Format

Send to

Choose Destination
Neoplasia. 2017 Mar;19(3):216-225. doi: 10.1016/j.neo.2017.01.002. Epub 2017 Feb 3.

Loss of Pin1 Suppresses Hedgehog-Driven Medulloblastoma Tumorigenesis.

Author information

1
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
2
Center for Cancer Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI 48109, USA.
3
Departments of Dermatology and Cell & Developmental Biology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
4
Department of Pathology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
5
Department of Human Development and Culture, Fukushima University, Fukushima, 960-1296, Japan.
6
Department of Molecular Cell Science, Tohoku University, Sendai 981-8555, Japan.
7
Department of Radiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
8
Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
9
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Electronic address: sandraca@umich.edu.
10
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Electronic address: jrual@umich.edu.

Abstract

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.

PMID:
28167297
PMCID:
PMC5293723
DOI:
10.1016/j.neo.2017.01.002
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center