Defining a role for Sonic hedgehog pathway activation in desmoplastic medulloblastoma by identifying GLI1 target genes.

Abstract:

:A subgroup of medulloblastomas shows constitutive activation of the Sonic hedgehog pathway with expression of GLI1. We identified the subset of GLI1 transforming target genes specifically expressed in medulloblastomas by comparing GLI1 targets in RK3E cells transformed by GLI1 with the gene expression profile of Sonic hedgehog signature medulloblastomas. We identified 1,823 genes whose expression was altered more than 2-fold in 2 independent RK3E + GLI1 cell lines. We identified 25 whose expression was altered similarly in medulloblastomas expressing GLI1. We identified potential GLI binding elements in the regulatory regions of 10 of these genes, confirmed that GLI1 binds the regulatory regions and activates transcription of select genes, and showed that GLI1 directly represses transcription of Krox-20. We identified upregulation of CXCR4, a chemokine receptor that plays roles in the proliferation and migration of granule cell neuron precursors during development, supporting the concept that reinitiation of developmental programs may contribute to medulloblastoma tumorigenesis. In addition, the targets suggest a pathway through which GLI1 may ultimately affect medulloblastoma cell proliferation, survival and genomic stability by converging on p53, SGK1, MGMT and NTRK2. We identify a p53 mutation in RK3E + GLI1 cells, suggesting that p53 mutations may sometimes shift the balance toward dysregulated tumor cell survival.

journal_name

Int J Cancer

authors

Yoon JW,Gilbertson R,Iannaccone S,Iannaccone P,Walterhouse D

doi

10.1002/ijc.23929

subject

Has Abstract

pub_date

2009-01-01 00:00:00

pages

109-19

issue

1

eissn

0020-7136

issn

1097-0215

journal_volume

124

pub_type

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