期刊
CELL STEM CELL
卷 12, 期 5, 页码 602-615出版社
CELL PRESS
DOI: 10.1016/j.stem.2013.03.002
关键词
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资金
- Cornell Nanobiotechnology Center, the Cornell Stem Cell Program
- [NIGMS R01GM95990]
- [NSF 1137269]
- [DARPA 19-1091726]
- [NCI R21CA162483]
- [NCI R21CA153049]
- Directorate For Engineering
- Div Of Chem, Bioeng, Env, & Transp Sys [1106153] Funding Source: National Science Foundation
- Directorate For Engineering
- Emerging Frontiers & Multidisciplinary Activities [1137269] Funding Source: National Science Foundation
microRNAs regulate developmental cell-fate decisions, tissue homeostasis, and oncogenesis in distinct ways relative to proteins. Here, we show that the tumor suppressor microRNA miR-34a is a cell-fate determinant in early-stage dividing colon cancer stem cells (CCSCs). In pair-cell assays, miR-34a distributes at high levels in differentiating progeny, whereas low levels of miR-34a demarcate self-renewing CCSCs. Moreover, miR-34a loss of function and gain of function alter the balance between self-renewal versus differentiation both in vitro and in vivo. Mechanistically, miR-34a sequesters Notch1 mRNA to generate a sharp threshold response where a bimodal Notch signal specifies the choice between self-renewal and differentiation. In contrast, the canonical cell-fate determinant Numb regulates Notch levels in a continuously graded manner. Altogether, our findings highlight a unique microRNA-regulated mechanism that converts noisy input into a toggle switch for robust cell-fate decisions in CCSCs.
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