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PMID:23740243

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Citation

Nakamura, I, Fernandez-Barrena, MG, Ortiz-Ruiz, MC, Almada, LL, Hu, C, Elsawa, SF, Mills, LD, Romecin, PA, Gulaid, KH, Moser, CD, Han, JJ, Vrabel, A, Hanse, EA, Akogyeram, NA, Albrecht, JH, Monga, SP, Sanderson, SO, Prieto, J, Roberts, LR and Fernandez-Zapico, ME (2013) Activation of the transcription factor GLI1 by WNT signaling underlies the role of SULFATASE 2 as a regulator of tissue regeneration. J. Biol. Chem. 288:21389-98

Abstract

Tissue regeneration requires the activation of a set of specific growth signaling pathways. The identity of these cascades and their biological roles are known; however, the molecular mechanisms regulating the interplay between these pathways remain poorly understood. Here, we define a new role for SULFATASE 2 (SULF2) in regulating tissue regeneration and define the WNT-GLI1 axis as a novel downstream effector for this sulfatase in a liver model of tissue regeneration. SULF2 is a heparan sulfate 6-O-endosulfatase, which releases growth factors from extracellular storage sites turning active multiple signaling pathways. We demonstrate that SULF2-KO mice display delayed regeneration after partial hepatectomy (PH). Mechanistic analysis of the SULF2-KO phenotype showed a decrease in WNT signaling pathway activity in vivo. In isolated hepatocytes, SULF2 deficiency blocked WNT-induced β-CATENIN nuclear translocation, TCF activation, and proliferation. Furthermore, we identified the transcription factor GLI1 as a novel target of the SULF2-WNT cascade. WNT induces GLI1 expression in a SULF2- and β-CATENIN-dependent manner. GLI1-KO mice phenocopied the SULF2-KO, showing delayed regeneration and decreased hepatocyte proliferation. Moreover, we identified CYCLIN D1, a key mediator of cell growth during tissue regeneration, as a GLI1 transcriptional target. GLI1 binds to the cyclin d1 promoter and regulates its activity and expression. Finally, restoring GLI1 expression in the liver of SULF2-KO mice after PH rescues CYCLIN D1 expression and hepatocyte proliferation to wild-type levels. Thus, together these findings define a novel pathway in which SULF2 regulates tissue regeneration in part via the activation of a novel WNT-GLI1-CYCLIN D1 pathway.

Links

PubMed PMC3774406 Online version:10.1074/jbc.M112.443440

Keywords

Animals; Cell Proliferation/drug effects; Down-Regulation/drug effects; Hedgehog Proteins/metabolism; Hepatectomy; Hepatocytes/cytology; Hepatocytes/drug effects; Hepatocytes/metabolism; Kruppel-Like Transcription Factors/genetics; Kruppel-Like Transcription Factors/metabolism; Liver Regeneration/drug effects; Mice; Mice, Inbred C57BL; Models, Biological; Sulfatases/deficiency; Sulfatases/metabolism; Wnt Signaling Pathway/drug effects; Wnt3A Protein/pharmacology; Zinc Finger Protein GLI1; beta Catenin/metabolism

Significance

Annotations

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

MOUSE:CCND1

acts_upstream_of_or_within

GO:0097421: liver regeneration

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:GLI1

enables

GO:0000978: RNA polymerase II cis-regulatory region sequence-specific DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

  • has_input:(MGI:MGI:88313)

Seeded From UniProt

complete

MOUSE:CTNB1

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0000182)

Seeded From UniProt

complete

MOUSE:ITF2

enables

GO:0000978: RNA polymerase II cis-regulatory region sequence-specific DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:ITF2

enables

GO:0000978: RNA polymerase II proximal promoter sequence-specific DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:SULF2

acts_upstream_of_or_within

GO:0090263: positive regulation of canonical Wnt signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3587954

P

Seeded From UniProt

complete

MOUSE:SULF2

acts_upstream_of_or_within

GO:0009611: response to wounding

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3587954

P

Seeded From UniProt

complete

MOUSE:SULF2

acts_upstream_of_or_within

GO:2000345: regulation of hepatocyte proliferation

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3587954

P

Seeded From UniProt

complete

MOUSE:SULF2

acts_upstream_of_or_within

GO:0097421: liver regeneration

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3587954

P

Seeded From UniProt

complete

MOUSE:SHH

acts_upstream_of_or_within

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

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:GLI1

acts_upstream_of_or_within

GO:0009611: response to wounding

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1857797

P

Seeded From UniProt

complete

MOUSE:GLI1

acts_upstream_of_or_within

GO:0009611: response to wounding

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:GLI1

enables

GO:0000978: RNA polymerase II proximal promoter sequence-specific DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:GLI1

acts_upstream_of_or_within

GO:2000345: regulation of hepatocyte proliferation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:GLI1

acts_upstream_of_or_within

GO:0097421: liver regeneration

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1857797

P

Seeded From UniProt

complete

MOUSE:GLI1

acts_upstream_of_or_within

GO:0060070: canonical Wnt signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:GLI1

acts_upstream_of_or_within

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

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:CTNB1

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

part_of:(CL:0000182)

Seeded From UniProt

complete

MOUSE:WNT3A

acts_upstream_of_or_within

GO:2000347: positive regulation of hepatocyte proliferation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:WNT3A

acts_upstream_of_or_within

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

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:WNT3A

acts_upstream_of_or_within

GO:0090263: positive regulation of canonical Wnt signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

Notes

See also

References

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