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Suppressor of fused negatively regulates beta-catenin signaling
1Program in Developmental Biology, The Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, Ontario M5G1X8, Canada.
Abstract:
Suppressor of fused (Su(fu)) is a negative regulator of the Hedgehog signaling pathway that controls the nuclear-cytoplasmic distribution of Gli/Ci transcription factors through direct protein-protein interactions. We show here that Su(fu) is present in a complex with the oncogenic transcriptional activator beta-catenin and functions as a negative regulator of T-cell factor (Tcf)-dependent transcription. Overexpression of Su(fu) in SW480 (APC(mut)) colon cancer cells in which beta-catenin protein is stabilized leads to a reduction in nuclear beta-catenin levels and in Tcf-dependent transcription. This effect of Su(fu) overexpression can be blocked by treatment of these cells with leptomycin B, a specific inhibitor of CRM1-mediated nuclear export. Overexpression of Su(fu) suppresses growth of SW480 (APC(mut)) tumor cells in nude mice. These observations indicate that Su(fu) negatively regulates beta-catenin signaling and that CRM-1-mediated nuclear export plays a role in this regulation. Our results also suggest that Su(fu) acts as a tumor suppressor.
Insights
Suppressor of fused (Su(fu)) negatively regulates beta-catenin signaling by controlling its nuclear export. This finding suggests Su(fu) acts as a tumor suppressor, impacting colon cancer cell growth.
Area of Science:
- Molecular Biology
- Cell Biology
- Oncology
Background:
- Suppressor of fused (Su(fu)) is a known negative regulator of the Hedgehog signaling pathway.
- Su(fu) influences the distribution of Gli/Ci transcription factors via protein-protein interactions.
Purpose of the Study:
- To investigate the role of Su(fu) in regulating beta-catenin signaling.
- To determine if Su(fu) affects T-cell factor (Tcf)-dependent transcription.
- To explore the therapeutic potential of Su(fu) in colon cancer.
Main Methods:
- Co-immunoprecipitation to identify protein complexes.
- Overexpression studies in SW480 colon cancer cells.
- Leptomycin B treatment to inhibit CRM1-mediated nuclear export.
- Tumor xenograft studies in nude mice.
Main Results:
- Su(fu) forms a complex with beta-catenin.
- Su(fu) overexpression reduces nuclear beta-catenin levels and Tcf-dependent transcription in SW480 cells.
- Leptomycin B blocks the effect of Su(fu) overexpression, indicating CRM1 involvement.
- Su(fu) overexpression suppresses SW480 tumor growth in vivo.
Conclusions:
- Su(fu) negatively regulates beta-catenin signaling.
- CRM1-mediated nuclear export is a key mechanism in Su(fu) regulation of beta-catenin.
- Su(fu) exhibits tumor suppressor activity and may be a therapeutic target in colon cancer.