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Published on: July 25, 2017
Loss of suppressor-of-fused function promotes tumorigenesis
1Department of Genetics and Tumor Cell Biology, St Jude Children's Research Hospital, Memphis, TN 38405, USA.
Oncogene
|April 25, 2007
Summary
Suppressor of Fused (Sufu) is crucial for embryonic development. Loss of Sufu, especially with p53 loss, promotes tumors like medulloblastoma, indicating its role as a tumor suppressor.
Area of Science:
- Developmental Biology
- Cancer Biology
- Molecular Oncology
Background:
- The Sonic Hedgehog (SHH) signaling pathway regulates critical developmental processes.
- Transcription factors GLI modulate SHH pathway activity.
- Suppressor of Fused (Sufu) and Patched1 (Ptch1) are key regulators of the SHH pathway.
Purpose of the Study:
- To investigate the role of Suppressor of Fused (Sufu) in embryonic development and tumor suppression.
- To determine the impact of Sufu loss of heterozygosity in conjunction with p53 deficiency on tumor formation.
Main Methods:
- Generation and analysis of Sufu+/- and Sufu+/-p53-/- mouse models.
- Tumorigenesis assessment, including medulloblastoma and rhabdomyosarcoma.
- Gene expression profiling of Sufu+/-p53-/- medulloblastomas.
- Evaluation of Smoothened inhibitor efficacy on Sufu-inactivated tumors.
Main Results:
- Sufu loss caused early embryonic lethality, similar to Ptch1 inactivation.
- Sufu+/- mice were not inherently tumor-prone, unlike Ptch1+/- mice.
- Sufu+/-p53-/- mice developed medulloblastoma and rhabdomyosarcoma due to Sufu loss of heterozygosity.
- Tumors exhibited aberrant SHH signaling gene expression, including N-myc and cyclin D1 upregulation.
- Hedgehog antagonist treatment did not inhibit tumor growth from Sufu inactivation.
Conclusions:
- Sufu is essential for normal embryonic development.
- Sufu acts as a tumor suppressor, with its loss contributing to specific cancers.
- SHH pathway dysregulation in Sufu-deficient tumors is independent of Smoothened activity.
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