科研之友
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摘要
Genetic analysis of TP63 indicates that Delta Np63 isoforms are required for preservation of self-renewing capacity in the stem cell compartments of diverse epithelial structures, however the underlying cellular and molecular mechanisms remain incompletely defined. Cellular quiescence is a common feature of adult stem cells that may account for their ability to retain long-term replicative capacity while simultaneously limiting cellular division. Similarly, quiescence within tumor stem cell populations may represent a mechanism by which these populations evade cytotoxic therapy and initiate tumor recurrence. Here we present evidence that Delta Np63 alpha, the predominant TP63 isoform in the regenerative compartment of diverse epithelial structures promotes cellular quiescence via activation of Notch signaling. In HC11 cells, ectopic Delta Np63 alpha mediates a proliferative arrest in the 2N state coincident with reduced RNA synthesis characteristic of cellular quiescence. Additionally Delta Np63 alpha and other quiescence-inducing stimuli enhanced expression of Notch3 in HC11s and breast cancer cell lines and ectopic expression of the Notch3 intracellular domain (N3(ICD)) was sufficient to cause accumulation in G(0)/G(1) and increased expression of two genes associated with quiescence, Hes1 and Mxi1. Pharmacologic inhibition of Notch signaling, or shRNA-mediated suppression of Notch3 were sufficient to bypass quiescence induced by Delta Np63 alpha and other quiescence-inducing stimuli. These studies identify a novel mechanism by which Delta Np63 alpha preserves long-term replicative capacity by promoting cellular quiescence and identify the Notch signaling pathway as a mediator of multiple quiescence-inducing stimuli, including Delta Np63 alpha expression.
- 出版日期2011-9-15
