title: New roles for Notch in tuberous sclerosis.
abstract: Tuberous sclerosis complex (TSC) is a dominantly inherited disease that is characterized by the growth of multiple benign tumors that are often difficult to treat. TSC is caused by mutations that inactivate the TSC1 or TSC2 genes, which normally function to inhibit activation of mammalian target of rapamycin signaling. In this issue of the JCI, two studies reported by Karbowniczek et al. and Ma et al. link TSC inactivation with activated Notch signaling (see the related articles beginning on pages 93 and 103, respectively). Using a variety of approaches, both studies show that inactivation of TSC leads to Notch1 activation. Furthermore, studies in tumor cells suggest that inhibiting Notch slows growth of the tumor cells. Although much remains to be learned about the precise mechanisms by which TSC loss leads to Notch activation, the newly identified link of TSC to Notch provides the rationale for testing Notch inhibitors in TSC-associated tumors.
authors.affiliation: Department of Pathology and Laboratory Medicine, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104-6160, USA. wpear@mail.med.upenn.edu
authors.forename: Warren S
authors.initials: WS
authors.lastname: Pear
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology; D018398:Homeodomain Proteins / Q000502:physiology; D006801:Humans; D020559:Monomeric GTP-Binding Proteins / Q000502:physiology; D009369:Neoplasms / Q000209:etiology; D009479:Neuropeptides / Q000502:physiology; D011494:Protein Kinases / Q000502:physiology; D000076205:Ras Homolog Enriched in Brain Protein; D051880:Receptors, Notch / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases; D000072056:Transcription Factor HES-1; D014157:Transcription Factors / Q000502:physiology; D014402:Tuberous Sclerosis / Q000209:etiology*; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000502:physiology
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D020559:Monomeric GTP-Binding Proteins; D009479:Neuropeptides; D011494:Protein Kinases; D000076205:Ras Homolog Enriched in Brain Protein; D051880:Receptors, Notch; D058570:TOR Serine-Threonine Kinases; D000072056:Transcription Factor HES-1; D014157:Transcription Factors; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; C500984:CRTC1 protein, human; C490211:RHEB protein, human; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; C078493:HES1 protein, human; C546842:MTOR protein, human