title: A microRNA miR-34a-regulated bimodal switch targets Notch in colon cancer stem cells.
abstract: 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.
authors: School of Electrical and Computer Engineering, Cornell University, Ithaca, NY 14853, USA.
authors: Pengcheng
authors: P
authors: Bu
authors: Kai-Yuan
authors: KY
authors: Chen
authors: Joyce Huan
authors: JH
authors: Chen
authors: Lihua
authors: L
authors: Wang
authors: Jewell
authors: J
authors: Walters
authors: Yong Jun
authors: YJ
authors: Shin
authors: Julian P
authors: JP
authors: Goerger
authors: Jian
authors: J
authors: Sun
authors: Mavee
authors: M
authors: Witherspoon
authors: Nikolai
authors: N
authors: Rakhilin
authors: Jiahe
authors: J
authors: Li
authors: Herman
authors: H
authors: Yang
authors: Jeff
authors: J
authors: Milsom
authors: Sang
authors: S
authors: Lee
authors: Warren
authors: W
authors: Zipfel
authors: Moonsoo M
authors: MM
authors: Jin
authors: Zeynep H
authors: ZH
authors: Gümüş
authors: Steven M
authors: SM
authors: Lipkin
authors: Xiling
authors: X
authors: Shen
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D060049:Asymmetric Cell Division; D063646:Carcinogenesis / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D019070:Cell Lineage / Q000235:genetics; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D008875:Middle Aged; D009367:Neoplasm Staging; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D021381:Protein Transport; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: C522425:MIRN34 microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; D009419:Nerve Tissue Proteins; C113026:NUMB protein, human; D051880:Receptors, Notch
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