Negative regulation of Gli1 and Gli2 activator function by Suppressor of fused through multiple mechanisms.
During animal development, the Hedgehog (Hh) signal transduction pathway plays critical roles in cell fate determination and tissue patterning. In humans, aberrant Hh signaling has been linked to several genetic disorders and cancers. Binding of Hh to its receptor initiates a signaling cascade, which ultimately results in the activation of the Gli/Ci transcription factors. Suppressor of fused (Su(fu)) is a Gli/Ci-interacting protein, which acts as a negative regulator of Hh signaling in Drosophila and vertebrates. Su(fu) is also implicated as a tumor suppressor as its mutations have been found in medulloblastoma and prostate cancer. Su(fu) is thought to act by preventing the nuclear accumulation of Gli/Ci, however, mechanistic insight into its mode of action has remained elusive. We demonstrate here that Su(fu) prevents the nuclear accumulation of Gli1 and Gli2 through multiple mechanisms. While Su(fu) itself is not subject to CRM1-dependent regulation, Su(fu) sequesters Gli1 in the cytoplasm mostly through a mechanism that depends on the activity of the nuclear export protein CRM1. In contrast, CRM1-mediated export is not required for Su(fu) to sequester Gli2. Furthermore, we show that the N-terminus of Su(fu) is sufficient for Gli inactivation in the absence of cytoplasmic sequestration. Together, these observations reveal that Su(fu) regulates the activity of Gli1 and Gli2 through distinct cytoplasmic and nuclear mechanisms.
Barnfield
Paul C
PC
Hospital for Sick Children, Program in Developmental Biology, 101 College Street, TMDT, Rm. 13-314, Toronto, ON, Canada M5G 1L7.
Zhang
Xiaoyun
X
Thanabalasingham
Vijitha
V
Yoshida
Minoru
M
Hui
Chi-chung
CC
D021581:Active Transport, Cell Nucleus; D000595:Amino Acid Sequence; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism*; D005786:Gene Expression Regulation; D016153:Genes, Suppressor; D028884:Karyopherins / Q000378:metabolism / Q000502:physiology; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D051379:Mice; D015513:Oncogene Proteins / Q000378:metabolism*; D017354:Point Mutation; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism / Q000502:physiology; D012097:Repressor Proteins / Q000378:metabolism / Q000502:physiology*; D015534:Trans-Activators; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2; D000097606:Exportin 1 Protein
D028884:Karyopherins; D051741:Kruppel-Like Transcription Factors; D015513:Oncogene Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2; D000097606:Exportin 1 Protein; C000618551:Gli2 protein, mouse; C490763:Sufu protein, mouse