Loss of Pin1 Suppresses Hedgehog-Driven Medulloblastoma Tumorigenesis
| Autor: | Kimberly Ha, Lowell Evan Michael, James M. Olson, Jean François Rual, Chiyoko Uchida, Tao Xu, Rork Kuick, Honglai Zhang, Takafumi Uchida, Ashok Srinivasan, Andrzej A. Dlugosz, Sandra Camelo-Piragua, Mariarita Santi, Sriram Venneti, Sung Soo Park |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Cancer Research H&E hematoxylin/eosin staining Short communication medicine.disease_cause Mice tTA tetracycline-regulated transactivators SAG SMO agonist Protein Interaction Mapping CIP calf intestinal alkaline phosphatase biology IP immunoprecipitation lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Prognosis Hedgehog signaling pathway PPIase peptidylprolyl cis/trans isomerase 3. Good health Hh Hedgehog Cell Transformation Neoplastic WB Western blot PIN1 IHC immunohistochemistry Protein Binding Signal Transduction Mice Transgenic CGNP cerebellar granular neuron progenitor cells lcsh:RC254-282 Zinc Finger Protein GLI1 03 medical and health sciences GLI1 Cell Line Tumor medicine Animals Humans Hedgehog Proteins Cerebellar Neoplasms pSer/Thr-Pro phosphorylated serine-proline or threonine-proline motifs Hedgehog Transcription factor FFPE formalin-fixed paraffin-embedded Medulloblastoma Y2H yeast two-hybrid HEK 293 cells AD activation domain medicine.disease NIMA-Interacting Peptidylprolyl Isomerase Disease Models Animal 030104 developmental biology biology.protein Cancer research Carcinogenesis EGCG epigallocatechin gallate MRI magnetic resonance imaging TRE tetracycline responsive element SBP streptavidin binding peptide tag DB DNA-binding domain |
| Zdroj: | Neoplasia (New York, N.Y.) Neoplasia: An International Journal for Oncology Research, Vol 19, Iss 3, Pp 216-225 (2017) |
| ISSN: | 1476-5586 |
| DOI: | 10.1016/j.neo.2017.01.002 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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