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.

中文翻译：

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CDK1 对 TFCP2L1 的磷酸化是干细胞多能性和膀胱癌发生所必需的。

参与胚胎发生的分子程序在致癌去分化和转移中经常上调。然而，它们的确切作用和监管机制仍然难以捉摸。在这里，我们发现 TFCP2L1（一种多能性相关转录因子）的 CDK1 磷酸化在胚胎干细胞 (ESC) 中协调多能性和细胞周期，并且在侵袭性膀胱癌 (BC) 中异常激活。在小鼠 ESC 中，Tfcp2l1 的蛋白质相互作用组和转录靶标表明其参与细胞周期调节。Tfcp2l1 在 Thr177 处被 Cdk1 磷酸化，从而影响 ESC 细胞周期进程、多能性和分化。CDK1-TFCP2L1 通路在人类 BC 细胞中被激活，刺激其增殖、自我更新和侵袭。TFCP2L1 磷酸化的缺乏会损害异种移植模型中 BC 细胞的致瘤能力。在 BC 患者中，TFCP2L1 和 CDK1 的高共表达与不利的临床特征相关，包括肿瘤分级、淋巴管和固有肌层侵犯以及远处转移，并且是癌症特异性生存的独立预后因素。这些发现证明了 CDK1 介导的 TFCP2L1 磷酸化在干细胞多能性以及与 BC 进展相关的致瘤干性特征中的分子和临床意义。