Mammalian suppressor-of-fused modulates nuclear-cytoplasmic shuttling of Gli-1.
Sonic hedgehog, Patched and Gli are components of a mammalian signalling pathway that has been conserved during evolution and which has a central role in the control of pattern formation and cellular proliferation during development. Here we identify the human Suppressor-of-Fused (SUFUH) complementary DNA and show that the gene product interacts physically with the transcriptional effector GLI-1, can sequester GLI-1 in the cytoplasm, but can also interact with GLI-1 on DNA. Functionally, SUFUH inhibits transcriptional activation by GLI-1, as well as osteogenic differentiation in response to signalling from Sonic hedgehog. Localization of GLI-1 is influenced by the presence of a nuclear-export signal, and GLI-1 becomes constitutively nuclear when this signal is mutated or nuclear export is inhibited. These results show that SUFUH is a conserved negative regulator of GLI-1 signalling that may affect nuclear-cytoplasmic shuttling of GLI-1 or the activity of GLI-1 in the nucleus and thereby modulate cellular responses.
Kogerman
P
P
Karolinska Institutet, Department of Biosciences, Huddinge, Sweden.
Grimm
T
T
Kogerman
L
L
Krause
D
D
Undén
A B
AB
Sandstedt
B
B
Toftgård
R
R
Zaphiropoulos
P G
PG
D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D002645:Chickens; D003593:Cytoplasm / Q000378:metabolism; D029721:Drosophila Proteins; D004331:Drosophila melanogaster / Q000235:genetics; D004622:Embryo, Mammalian; D004625:Embryo, Nonmammalian; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D008322:Mammals; D051379:Mice; D008969:Molecular Sequence Data; D015513:Oncogene Proteins / Q000378:metabolism*; D010006:Osteoblasts / Q000378:metabolism; D010012:Osteogenesis; D011994:Recombinant Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D015534:Trans-Activators; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D000071676:Zinc Finger Protein GLI1
D029721:Drosophila Proteins; D015513:Oncogene Proteins; D011994:Recombinant Proteins; D012097:Repressor Proteins; C490764:SUFU protein, human; C097059:Su(fu) protein, Drosophila; C490763:Sufu protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1