The CAG repeat in SCA12 functions as a cis element to up-regulate PPP2R2B expression

Chih Hsin Lin, Chiung Mei Chen, Yi Ting Hou, Yih Ru Wu, Hsiu Mei Hsieh, Ming-Tsan Su, Guey-Jen Lee

Research output: Contribution to journalArticle

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Abstract

PPP2R2B, a protein widely expressed in neurons, regulates the protein phosphatase 2A (PP2A) activity for dephosphorylation of tau and other substrates. CAG repeat expansion at the 5′-end of the PPP2R2B gene causes autosomal dominant spinocerebellar ataxia type 12. In the present study, we investigated the roles of CAG repeats and flanking cis elements and the associated proteins in controlling PPP2R2B expression. Deletion/site-directed mutagenesis, in silico searches and cDNA overexpression revealed that CREB1 and SP1 bind to the conserved sequence upstream the CAG repeats to up-regulate PPP2R2B expression, whereas TFAP4 binds to the conserved sequence downstream the CAG repeats to down-regulate PPP2R2B expression. The binding of CREB1, SP1, and TFAP4 to the PPP2R2B promoter was further confirmed by DNA pull-down and ChIP-PCR assays. CAG repeats itself also function as a cis element to up-regulate PPP2R2B expression as AT repeat length has no effect on PPP2R2B expression. Together, our data provide evidence that CREB1, SP1, and TFAP4 play roles in modulating PPP2R2B expression, thus offering a mechanism of regulating PP2A activity as the treatment of neurodegenerative diseases associated with abnormal PP2A activity.

Original languageEnglish
Pages (from-to)205-212
Number of pages8
JournalHuman Genetics
Volume128
Issue number2
DOIs
Publication statusPublished - 2010 Aug 1

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Protein Phosphatase 2
Up-Regulation
Conserved Sequence
Site-Directed Mutagenesis
Neurodegenerative Diseases
Computer Simulation
Proteins
Down-Regulation
Complementary DNA
Neurons
Polymerase Chain Reaction
DNA
Genes

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

The CAG repeat in SCA12 functions as a cis element to up-regulate PPP2R2B expression. / Lin, Chih Hsin; Chen, Chiung Mei; Hou, Yi Ting; Wu, Yih Ru; Hsieh, Hsiu Mei; Su, Ming-Tsan; Lee, Guey-Jen.

In: Human Genetics, Vol. 128, No. 2, 01.08.2010, p. 205-212.

Research output: Contribution to journalArticle

Lin, Chih Hsin ; Chen, Chiung Mei ; Hou, Yi Ting ; Wu, Yih Ru ; Hsieh, Hsiu Mei ; Su, Ming-Tsan ; Lee, Guey-Jen. / The CAG repeat in SCA12 functions as a cis element to up-regulate PPP2R2B expression. In: Human Genetics. 2010 ; Vol. 128, No. 2. pp. 205-212.
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