WIP1 enhances tumor formation in a sonic hedgehog-dependent model of medulloblastoma.
BACKGROUND
A significant number of medulloblastomas (MBs) originate from abnormal activation of the sonic hedgehog/patched (SHH/PTC) signaling pathway. Although p53 deficiency enhances tumor formation in mice, inactivation of the p53 gene is seen in a minority of MBs. Wild-type p53-induced phosphatase 1 (WIP1) downregulates p53 expression and has been shown to be overexpressed in MBs.


OBJECTIVE
We tested the hypothesis that overexpression of WIP1 enhances tumor formation in an SHH-dependent model of MB.


METHODS
We used the RCAS/Ntv-a system to study the effect of WIP1 in vitro and in vivo. We transfected A375-TVA cells with RCAS-WIP1 and then exposed these cells to cisplatin to determine the effect on p53 expression. We modeled ectopic WIP1 expression independently and in combination with SHH in the cerebella of newborn mice to assess the effect on tumor formation. Mice were observed for 12 weeks or until neurological symptoms developed. The brains were examined for tumor formation.


RESULTS
A375-TVA cells infected with RCAS-WIP1 demonstrated reduced p53 expression after exposure to cisplatin compared with controls. We detected tumors in 12 of 35 mice (34%) injected with RCAS-WIP1 and RCAS-SHH. Tumors were detected in 3 of 40 mice (8%) injected with RCAS-SHH alone. The difference in tumor formation rates was significant (χ(2) test, P = < .01). Tumors did not form in mice injected with RCAS-WIP1 alone.


CONCLUSIONS
We show that ectopic expression of WIP1 cooperates with SHH to enhance formation of MB, although it is insufficient to induce tumors independently. Our results verify the role of WIP1 in MB formation and provide a crucial link to the inactivation of p53 in MBs.
Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Tiffany A
TA
Doucette
Yuhui
Y
Yang
Carolyn
C
Pedone
John Y H
JY
Kim
Adrian
A
Dubuc
Paul D
PD
Northcott
Michael D
MD
Taylor
Daniel W
DW
Fults
Ganesh
G
Rao
D000818:Animals; D015153:Blotting, Western; D002528:Cerebellar Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D008527:Medulloblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism*; D000071636:Protein Phosphatase 2C; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D053823:Hedgehog Proteins; C465570:Shh protein, mouse; D016159:Tumor Suppressor Protein p53; D010749:Phosphoprotein Phosphatases; C000607468:Ppm1d protein, mouse; D000071636:Protein Phosphatase 2C