Phosphorylation of TFCP2L1 by CDK1 is required for stem cell pluripotency and bladder carcinogenesis
Abstract Molecular programs involved in embryogenesis are frequently upregulated in oncogenic dedifferentiation and metastasis. However, their precise roles and regulatory mechanisms remain elusive. Here, we showed that CDK1 phosphorylation of TFCP2L1, a pluripotency‐associated transcription factor,...
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| Format: | Article |
| Language: | English |
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Springer Nature
2019-11-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201910880 |
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| author | Jinbeom Heo Byeong‐Joo Noh Seungun Lee Hye‐Yeon Lee YongHwan Kim Jisun Lim Hyein Ju Hwan Yeul Yu Chae‐Min Ryu Peter CW Lee Hwangkyo Jeong Yumi Oh Kyunggon Kim Sang‐Yeob Kim Jaekyoung Son Bumsik Hong Jong Soo Kim Yong Mee Cho Dong‐Myung Shin |
| author_facet | Jinbeom Heo Byeong‐Joo Noh Seungun Lee Hye‐Yeon Lee YongHwan Kim Jisun Lim Hyein Ju Hwan Yeul Yu Chae‐Min Ryu Peter CW Lee Hwangkyo Jeong Yumi Oh Kyunggon Kim Sang‐Yeob Kim Jaekyoung Son Bumsik Hong Jong Soo Kim Yong Mee Cho Dong‐Myung Shin |
| author_sort | Jinbeom Heo |
| collection | DOAJ |
| description | Abstract Molecular programs involved in embryogenesis are frequently upregulated in oncogenic dedifferentiation and metastasis. However, their precise roles and regulatory mechanisms remain elusive. Here, we showed that CDK1 phosphorylation of TFCP2L1, a pluripotency‐associated transcription factor, orchestrated pluripotency and cell‐cycling in embryonic stem cells (ESCs) and was aberrantly activated in aggressive bladder cancers (BCs). In murine ESCs, the protein interactome and transcription targets of Tfcp2l1 indicated its involvement in cell cycle regulation. Tfcp2l1 was phosphorylated at Thr177 by Cdk1, which affected ESC cell cycle progression, pluripotency, and differentiation. The CDK1‐TFCP2L1 pathway was activated in human BC cells, stimulating their proliferation, self‐renewal, and invasion. Lack of TFCP2L1 phosphorylation impaired the tumorigenic potency of BC cells in a xenograft model. In patients with BC, high co‐expression of TFCP2L1 and CDK1 was associated with unfavorable clinical characteristics including tumor grade, lymphovascular and muscularis propria invasion, and distant metastasis and was an independent prognostic factor for cancer‐specific survival. These findings demonstrate the molecular and clinical significance of CDK1‐mediated TFCP2L1 phosphorylation in stem cell pluripotency and in the tumorigenic stemness features associated with BC progression. |
| format | Article |
| id | doaj-art-29e83acab2ea41f18bc970a3809a70c1 |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2019-11-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-29e83acab2ea41f18bc970a3809a70c12025-08-20T03:43:10ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842019-11-0112112310.15252/emmm.201910880Phosphorylation of TFCP2L1 by CDK1 is required for stem cell pluripotency and bladder carcinogenesisJinbeom Heo0Byeong‐Joo Noh1Seungun Lee2Hye‐Yeon Lee3YongHwan Kim4Jisun Lim5Hyein Ju6Hwan Yeul Yu7Chae‐Min Ryu8Peter CW Lee9Hwangkyo Jeong10Yumi Oh11Kyunggon Kim12Sang‐Yeob Kim13Jaekyoung Son14Bumsik Hong15Jong Soo Kim16Yong Mee Cho17Dong‐Myung Shin18Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of MedicineDepartment of Pathology, Gangneung Asan Hospital, University of Ulsan College of MedicineDepartment of Biomedical Sciences, Asan Medical Center, University of Ulsan College of MedicineDepartment of Biomedical Sciences, Asan Medical Center, University of Ulsan College of MedicineDepartment of Biomedical Sciences, Asan Medical Center, University of Ulsan College of MedicineDepartment of Biomedical Sciences, Asan Medical Center, University of Ulsan College of MedicineDepartment of Biomedical Sciences, Asan Medical Center, University of Ulsan College of MedicineDepartment of Biomedical Sciences, Asan Medical Center, University of Ulsan College of MedicineDepartment of Biomedical Sciences, Asan Medical Center, University of Ulsan College of MedicineDepartment of Biomedical Sciences, Asan Medical Center, University of Ulsan College of MedicineDepartment of Convergence Medicine, Asan Medical Center, University of Ulsan College of MedicineDepartment of Convergence Medicine, Asan Medical Center, University of Ulsan College of MedicineDepartment of Convergence Medicine, Asan Medical Center, University of Ulsan College of MedicineDepartment of Convergence Medicine, Asan Medical Center, University of Ulsan College of MedicineDepartment of Biomedical Sciences, Asan Medical Center, University of Ulsan College of MedicineDepartment of Urology, Asan Medical Center, University of Ulsan College of MedicineDepartment of Stem Cell Biology, School of Medicine, Konkuk UniversityDepartment of Pathology, Asan Medical Center, University of Ulsan College of MedicineDepartment of Biomedical Sciences, Asan Medical Center, University of Ulsan College of MedicineAbstract Molecular programs involved in embryogenesis are frequently upregulated in oncogenic dedifferentiation and metastasis. However, their precise roles and regulatory mechanisms remain elusive. Here, we showed that CDK1 phosphorylation of TFCP2L1, a pluripotency‐associated transcription factor, orchestrated pluripotency and cell‐cycling in embryonic stem cells (ESCs) and was aberrantly activated in aggressive bladder cancers (BCs). In murine ESCs, the protein interactome and transcription targets of Tfcp2l1 indicated its involvement in cell cycle regulation. Tfcp2l1 was phosphorylated at Thr177 by Cdk1, which affected ESC cell cycle progression, pluripotency, and differentiation. The CDK1‐TFCP2L1 pathway was activated in human BC cells, stimulating their proliferation, self‐renewal, and invasion. Lack of TFCP2L1 phosphorylation impaired the tumorigenic potency of BC cells in a xenograft model. In patients with BC, high co‐expression of TFCP2L1 and CDK1 was associated with unfavorable clinical characteristics including tumor grade, lymphovascular and muscularis propria invasion, and distant metastasis and was an independent prognostic factor for cancer‐specific survival. These findings demonstrate the molecular and clinical significance of CDK1‐mediated TFCP2L1 phosphorylation in stem cell pluripotency and in the tumorigenic stemness features associated with BC progression.https://doi.org/10.15252/emmm.201910880bladder cancerCDK1embryonic stem cellpluripotencystemness features |
| spellingShingle | Jinbeom Heo Byeong‐Joo Noh Seungun Lee Hye‐Yeon Lee YongHwan Kim Jisun Lim Hyein Ju Hwan Yeul Yu Chae‐Min Ryu Peter CW Lee Hwangkyo Jeong Yumi Oh Kyunggon Kim Sang‐Yeob Kim Jaekyoung Son Bumsik Hong Jong Soo Kim Yong Mee Cho Dong‐Myung Shin Phosphorylation of TFCP2L1 by CDK1 is required for stem cell pluripotency and bladder carcinogenesis EMBO Molecular Medicine bladder cancer CDK1 embryonic stem cell pluripotency stemness features |
| title | Phosphorylation of TFCP2L1 by CDK1 is required for stem cell pluripotency and bladder carcinogenesis |
| title_full | Phosphorylation of TFCP2L1 by CDK1 is required for stem cell pluripotency and bladder carcinogenesis |
| title_fullStr | Phosphorylation of TFCP2L1 by CDK1 is required for stem cell pluripotency and bladder carcinogenesis |
| title_full_unstemmed | Phosphorylation of TFCP2L1 by CDK1 is required for stem cell pluripotency and bladder carcinogenesis |
| title_short | Phosphorylation of TFCP2L1 by CDK1 is required for stem cell pluripotency and bladder carcinogenesis |
| title_sort | phosphorylation of tfcp2l1 by cdk1 is required for stem cell pluripotency and bladder carcinogenesis |
| topic | bladder cancer CDK1 embryonic stem cell pluripotency stemness features |
| url | https://doi.org/10.15252/emmm.201910880 |
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