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PINCH1 is transcriptional regulator in podocytes that interacts with WT1 and represses podocalyxin expression

Wang, D and Li, Y and Wu, C and Liu, Y (2011) PINCH1 is transcriptional regulator in podocytes that interacts with WT1 and represses podocalyxin expression. PLoS ONE, 6 (2).

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Background: PINCH1, an adaptor protein containing five LIM domains, plays an important role in regulating the integrin-mediated cell adhesion, migration and epithelial-mesenchymal transition. PINCH1 is induced in the fibrotic kidney after injury, and it primarily localizes at the sites of focal adhesion. Whether it can translocate to the nucleus and directly participate in gene regulation is completely unknown. Methodology/Principal Findings: Using cultured glomerular podocytes as a model system, we show that PINCH1 expression was induced by TGF-β1, a fibrogenic cytokine that promotes podocyte dysfunction. Interestingly, increased PINCH1 not only localized at the sites of focal adhesions, but also underwent nuclear translocation after TGF-β1 stimulation. This nuclear translocation of PINCH1 was apparently dependent on the putative nuclear export/localization signals (NES/NLS) at its C-terminus, as deletion or site-directed mutations abolished its nuclear shuttling. Co-immunoprecipitation and pull-down experiments revealed that PINCH1 interacted with Wilms tumor 1 protein (WT1), a nuclear transcription factor that is essential for regulating podocyte-specific gene expression in adult kidney. Interaction of PINCH1 and WT1 was mediated by the LIM1 domain of PINCH1 and C-terminal zinc-finger domain of WT1, which led to the suppression of the WT1-mediated podocalyxin expression in podocytes. PINCH1 also repressed podocalyxin gene transcription in a promoter-luciferase reporter assay. Conclusion/Significance: These results indicate that PINCH1 can shuttle into the nucleus from cytoplasm in podocytes, wherein it interacts with WT1 and suppresses podocyte-specific gene expression. Our studies reveal a previously unrecognized, novel function of PINCH1, in which it acts as a transcriptional regulator through controlling specific gene expression. © 2011 Wang et al.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Wang, D
Li, Yyil2@pitt.eduYIL2
Wu, Ccarywu@pitt.eduCARYWU
Liu, Yyhliu@pitt.eduYHLIU
Date: 4 March 2011
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 6
Number: 2
DOI or Unique Handle: 10.1371/journal.pone.0017048
Refereed: Yes
MeSH Headings: Adaptor Proteins, Signal Transducing; Amino Acid Sequence; Cell Line; DNA-Binding Proteins--chemistry; DNA-Binding Proteins--genetics; DNA-Binding Proteins--metabolism; DNA-Binding Proteins--physiology; Down-Regulation--genetics; Gene Expression Regulation--genetics; Humans; LIM Domain Proteins; Membrane Proteins; Molecular Sequence Data; Podocytes--metabolism; Podocytes--physiology; Protein Binding; Protein Interaction Domains and Motifs--genetics; Protein Interaction Domains and Motifs--physiology; Protein Interaction Mapping; Repressor Proteins--genetics; Repressor Proteins--metabolism; Repressor Proteins--physiology; Sequence Homology, Amino Acid; Sialoglycoproteins--genetics; Sialoglycoproteins--metabolism; Transcription, Genetic--genetics; WT1 Proteins--chemistry; WT1 Proteins--metabolism
Other ID: NLM PMC3044754
PubMed Central ID: PMC3044754
PubMed ID: 21390327
Date Deposited: 07 Aug 2012 15:48
Last Modified: 02 Feb 2019 16:56


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