scholarly journals YB-1 is elevated in medulloblastoma and drives proliferation in Sonic hedgehog-dependent cerebellar granule neuron progenitor cells and medulloblastoma cells

Oncogene ◽  
2016 ◽  
Vol 35 (32) ◽  
pp. 4256-4268 ◽  
Author(s):  
A Dey ◽  
M Robitaille ◽  
M Remke ◽  
C Maier ◽  
A Malhotra ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Sonic Hedgehog ◽  
Cerebellar Granule Neuron ◽  
Cerebellar Granule ◽  
Granule Neuron

scholarly journals MBRS-08. SONIC HEDGEHOG SIGNALING PRIMES CEREBELLAR GRANULE NEURON PROGENITORS, THE CELL OF ORIGIN FOR MEDULLOBLASTOMA, FOR APOPTOSIS BY INDUCING PRO APOPTOTIC BIM

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii400-iii400
Author(s):  
Abigail Cleveland ◽  
Timothy Gershon
Keyword(s):  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
Mechanistic Model ◽  
Radiation Sensitivity ◽  
Cell Of Origin ◽  
Cerebellar Granule Neuron ◽  
Shh Signaling ◽  
Cerebellar Granule ◽  
Granule Neuron ◽  
Proapoptotic Protein

Abstract Medulloblastomas, unlike other malignant brain tumors, are typically sensitive to radiation therapy, but the mechanisms that mediate this sensitivity are unclear. Cerebellar granule neuron progenitors (CGNPs), the cell of origin for SHH-subgroup medulloblastoma, are also highly sensitive to radiation. In early life, CGNPs proliferate in response to Sonic Hedgehog (SHH) signaling, and hyperactivation of SHH signaling in CGNPs can lead to the development of SHH-subgroup medulloblastoma. We propose that SHH activation induces radiation sensitivity along with tumorigenesis. We have previously shown that the proapoptotic protein BAX is required for radiation sensitivity of both SHH-driven medulloblastomas and CGNPs in mice, and that BCL-xL supplies critical regulation of BAX, preventing spontaneous cell death. Here, we show that SHH signaling increases the radiation sensitivity of CGNPs by inducing the proapoptotic protein BIM. We found that BIM expression depends on SHH activity, and that genetic deletion of Bim decreases the radiation-sensitivity of CGNPs. Mechanistically, we show that BIM binds to anti-apoptotic proteins BCL-xL and MCL-1, where it may alter the balance of BAX and BCL-xL interactions. Consistent with our mechanistic model, human medulloblastoma patients with high BIM expression show a better prognosis. Based on these observations, we propose that SHH-induced BIM mediates the typical radiation sensitivity of SHH-driven medulloblastoma. Finding ways to enhance BIM activity may open new opportunities for targeted medulloblastoma therapy.

scholarly journals Reciprocal actions of ATF5 and Shh in proliferation of cerebellar granule neuron progenitor cells

2012 ◽  
Vol 72 (6) ◽  
pp. 789-804 ◽  
Author(s):  
Hae Young Lee ◽  
James M. Angelastro ◽  
Anna Marie Kenney ◽  
Carol A. Mason ◽  
Lloyd A. Greene
Keyword(s):  
Progenitor Cells ◽  
Cerebellar Granule Neuron ◽  
Cerebellar Granule ◽  
Granule Neuron
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