REN(KCTD11) is a suppressor of Hedgehog signaling and is deleted in human medulloblastoma.
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.
Di Marcotullio
Lucia
L
Department of Experimental Medicine and Pathology, University La Sapienza, 324 Viale Regina Elena, 00161 Rome, Italy.
Ferretti
Elisabetta
E
De Smaele
Enrico
E
Argenti
Beatrice
B
Mincione
Claudia
C
Zazzeroni
Francesca
F
Gallo
Rita
R
Masuelli
Laura
L
Napolitano
Maddalena
M
Maroder
Marella
M
Modesti
Andrea
A
Giangaspero
Felice
F
Screpanti
Isabella
I
Alesse
Edoardo
E
Gulino
Alberto
A
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
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