TY - JOUR
T1 - Loss of Pin1 Suppresses Hedgehog-Driven Medulloblastoma Tumorigenesis
AU - Xu, Tao
AU - Zhang, Honglai
AU - Park, Sung Soo
AU - Venneti, Sriram
AU - Kuick, Rork
AU - Ha, Kimberly
AU - Michael, Lowell Evan
AU - Santi, Mariarita
AU - Uchida, Chiyoko
AU - Uchida, Takafumi
AU - Srinivasan, Ashok
AU - Olson, James M.
AU - Dlugosz, Andrzej A.
AU - Camelo-Piragua, Sandra
AU - Rual, Jean François
N1 - Funding Information:
We thank UM Comprehensive Cancer Center Tissue for technical support with the IHC experiments, specifically Dafydd Thomas and Tina Fields; UM Vector Core Facility for the lentiviral sh-RNA plasmids; UM Center for Molecular Imaging for technical support with the MRI experiments, specifically Amanda Fair; CCSB for sharing ORFeome and Y2H clones. This work was supported by Padnos Fund for Innovative Cancer Research of the UM Comprehensive Cancer Center awarded to J. F. R.; Bench to Bedside Translation Award awarded to J. F. R. by the Michigan Institute for Clinical and Health Research and the National Center for Advancing Translational Sciences of the National Institutes of Health (NIH) under Award Number UL1TR000433; M-Cubed Grant awarded to J. F. R. and S. C. P.; grant R01CA155360 awarded to J. M. O. by the National Cancer Institute of the NIH; Seattle Children's Neuro-oncology endowment awarded to J. M. O; UM Cancer Center Support Grant (P30CA046592); and funds from the UM Department of Pathology provided to J. F. R. The sponsors were not involved in any of the following: study design; collection, analysis, and interpretation of data; the writing of the report; and the decision to submit the article for publication.
Publisher Copyright:
© 2017 The Authors
PY - 2017/3/1
Y1 - 2017/3/1
N2 - Medulloblastoma is the most common malignant brain tumor in children. Therapeutic approaches to medulloblastoma (combination of surgery, radiotherapy, and chemotherapy) have led to significant improvements, but these are achieved at a high cost to quality of life. Alternative therapeutic approaches are needed. Genetic mutations leading to the activation of the Hedgehog pathway drive tumorigenesis in ~30% of medulloblastoma. In a yeast two-hybrid proteomic screen, we discovered a novel interaction between GLI1, a key transcription factor for the mediation of Hedgehog signals, and PIN1, a peptidylprolyl cis/trans isomerase that regulates the postphosphorylation fate of its targets. The GLI1/PIN1 interaction was validated by reciprocal pulldowns using epitope-tagged proteins in HEK293T cells as well as by co-immunoprecipiations of the endogenous proteins in a medulloblastoma cell line. Our results support a molecular model in which PIN1 promotes GLI1 protein abundance, thus contributing to the positive regulation of Hedgehog signals. Most importantly, in vivo functional analyses of Pin1 in the GFAP-tTA;TRE-SmoA1 mouse model of Hedgehog-driven medulloblastoma demonstrate that the loss of Pin1 impairs tumor development and dramatically increases survival. In summary, the discovery of the GLI1/PIN1 interaction uncovers PIN1 as a novel therapeutic target in Hedgehog-driven medulloblastoma tumorigenesis.
AB - Medulloblastoma is the most common malignant brain tumor in children. Therapeutic approaches to medulloblastoma (combination of surgery, radiotherapy, and chemotherapy) have led to significant improvements, but these are achieved at a high cost to quality of life. Alternative therapeutic approaches are needed. Genetic mutations leading to the activation of the Hedgehog pathway drive tumorigenesis in ~30% of medulloblastoma. In a yeast two-hybrid proteomic screen, we discovered a novel interaction between GLI1, a key transcription factor for the mediation of Hedgehog signals, and PIN1, a peptidylprolyl cis/trans isomerase that regulates the postphosphorylation fate of its targets. The GLI1/PIN1 interaction was validated by reciprocal pulldowns using epitope-tagged proteins in HEK293T cells as well as by co-immunoprecipiations of the endogenous proteins in a medulloblastoma cell line. Our results support a molecular model in which PIN1 promotes GLI1 protein abundance, thus contributing to the positive regulation of Hedgehog signals. Most importantly, in vivo functional analyses of Pin1 in the GFAP-tTA;TRE-SmoA1 mouse model of Hedgehog-driven medulloblastoma demonstrate that the loss of Pin1 impairs tumor development and dramatically increases survival. In summary, the discovery of the GLI1/PIN1 interaction uncovers PIN1 as a novel therapeutic target in Hedgehog-driven medulloblastoma tumorigenesis.
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U2 - 10.1016/j.neo.2017.01.002
DO - 10.1016/j.neo.2017.01.002
M3 - Article
C2 - 28167297
AN - SCOPUS:85015625992
VL - 19
SP - 216
EP - 225
JO - Neoplasia
JF - Neoplasia
SN - 1522-8002
IS - 3
ER -