p53 directly represses Id2 to inhibit the proliferation of neural progenitor cells.

Neural progenitor cells (NPCs) have the capacity to proliferate and give rise to all major central nervous system cell types and represent a possible cell of origin in gliomagenesis. Deletion of the tumor suppressor gene Tp53 (p53) results in increased proliferation and self-renewal of NPCs and is a common genetic mutation found in glioma. We have identified inhibitor of DNA binding 2 (Id2) as a novel target gene directly repressed by p53 to maintain normal NPC proliferation. p53((-/-)) NPCs express elevated levels of Id2 and suppression of Id2 expression is sufficient to inhibit the increased proliferation and self-renewal which results from p53 loss. Elevated expression of Id2 in wild-type NPCs phenocopies the behavior of p53((-/-)) NPCs by enhancing NPC proliferation and self-renewal. Interestingly, p53 directly binds to a conserved site within the Id2 promoter to mediate these effects. Finally, we have identified elevated Id2 expression in glioma cell lines with mutated p53 and demonstrated that constitutive expression of Id2 plays a key role in the proliferation of glioma stem-like cells. These findings indicate that Id2 functions as a proproliferative gene that antagonizes p53-mediated cell cycle regulation in NPCs and may contribute to the malignant proliferation of glioma-derived tumor stem cells.

Hypoglossal nerve stimulation for obstructive sleep apnea: A review of the literature.

OBJECTIVE: To review the indications and clinical evidence supporting hypoglossal nerve stimulation (HNS) therapy for the treatment of moderate-to-severe obstructive sleep apnea (OSA). METHODS: Peer reviewed literature on hypoglossal nerve stimulation therapy for obstructive sleep apnea from 2001 to 2016. RESULTS: The only currently FDA-approved HNS device for the treatment of moderate-to-severe OSA is produced by Inspire Medical Systems, which recently published its 36-month outcomes data from its Stimulation Therapy for Apnea Reduction (STAR) trial. HNS therapy is currently indicated for moderate-to-severe OSA patients who are CPAP-intolerant, have a body mass index <32, apnea-hypopnea index <50, and without a concentric pattern of upper airway collapse on sleep endoscopy. CONCLUSIONS: Data from the STAR trial suggests that a subset of OSA patients can achieve a significant therapeutic response from hypoglossal nerve stimulation. However, these results may be limited in their generalizability to the broader OSA population.

Id2 mediates oligodendrocyte precursor cell maturation arrest and is tumorigenic in a PDGF-rich microenvironment.

Maturation defects occurring in adult tissue progenitor cells have the potential to contribute to tumor development; however, there is little experimental evidence implicating this cellular mechanism in the pathogenesis of solid tumors. Inhibitor of DNA-binding 2 (Id2) is a transcription factor known to regulate the proliferation and differentiation of primitive stem and progenitor cells. Id2 is derepressed in adult tissue neural stem cells (NSC) lacking the tumor suppressor Tp53 and modulates their proliferation. Constitutive expression of Id2 in differentiating NSCs resulted in maturation-resistant oligodendroglial precursor cells (OPC), a cell population implicated in the initiation of glioma. Mechanistically, Id2 overexpression was associated with inhibition of the Notch effector Hey1, a bHLH transcription factor that we here characterize as a direct transcriptional repressor of the oligodendroglial lineage determinant Olig2. Orthotopic inoculation of NSCs with enhanced Id2 expression into brains of mice engineered to express platelet-derived growth factor in the central nervous system resulted in glioma. These data implicate a mechanism of altered NSC differentiation in glioma development and characterize a novel mouse model that reflects key characteristics of the recently described proneural subtype of glioblastoma multiforme. Such findings support the emerging concept that the cellular and molecular characteristics of tumor cells are linked to the transformation of distinct subsets of adult tissue progenitors.