Molecular, Cellular and Developmental Biology Department (MCD), Centre de Biologie Intégrative (CBI), University of Toulouse, CNRS, UPS, 31062 Toulouse, France.
Molecular, Cellular and Developmental Biology Department (MCD), Centre de Biologie Intégrative (CBI), University of Toulouse, CNRS, UPS, 31062 Toulouse, France.
Cell Rep. 2023 Jun 27;42(6):112659. doi: 10.1016/j.celrep.2023.112659. Epub 2023 Jun 15.
p57 is a cyclin/CDK inhibitor and a negative regulator of cell proliferation. Here, we report that p57 regulates intestinal stem cell (ISC) fate and proliferation in a CDK-independent manner during intestinal development. In the absence of p57, intestinal crypts exhibit an increased proliferation and an amplification of transit-amplifying cells and of Hopx ISCs, which are no longer quiescent, while Lgr5 ISCs are unaffected. RNA sequencing (RNA-seq) analyses of Hopx ISCs show major gene expression changes in the absence of p57. We found that p57 binds to and inhibits the activity of Ascl2, a transcription factor critical for ISC specification and maintenance, by participating in the recruitment of a corepressor complex to Ascl2 target gene promoters. Thus, our data suggest that, during intestinal development, p57 plays a key role in maintaining Hopx ISC quiescence and repressing the ISC phenotype outside of the crypt bottom by inhibiting the transcription factor Ascl2 in a CDK-independent manner.
p57 是细胞周期蛋白/CDK 抑制剂，也是细胞增殖的负调控因子。在这里，我们报告 p57 在肠道发育过程中以不依赖 CDK 的方式调节肠道干细胞（ISC）的命运和增殖。在没有 p57 的情况下，肠隐窝表现出增殖增加和过渡扩增细胞以及 Hopx ISC 的扩增，这些细胞不再静止，而 Lgr5 ISC 不受影响。对 Hopx ISC 的 RNA 测序（RNA-seq）分析表明，在没有 p57 的情况下，主要基因表达发生变化。我们发现 p57 通过参与募集核心抑制复合物到 Ascl2 靶基因启动子，与转录因子 Ascl2 结合并抑制其活性，Ascl2 对于 ISC 的特化和维持至关重要。因此，我们的数据表明，在肠道发育过程中，p57 通过不依赖 CDK 的方式抑制转录因子 Ascl2 的活性，在维持 Hopx ISC 静止和抑制隐窝底部以外的 ISC 表型方面发挥关键作用。
