Loss of Pin1 Suppresses Hedgehog-Driven Medulloblastoma Tumorigenesis.
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.
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Tao
T
Xu
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Honglai
H
Zhang
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Sung-Soo
SS
Park
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Sriram
S
Venneti
Center for Cancer Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI 48109, USA.
Rork
R
Kuick
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Kimberly
K
Ha
Departments of Dermatology and Cell & Developmental Biology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
Lowell Evan
LE
Michael
Department of Pathology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Mariarita
M
Santi
Department of Human Development and Culture, Fukushima University, Fukushima, 960-1296, Japan.
Chiyoko
C
Uchida
Department of Molecular Cell Science, Tohoku University, Sendai 981-8555, Japan.
Takafumi
T
Uchida
Department of Radiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Ashok
A
Srinivasan
Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
James M
JM
Olson
Departments of Dermatology and Cell & Developmental Biology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
Andrzej A
AA
Dlugosz
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Electronic address: sandraca@umich.edu.
Sandra
S
Camelo-Piragua
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Electronic address: jrual@umich.edu.
Jean-François
JF
Rual
D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism*; D002528:Cerebellar Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D004195:Disease Models, Animal; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D008527:Medulloblastoma / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D000072340:NIMA-Interacting Peptidylprolyl Isomerase / Q000172:deficiency*; D011379:Prognosis; D011485:Protein Binding; D025941:Protein Interaction Mapping; D015398:Signal Transduction; D000071676:Zinc Finger Protein GLI1 / Q000378:metabolism
D053823:Hedgehog Proteins; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D000071676:Zinc Finger Protein GLI1