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PMID:19952108

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Citation

Fernandez-L, A, Northcott, PA, Dalton, J, Fraga, C, Ellison, D, Angers, S, Taylor, MD and Kenney, AM (2009) YAP1 is amplified and up-regulated in hedgehog-associated medulloblastomas and mediates Sonic hedgehog-driven neural precursor proliferation. Genes Dev. 23:2729-41

Abstract

Medulloblastoma is the most common solid malignancy of childhood, with treatment side effects reducing survivors' quality of life and lethality being associated with tumor recurrence. Activation of the Sonic hedgehog (Shh) signaling pathway is implicated in human medulloblastomas. Cerebellar granule neuron precursors (CGNPs) depend on signaling by the morphogen Shh for expansion during development, and have been suggested as a cell of origin for certain medulloblastomas. Mechanisms contributing to Shh pathway-mediated proliferation and transformation remain poorly understood. We investigated interactions between Shh signaling and the recently described tumor-suppressive Hippo pathway in the developing brain and medulloblastomas. We report up-regulation of the oncogenic transcriptional coactivator yes-associated protein 1 (YAP1), which is negatively regulated by the Hippo pathway, in human medulloblastomas with aberrant Shh signaling. Consistent with conserved mechanisms between brain tumorigenesis and development, Shh induces YAP1 expression in CGNPs. Shh also promotes YAP1 nuclear localization in CGNPs, and YAP1 can drive CGNP proliferation. Furthermore, YAP1 is found in cells of the perivascular niche, where proposed tumor-repopulating cells reside. Post-irradiation, YAP1 was found in newly growing tumor cells. These findings implicate YAP1 as a new Shh effector that may be targeted by medulloblastoma therapies aimed at eliminating medulloblastoma recurrence.

Links

PubMed PMC2788333 Online version:10.1101/gad.1824509

Keywords

Animals; Cell Proliferation; Cells, Cultured; Cerebellar Neoplasms/metabolism; Cerebellar Neoplasms/pathology; Hedgehog Proteins/metabolism; Humans; Insulin Receptor Substrate Proteins/metabolism; Medulloblastoma/metabolism; Medulloblastoma/pathology; Mice; Neurons/cytology; Neurons/metabolism; Protein Transport; Signal Transduction; Transcription Factors/metabolism; Up-Regulation

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:TEAD1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:P46938

F

Seeded From UniProt

complete

MOUSE:IRS1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:P46938

F

  • occurs_in:(CL:0000047)

Seeded From UniProt

complete

MOUSE:IRS1

acts_upstream_of_or_within

GO:0034504: protein localization to nucleus

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:IRS1

acts_upstream_of_or_within

GO:0034504: protein localization to nucleus

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:YAP1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:P30051
PR:P35569

F

  • occurs_in:(CL:0000047)

Seeded From UniProt

complete

MOUSE:YAP1

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:YAP1

acts_upstream_of_or_within

GO:0008284: positive regulation of cell population proliferation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:YAP1

enables

GO:0003682: chromatin binding

ECO:0000314: direct assay evidence used in manual assertion

F

  • has_input:(MGI:MGI:95728)

Seeded From UniProt

complete

MOUSE:YAP1

acts_upstream_of_or_within

GO:0072091: regulation of stem cell proliferation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SHH

acts_upstream_of_or_within

GO:0034504: protein localization to nucleus

ECO:0000314: direct assay evidence used in manual assertion

P

  • occurs_in:(CL:0000047)

Seeded From UniProt

complete

MOUSE:XPO1

acts_upstream_of_or_within

GO:0006611: protein export from nucleus

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(CL:0000047)

Seeded From UniProt

complete

MOUSE:SHH

acts_upstream_of_or_within

GO:0034504: protein localization to nucleus

ECO:0000314: direct assay evidence used in manual assertion

P

occurs_in:(CL:0000047)

Seeded From UniProt

complete

MOUSE:SMO

acts_upstream_of_or_within

GO:0034504: protein localization to nucleus

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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