期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：30
DOI：10.1073/pnas.2203849119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
As a general model for cell cycle control, repressors keep cells quiescent until growth signals remove the inhibition. For S phase, this is exemplified by the Retinoblastoma (RB) protein and its inactivation. It was unknown whether similar mechanisms operate in the M phase. The Wnt signaling pathway is an important regulator of cell proliferation. Here, we find that Wnt induces expression of the transcription factor
Tbx3, which in turn represses mitotic inhibitors
E2f7 and
E2f8 to permit mitotic progression. Such a cascade of transcriptional repressors may be a general mechanism for cell division control. These findings have implications for tissue homeostasis and disease, as the function for Wnt signaling in mitosis is relevant to its widespread role in stem cells and cancer.
Cell proliferation is tightly controlled by inhibitors that block cell cycle progression until growth signals relieve this inhibition, allowing cells to divide. In several tissues, including the liver, cell proliferation is inhibited at mitosis by the transcriptional repressors E2F7 and E2F8, leading to formation of polyploid cells. Whether growth factors promote mitosis and cell cycle progression by relieving the E2F7/E2F8-mediated inhibition is unknown. We report here on a mechanism of cell division control in the postnatal liver, in which Wnt/β-catenin signaling maintains active hepatocyte cell division through
Tbx3, a Wnt target gene. The TBX3 protein directly represses transcription of
E2f7 and
E2f8, thereby promoting mitosis. This cascade of sequential transcriptional repressors, initiated by Wnt signals, provides a paradigm for exploring how commonly active developmental signals impact cell cycle completion.
