<i>O</i>-tetradecanoylphorbol-13-acetate) stimulate the degradation of PDCD4 protein. However, the whole picture of PDCD4 degradation mechanisms is still unclear, we therefore investigated the relationship between PDCD4 and autophagy. The proteasome inhibitor MG132 and the autophagy inhibitor bafilomycin A1 were found to upregulate the PDCD4 levels. PDCD4 protein levels increased synergistically in the presence of both inhibitors. Knockdown of p62/SQSTM1 (sequestosome-1), a polyubiquitin binding partner, also upregulated the PDCD4 levels. P62 and LC3 (microtubule-associated protein 1A/1B-light chain 3)-II were co-immunoprecipitated by an anti-PDCD4 antibody. Colocalization particles of PDCD4, p62 and the autophagosome marker LC3 were observed and the colocalization areas increased in the presence of autophagy and/or proteasome inhibitor(s) in Huh7 cells. In ATG (autophagy related) 5-deficient Huh7 cells in which autophagy was impaired, the PDCD4 levels were increased at the basal levels and upregulated in the presence of autophagy inhibitors. Based on the above findings, we concluded that after phosphorylation in the degron and ubiquitination, PDCD4 is degraded by both the proteasome and autophagy systems.https://www.mdpi.com/2073-4409/9/1/218autophagyp62/sqstm1pdcd4proteasomeubiquitination |
| spellingShingle | M. Manirujjaman Iwata Ozaki Yuzo Murata Jing Guo Jinghe Xia Kenichi Nishioka Rasheda Perveen Hirokazu Takahashi Keizo Anzai Sachiko Matsuhashi Degradation of the Tumor Suppressor PDCD4 Is Impaired by the Suppression of p62/SQSTM1 and Autophagy Cells autophagy p62/sqstm1 pdcd4 proteasome ubiquitination |
| title | Degradation of the Tumor Suppressor PDCD4 Is Impaired by the Suppression of p62/SQSTM1 and Autophagy |
| title_full | Degradation of the Tumor Suppressor PDCD4 Is Impaired by the Suppression of p62/SQSTM1 and Autophagy |
| title_fullStr | Degradation of the Tumor Suppressor PDCD4 Is Impaired by the Suppression of p62/SQSTM1 and Autophagy |
| title_full_unstemmed | Degradation of the Tumor Suppressor PDCD4 Is Impaired by the Suppression of p62/SQSTM1 and Autophagy |
| title_short | Degradation of the Tumor Suppressor PDCD4 Is Impaired by the Suppression of p62/SQSTM1 and Autophagy |
| title_sort | degradation of the tumor suppressor pdcd4 is impaired by the suppression of p62 sqstm1 and autophagy |
| topic | autophagy p62/sqstm1 pdcd4 proteasome ubiquitination |
| url | https://www.mdpi.com/2073-4409/9/1/218 |
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