Dexamethasone destabilizes Nmyc to inhibit the growth of hedgehog-associated medulloblastoma
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Dexamethasone destabilizes Nmyc to inhibit the growth of hedgehog-associated medulloblastoma. / Heine, Vivi M; Priller, Markus; Ling, Jason; Rowitch, David H; Schüller, Ulrich.
In: CANCER RES, Vol. 70, No. 13, 01.07.2010, p. 5220-5.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Dexamethasone destabilizes Nmyc to inhibit the growth of hedgehog-associated medulloblastoma
AU - Heine, Vivi M
AU - Priller, Markus
AU - Ling, Jason
AU - Rowitch, David H
AU - Schüller, Ulrich
N1 - Copyright 2010 AACR.
PY - 2010/7/1
Y1 - 2010/7/1
N2 - Mouse studies indicate that the synthetic glucocorticoid dexamethasone (Dex) impairs the proliferation of granule neuron precursors in the cerebellum, which are transformed to medulloblastoma by activation of Sonic hedgehog (Shh) signaling. Here, we show that Dex treatment also inhibits Shh-induced tumor growth, enhancing the survival of tumor-prone transgenic mice. We found that Nmyc was specifically required in granule cells for Shh-induced tumorigenesis and that Dex acted to reduce Nmyc protein levels. Moreover, we found that Dex-induced destabilization of Nmyc is mediated by activation of glycogen synthase kinase 3beta, which targets Nmyc for proteasomal degradation. Together, our findings show that Dex antagonizes Shh signaling downstream of Smoothened in medulloblastoma.
AB - Mouse studies indicate that the synthetic glucocorticoid dexamethasone (Dex) impairs the proliferation of granule neuron precursors in the cerebellum, which are transformed to medulloblastoma by activation of Sonic hedgehog (Shh) signaling. Here, we show that Dex treatment also inhibits Shh-induced tumor growth, enhancing the survival of tumor-prone transgenic mice. We found that Nmyc was specifically required in granule cells for Shh-induced tumorigenesis and that Dex acted to reduce Nmyc protein levels. Moreover, we found that Dex-induced destabilization of Nmyc is mediated by activation of glycogen synthase kinase 3beta, which targets Nmyc for proteasomal degradation. Together, our findings show that Dex antagonizes Shh signaling downstream of Smoothened in medulloblastoma.
KW - Animals
KW - Brain Neoplasms
KW - Dexamethasone
KW - Glycogen Synthase Kinase 3
KW - Glycogen Synthase Kinase 3 beta
KW - Hedgehog Proteins
KW - Medulloblastoma
KW - Mice
KW - Mice, Transgenic
KW - Phosphorylation
KW - Protein Structure, Tertiary
KW - Proto-Oncogene Proteins c-myc
KW - Signal Transduction
KW - Tumor Cells, Cultured
KW - Journal Article
KW - Research Support, N.I.H., Extramural
KW - Research Support, Non-U.S. Gov't
U2 - 10.1158/0008-5472.CAN-10-0554
DO - 10.1158/0008-5472.CAN-10-0554
M3 - SCORING: Journal article
C2 - 20530674
VL - 70
SP - 5220
EP - 5225
JO - CANCER RES
JF - CANCER RES
SN - 0008-5472
IS - 13
ER -