Suppressor of fused negatively regulates beta-catenin signaling.
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.
Meng
X
X
Program in Developmental Biology, The Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, Ontario M5G1X8, Canada.
Poon
R
R
Zhang
X
X
Cheah
A
A
Ding
Q
Q
Hui
C C
CC
Alman
B
B
D021581:Active Transport, Cell Nucleus; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism*; D002451:Cell Compartmentation; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D028884:Karyopherins / Q000037:antagonists & inhibitors; D051379:Mice; D008819:Mice, Nude; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction; D013491:Suppressor Factors, Immunologic; D015534:Trans-Activators; D014157:Transcription Factors; D014407:Tumor Cells, Cultured; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin; D000097606:Exportin 1 Protein
D000903:Antibiotics, Antineoplastic; D003598:Cytoskeletal Proteins; D005231:Fatty Acids, Unsaturated; D028884:Karyopherins; D011518:Proto-Oncogene Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; D013491:Suppressor Factors, Immunologic; D015534:Trans-Activators; D014157:Transcription Factors; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin; D000097606:Exportin 1 Protein; C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; C490764:SUFU protein, human; C490763:Sufu protein, mouse; C038753:leptomycin B