Characterization of the human suppressor of fused, a negative regulator of the zinc-finger transcription factor Gli.
Drosophila Suppressor of fused (Su(fu)) encodes a novel 468-amino-acid cytoplasmic protein which, by genetic analysis, functions as a negative regulator of the Hedgehog segment polarity pathway. Here we describe the primary structure, tissue distribution, biochemical and functional analyses of a human Su(fu) (hSu(fu)). Two alternatively spliced isoforms of hSu(fu) were ... identified, predicting proteins of 433 and 484 amino acids, with a calculated molecular mass of 48 and 54 kDa, respectively. The two proteins differ only by the inclusion or exclusion of a 52-amino-acid extension at the carboxy terminus. Both isoforms were expressed in multiple embryonic and adult tissues, and exhibited a developmental profile consistent with a role in Hedgehog signaling. The hSu(fu) contains a high-scoring PEST-domain, and exhibits an overall 37% sequence identity (63% similarity) with the Drosophila protein and 97% sequence identity with the mouse Su(fu). The hSu(fu) locus mapped to chromosome 10q24-q25, a region which is deleted in glioblastomas, prostate cancer, malignant melanoma and endometrial cancer. HSu(fu) was found to repress activity of the zinc-finger transcription factor Gli, which mediates Hedgehog signaling in vertebrates, and to physically interact with Gli, Gli2 and Gli3 as well as with Slimb, an F-box containing protein which, in the fly, suppresses the Hedgehog response, in part by stimulating the degradation of the fly Gli homologue. Coexpression of Slimb with Su(fu) potentiated the Su(fu)-mediated repression of Gli. Taken together, our data provide biochemical and functional evidence for the hypothesis that Su(fu) is a key negative regulator in the vertebrate Hedgehog signaling pathway. The data further suggest that Su(fu) can act by binding to Gli and inhibiting Gli-mediated transactivation as well as by serving as an adaptor protein, which links Gli to the Slimb-dependent proteasomal degradation pathway.
Mesh Terms:
Adult, Alternative Splicing, Amino Acid Sequence, Animals, Cell Line, Chromosome Mapping, Chromosomes, Human, Pair 10, Cloning, Molecular, Drosophila, Drosophila Proteins, Female, Fetus, Gene Expression Regulation, Gene Expression Regulation, Developmental, Humans, Luciferases, Male, Mice, Molecular Sequence Data, Oncogene Proteins, Polymerase Chain Reaction, Protein Isoforms, Recombinant Fusion Proteins, Repressor Proteins, Sequence Alignment, Sequence Homology, Amino Acid, Trans-Activators, Transcription Factors, Zinc Fingers
Adult, Alternative Splicing, Amino Acid Sequence, Animals, Cell Line, Chromosome Mapping, Chromosomes, Human, Pair 10, Cloning, Molecular, Drosophila, Drosophila Proteins, Female, Fetus, Gene Expression Regulation, Gene Expression Regulation, Developmental, Humans, Luciferases, Male, Mice, Molecular Sequence Data, Oncogene Proteins, Polymerase Chain Reaction, Protein Isoforms, Recombinant Fusion Proteins, Repressor Proteins, Sequence Alignment, Sequence Homology, Amino Acid, Trans-Activators, Transcription Factors, Zinc Fingers
J. Cell. Sci.
Date: Dec. 01, 1999
PubMed ID: 10564661
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