title: ΔNp63α promotes cellular quiescence via induction and activation of Notch3.
abstract: Genetic analysis of TP63 indicates that ΔNp63 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 ΔNp63α, the predominant TP63 isoform in the regenerative compartment of diverse epithelial structuresm, promotes cellular quiescence via activation of Notch signaling. In HC11 cells, ectopic ΔNp63α mediates a proliferative arrest in the 2N state coincident with reduced RNA synthesis characteristic of cellular quiescence. Additionally, ΔNp63α 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 ΔNp63α and other quiescence-inducing stimuli. These studies identify a novel mechanism by which ΔNp63α preserves long-term replicative capacity by promoting cellular quiescence and identify the Notch signaling pathway as a mediator of multiple quiescence-inducing stimuli, including ΔNp63α expression.
authors.affiliation: Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, NH, USA.
authors.forename: Sierra
authors.initials: S
authors.lastname: Kent
authors.forename: Justine
authors.initials: J
authors.lastname: Hutchinson
authors.forename: Amanda
authors.initials: A
authors.lastname: Balboni
authors.forename: Andrew
authors.initials: A
authors.lastname: Decastro
authors.forename: Pratima
authors.initials: P
authors.lastname: Cherukuri
authors.forename: James
authors.initials: J
authors.lastname: Direnzo
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism; D053687:Adult Stem Cells / Q000166:cytology / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003001:Cloning, Molecular; D004261:DNA Replication; D005260:Female; D005434:Flow Cytometry; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D016086:Lentivirus / Q000235:genetics / Q000378:metabolism; D051379:Mice; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D000072056:Transcription Factor HES-1; D015533:Transcriptional Activation; D014162:Transfection
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D010750:Phosphoproteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000071656:Receptor, Notch3; D051880:Receptors, Notch; D015534:Trans-Activators; D000072056:Transcription Factor HES-1; C499373:Notch3 protein, mouse; C486419:Trp63 protein, mouse; C078493:HES1 protein, human