title: REN(KCTD11) is a suppressor of Hedgehog signaling and is deleted in human medulloblastoma.
abstract: Hedgehog signaling is suggested to be a major oncogenic pathway in medulloblastoma, which arises from aberrant development of cerebellar granule progenitors. Allelic loss of chromosome 17p has also been described as the most frequent genetic defect in this human neoplasia. This observation raises the question of a possible interplay between 17p deletion and the Hedgehog tumorigenic pathway. Here, we identify the human orthologue of mouse REN(KCTD11), previously reported to be expressed in differentiating and low proliferating neuroblasts. Human REN(KCTD11) maps to 17p13.2 and displays allelic deletion as well as significantly reduced expression in medulloblastoma. REN(KCTD11) inhibits medulloblastoma cell proliferation and colony formation in vitro and suppresses xenograft tumor growth in vivo. REN(KCTD11) seems to inhibit medulloblastoma growth by negatively regulating the Hedgehog pathway because it antagonizes the Gli-mediated transactivation of Hedgehog target genes, by affecting Gli1 nuclear transfer, and its growth inhibitory activity is impaired by Gli1 inactivation. Therefore, we identify REN(KCTD11) as a suppressor of Hedgehog signaling and suggest that its inactivation might lead to a deregulation of the tumor-promoting Hedgehog pathway in medulloblastoma.
authors.affiliation: Department of Experimental Medicine and Pathology, University La Sapienza, 324 Viale Regina Elena, 00161 Rome, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Di Marcotullio
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Ferretti
authors.forename: Enrico
authors.initials: E
authors.lastname: De Smaele
authors.forename: Beatrice
authors.initials: B
authors.lastname: Argenti
authors.forename: Claudia
authors.initials: C
authors.lastname: Mincione
authors.forename: Francesca
authors.initials: F
authors.lastname: Zazzeroni
authors.forename: Rita
authors.initials: R
authors.lastname: Gallo
authors.forename: Laura
authors.initials: L
authors.lastname: Masuelli
authors.forename: Maddalena
authors.initials: M
authors.lastname: Napolitano
authors.forename: Marella
authors.initials: M
authors.lastname: Maroder
authors.forename: Andrea
authors.initials: A
authors.lastname: Modesti
authors.forename: Felice
authors.initials: F
authors.lastname: Giangaspero
authors.forename: Isabella
authors.initials: I
authors.lastname: Screpanti
authors.forename: Edoardo
authors.initials: E
authors.lastname: Alesse
authors.forename: Alberto
authors.initials: A
authors.lastname: Gulino
mesh_terms: D000483:Alleles; D000818:Animals; D018797:Cell Cycle Proteins; D002528:Cerebellar Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002886:Chromosomes, Human, Pair 17; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D053823:Hedgehog Proteins; D006801:Humans; D008527:Medulloblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014166:Transferases; D014183:Transplantation, Heterologous; D000071676:Zinc Finger Protein GLI1
chemical_list: D018797:Cell Cycle Proteins; D053823:Hedgehog Proteins; D009419:Nerve Tissue Proteins; D015513:Oncogene Proteins; D015221:Potassium Channels; D015534:Trans-Activators; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; C488725:KCTD11 protein, human; C466095:Kctd11 protein, mouse; D014166:Transferases