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Updated: Mar 7, 2026
Isolation, Enrichment, and Maintenance of Medulloblastoma Stem Cells
Published on: September 1, 2010
Loss of Pin1 Suppresses Hedgehog-Driven Medulloblastoma Tumorigenesis
Tao Xu1, Honglai Zhang1, Sung-Soo Park1
1Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
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.
Insights
Researchers identified a new interaction between GLI1 and PIN1, crucial for Hedgehog pathway signaling in pediatric medulloblastoma. Inhibiting PIN1 shows promise as a novel therapeutic strategy for this common childhood brain tumor.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Medulloblastoma is the most common pediatric malignant brain tumor, with current therapies impacting quality of life.
- The Hedgehog signaling pathway is implicated in tumorigenesis for approximately 30% of medulloblastoma cases.
- Novel therapeutic targets are needed to improve treatment outcomes and patient quality of life.
Purpose of the Study:
- To identify novel molecular interactions involved in Hedgehog-driven medulloblastoma.
- To investigate the role of the peptidylprolyl cis/trans isomerase PIN1 in medulloblastoma pathogenesis.
- To evaluate PIN1 as a potential therapeutic target for medulloblastoma.
Main Methods:
- Yeast two-hybrid screening to identify protein interactions.
- Validation of protein interactions using co-immunoprecipitation and pulldown assays.
- In vivo functional analysis in a genetically engineered mouse model of medulloblastoma.
Main Results:
- A novel interaction between the Hedgehog pathway transcription factor GLI1 and PIN1 was discovered and validated.
- PIN1 was found to promote GLI1 protein stability, enhancing Hedgehog signaling.
- Loss of Pin1 function in a mouse model significantly inhibited medulloblastoma development and improved survival.
Conclusions:
- The interaction between GLI1 and PIN1 represents a key regulatory mechanism in Hedgehog-driven medulloblastoma.
- PIN1 is identified as a novel therapeutic target for medulloblastoma.
- Targeting PIN1 may offer a new strategy to treat medulloblastoma with potentially fewer side effects.
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