Phosphorylation of TFCP2L1 by CDK1 is required for stem cell pluripotency and bladder carcinogenesis

Autor: 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
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Zdroj: EMBO Molecular Medicine, Vol 12, Iss 1, Pp n/a-n/a (2020)
Druh dokumentu: article
ISSN: 1757-4684
1757-4676
DOI: 10.15252/emmm.201910880
Popis: 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.
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