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PMID:19368795

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Citation

Mosimann, C, Hausmann, G and Basler, K The role of Parafibromin/Hyrax as a nuclear Gli/Ci-interacting protein in Hedgehog target gene control. Mech. Dev. 126:394-405

Abstract

The Hedgehog (Hh) pathway, an evolutionarily conserved key regulator of embryonic patterning and tissue homeostasis, controls its target genes by managing the processing and activities of the Gli/Ci transcription factors. Little is known about the nuclear co-factors the Gli/Ci proteins recruit, and how they mechanistically control Hh target genes. Here, we provide evidence for the involvement of Parafibromin/Hyx as a positive component in Hh signaling. We found that hyx RNAi impaired Hh pathway activity in Drosophila cell culture. Consistent with an evolutionarily conserved function in Hh signaling, RNAi-mediated knockdown of Parafibromin in mammalian cell culture experiments diminished the transcriptional activity of Gli1 and Gli2. In vivo, in Drosophila, genetic impairment of hyx decreased the expression of the high-threshold Hh target gene knot/collier. Conversely, hyx overexpression ameliorated the inhibitory activity of Ptc and Ci(75) misexpression during Drosophila wing development. We subsequently found that Parafibromin can form a complex with all three Glis, and provide evidence that Parafibromin/Hyx directly binds Region 1, the Su(fu) interaction domain, in the N-terminus of all Glis and Ci. Taken together, our results suggest a target gene-selective involvement of the PAF1 complex in Hh signaling via the Parafibromin/Hyx-mediated recruitment to Gli/Ci.

Links

PubMed Online version:10.1016/j.mod.2009.02.002

Keywords

Animals; Carboxy-Lyases/chemistry; Carboxy-Lyases/metabolism; Cell Line; Cell Nucleus/metabolism; Conserved Sequence; DNA-Binding Proteins/metabolism; Drosophila Proteins/chemistry; Drosophila Proteins/metabolism; Drosophila melanogaster/cytology; Drosophila melanogaster/genetics; Drosophila melanogaster/metabolism; Gene Expression Regulation, Developmental; Genes, Insect; Genes, Reporter; Hedgehog Proteins/metabolism; Oncogene Proteins/chemistry; Oncogene Proteins/metabolism; Protein Binding; RNA Interference; Signal Transduction; Trans-Activators/chemistry; Trans-Activators/metabolism; Transcription Factors/metabolism; Transcriptional Activation/genetics; Wing/cytology; Wing/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

DROME:CI

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

FB:FBgn0037657

F

Seeded From UniProt

complete

DROME:Q9VHI1

enables

GO:0008134: transcription factor binding

ECO:0000353: physical interaction evidence used in manual assertion

FB:FBgn0004859

F

Seeded From UniProt

complete

DROME:Q9VHI1

part_of

GO:0005667: transcription regulator complex

ECO:0000353: physical interaction evidence used in manual assertion

FB:FBgn0004859

C

Seeded From UniProt

complete

DROME:Q9VHI1

involved_in

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:Q9VHI1

involved_in

GO:0045880: positive regulation of smoothened signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:Q9VHI1

involved_in

GO:0045880: positive regulation of smoothened signaling pathway

ECO:0000316: genetic interaction evidence used in manual assertion

FB:FBgn0003892

P

Seeded From UniProt

complete

DROME:Q9VHI1

involved_in

GO:0045880: positive regulation of smoothened signaling pathway

ECO:0000316: genetic interaction evidence used in manual assertion

FB:FBgn0004859

P

Seeded From UniProt

complete


See also

References

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