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The Adaptor-Related Protein Complex 2, Alpha 2 Subunit (AP2α2) Gene is a Peroxisome Proliferator-Activated Receptor Cardiac Target Gene

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Abstract

A peroxisome proliferator-actived receptor (PPAR) response element (RE) in the promoter region of the adaptor-related protein complex 2, alpha 2 subunit (AP2α2) of mouse heart has been identified. The steroid hormone nuclear PPARs and the retinoid X receptors (RXRs) are important transcriptional factors that regulate gene expression, cell differentiation and lipid metabolism. They form homo- (RXR) and hetero- (PPAR-RXR) dimers that bind DNA at various REs. The AP2α2 gene is part of complex and process that transports lipids and proteins from the plasma membrane to the endosomal system. A PPAR activator (Wy14643) and DMSO (vehicle) was introduced into control and δ337T thyroid hormone receptor (TRβ1) transgenic mice. Heart tissue was extracted and AP2α2 gene expression was compared using Affymetrix expression arrays and qRT PCR among four groups [control, control with Wy14643, δ337T TRβ1 and δ337T TRβ1 with Wy14643]. The gene expression of AP2α2 in the Wy14643 control and transgenic mouse groups was significantly up regulated over the vehicle mouse groups in both the array (p < 0.01) and qRT PCR (p < 0.01) studies. Duplex oligo DNAs containing the PPAR/RXR motif (AGGTCA/TCCAGT) from the AP2α2 promoter were used in EMSA to verify binding of the PPAR and RXR receptors to their REs. pGL4.0 [Luc] constructs of the AP2α2 promoter with and without the PPAR/RXR motifs were co-transfected with mouse PPARα, β or γ1 into HepG2 cells and used in lucerifase assays to verify gene activation. In conclusion our study revealed that PPARα regulates the mouse cardiac AP2α2 gene in both the control and transgenic mouse.

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Abbreviations

PPAR:

Peroxisome proliferator-actived receptor

RE:

Response element

PPREs:

Peroxisomal proliferator-actived receptor response elements

AP2α2:

Adaptor-related protein complex 2, alpha 2 subunit

RXRs:

Retinoid X receptors

DMSO:

Dimethyl sulfoxide

Wy14643:

PPAR activator

TRβ:

Thyroid hormone receptor beta

δ337T TRβ:

Deleted thymine at amino acid 337 in thyroid hormone receptor

HepG2:

Liver tissue culture cell line

CCVs:

Clathrin-coated vesicles

CME:

Clathrin-mediated endocytosis

TSS:

Transcriptional start site

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Acknowledgments

We thank Walter Wahli for kindly providing the human and mouse RXRα, PPARα, PPARβ and PPARγ pSG5 expression vectors and Sander Kersten for providing the acyl-CoA oxidase PPRE used in this study. This work was supported by a grant from the National Heart, Lung, and Blood Institute, R01-HL-60666, to M.A. Portman.

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Authors and Affiliations

  1. Department of Cardiology, Seattle Children’s Research Institute, 1900 9th Avenue, Seattle, WA, 98101, USA

    Norman E. Buroker, Dolena R. Ledee, Xue-Han Ning & Michael A. Portman

  2. Department of Pediatrics, School of Medicine, University of Washington, Seattle, WA, 98195, USA

    Norman E. Buroker, Jie-Yu Huang, Dolena R. Ledee, Xue-Han Ning & Michael A. Portman

  3. Department of Immunology, Seattle Children’s Research Institute, 1900 9th Avenue, Seattle, WA, 98101, USA

    Julia Barboza

  4. Program in Human Urothelial Biology, Center for Tissue and Cell Sciences, Seattle Children’s Research Institute, 1900 9th Avenue, Seattle, WA, 98101, USA

    Rocky J. Eastman Jr & James A. Bassuk

  5. Center for Cardiovascular Biology, University of Washington, Seattle, WA, 98195, USA

    Hans Reinecke

Authors
  1. Norman E. Buroker
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  2. Jie-Yu Huang
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  3. Julia Barboza
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  5. Rocky J. Eastman Jr
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  6. Hans Reinecke
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  7. Xue-Han Ning
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  8. James A. Bassuk
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  9. Michael A. Portman
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Corresponding author

Correspondence to Norman E. Buroker.

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All authors have contributed equally to the work.

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Buroker, N.E., Huang, JY., Barboza, J. et al. The Adaptor-Related Protein Complex 2, Alpha 2 Subunit (AP2α2) Gene is a Peroxisome Proliferator-Activated Receptor Cardiac Target Gene. Protein J 31, 75–83 (2012). https://doi.org/10.1007/s10930-011-9379-0

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  • DOI: https://doi.org/10.1007/s10930-011-9379-0

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