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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Active Transport, Cell Nucleus
-
Animals
-
Antibiotics, Antineoplastic / pharmacology
-
Carcinoma / genetics
-
Carcinoma / metabolism*
-
Cell Compartmentation
-
Colonic Neoplasms / genetics
-
Colonic Neoplasms / metabolism*
-
Cytoskeletal Proteins / metabolism*
-
Exportin 1 Protein
-
Fatty Acids, Unsaturated / pharmacology
-
Gene Expression Regulation, Neoplastic
-
Humans
-
Karyopherins / antagonists & inhibitors
-
Mice
-
Mice, Nude
-
Proto-Oncogene Proteins / metabolism
-
Receptors, Cytoplasmic and Nuclear*
-
Repressor Proteins / metabolism*
-
Signal Transduction
-
Suppressor Factors, Immunologic
-
Trans-Activators*
-
Transcription Factors
-
Tumor Cells, Cultured
-
Wnt Proteins
-
Zebrafish Proteins*
-
beta Catenin
Substances
-
Antibiotics, Antineoplastic
-
CTNNB1 protein, human
-
CTNNB1 protein, mouse
-
Cytoskeletal Proteins
-
Fatty Acids, Unsaturated
-
Karyopherins
-
Proto-Oncogene Proteins
-
Receptors, Cytoplasmic and Nuclear
-
Repressor Proteins
-
SUFU protein, human
-
Sufu protein, mouse
-
Suppressor Factors, Immunologic
-
Trans-Activators
-
Transcription Factors
-
Wnt Proteins
-
Zebrafish Proteins
-
beta Catenin
-
leptomycin B