These TFs form the pluripotency “core circuitry” by reinforcing the expression of genes involved in keeping pluripotent SCs (PSCs) in an undifferentiated state and repressing differentiation-inducing transcription. To maintain pluripotency, embryonic SCs (ESCs) express TFs such as octamer-binding protein 4 (Oct-4), homeobox protein NANOG (Nanog), and SRY-box2 (SOX-2) (Kim et al, 2008), which are not expressed in differentiated somatic cells. Transcription factors (TFs) and chromatin regulatory proteins regulate core functions of SCs by maintaining their specific gene expression patterns (Lambert et al, 2018). Synopsisīoth embryonic development and homeostasis in adult tissues are regulated by a population of stem cells (SCs) that undergo self-renewal and also give rise to differentiated progenitors to replace lost cells. 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. 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. Lack of TFCP2L1 phosphorylation impaired the tumorigenic potency of BC cells in a xenograft model. The CDK1-TFCP2L1 pathway was activated in human BC cells, stimulating their proliferation, self-renewal, and invasion. Tfcp2l1 was phosphorylated at Thr177 by Cdk1, which affected ESC cell cycle progression, pluripotency, and differentiation.
In murine ESCs, the protein interactome and transcription targets of Tfcp2l1 indicated its involvement in cell cycle regulation. 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). However, their precise roles and regulatory mechanisms remain elusive. Molecular programs involved in embryogenesis are frequently upregulated in oncogenic dedifferentiation and metastasis. ‡ These authors contributed equally to this work.7 Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.6 Department of Stem Cell Biology, School of Medicine, Konkuk University, Seoul, Korea.5 Department of Urology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.4 Department of Convergence Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.3 Department of Pathology, Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangneung, Korea.2 Department of Physiology, University of Ulsan College of Medicine, Seoul, Korea.1 Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
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