PUBLICATION
The γ-Secretase Cleavage Product of Polycystin-1 Regulates TCF and CHOP-Mediated Transcriptional Activation through a p300-Dependent Mechanism
- Authors
- Merrick, D., Chapin, H., Baggs, J.E., Yu, Z., Somlo, S., Sun, Z., Hogenesch, J.B., and Caplan, M.J.
- ID
- ZDB-PUB-120105-58
- Date
- 2012
- Source
- Developmental Cell 22(1): 197-210 (Journal)
- Registered Authors
- Sun, Zhaoxia
- Keywords
- none
- MeSH Terms
-
- Animals
- Cell Proliferation
- Wnt Signaling Pathway
- Zebrafish/genetics
- Zebrafish/growth & development
- Zebrafish/metabolism*
- TCF Transcription Factors/genetics
- TCF Transcription Factors/metabolism*
- Embryo, Nonmammalian/cytology
- Embryo, Nonmammalian/metabolism
- Humans
- Cells, Cultured
- Amyloid Precursor Protein Secretases/metabolism*
- Apoptosis*
- TRPP Cation Channels/antagonists & inhibitors
- TRPP Cation Channels/physiology*
- Transcriptional Activation
- p300-CBP Transcription Factors/genetics*
- p300-CBP Transcription Factors/metabolism
- Transcription Factor CHOP/genetics
- Transcription Factor CHOP/metabolism*
- Kidney/metabolism
- Kidney/pathology
- Immunoprecipitation
- Cysts/etiology
- Cysts/metabolism
- Cysts/pathology
- Polycystic Kidney, Autosomal Dominant/physiopathology
- Phenotype
- Immunoblotting
- PubMed
- 22178500 Full text @ Dev. Cell
Citation
Merrick, D., Chapin, H., Baggs, J.E., Yu, Z., Somlo, S., Sun, Z., Hogenesch, J.B., and Caplan, M.J. (2012) The γ-Secretase Cleavage Product of Polycystin-1 Regulates TCF and CHOP-Mediated Transcriptional Activation through a p300-Dependent Mechanism. Developmental Cell. 22(1):197-210.
Abstract
Mutations in Pkd1, encoding polycystin-1 (PC1), cause autosomal-dominant polycystic kidney disease (ADPKD). We show that the carboxy-terminal tail (CTT) of PC1 is released by γ-secretase-mediated cleavage and regulates the Wnt and CHOP pathways by binding the transcription factors TCF and CHOP, disrupting their interaction with the common transcriptional coactivator p300. Loss of PC1 causes increased proliferation and apoptosis, while reintroducing PC1-CTT into cultured Pkd1 null cells reestablishes normal growth rate, suppresses apoptosis, and prevents cyst formation. Inhibition of γ-secretase activity impairs the ability of PC1 to suppress growth and apoptosis and leads to cyst formation in cultured renal epithelial cells. Expression of the PC1-CTT is sufficient to rescue the dorsal body curvature phenotype in zebrafish embryos resulting from either γ-secretase inhibition or suppression of Pkd1 expression. Thus, γ-secretase-dependent release of the PC1-CTT creates a protein fragment whose expression is sufficient to suppress ADPKD-related phenotypes in vitro and in vivo.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping