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Cooperation of p300 and PCAF in the control of microRNA 200c/141 transcription and epithelial characteristics

Mizuguchi, Y and Specht, S and Lunz, JG and Isse, K and Corbitt, N and Takizawa, T and Demetris, AJ (2012) Cooperation of p300 and PCAF in the control of microRNA 200c/141 transcription and epithelial characteristics. PLoS ONE, 7 (2).

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Abstract

Epithelial to mesenchymal transition (EMT) not only occurs during embryonic development and in response to injury, but is an important element in cancer progression. EMT and its reverse process, mesenchymal to epithelial transition (MET) is controlled by a network of transcriptional regulators and can be influenced by posttranscriptional and posttranslational modifications. EMT/MET involves many effectors that can activate and repress these transitions, often yielding a spectrum of cell phenotypes. Recent studies have shown that the miR-200 family and the transcriptional suppressor ZEB1 are important contributors to EMT. Our previous data showed that forced expression of SPRR2a was a powerful inducer of EMT and supports the findings by others that SPRR gene members are highly upregulated during epithelial remodeling in a variety of organs. Here, using SPRR2a cells, we characterize the role of acetyltransferases on the microRNA-200c/141 promoter and their effect on the epithelial/mesenchymal status of the cells. We show that the deacetylase inhibitor TSA as well as P300 and PCAF can cause a shift towards epithelial characteristics in HUCCT-1-SPRR2a cells. We demonstrate that both P300 and PCAF act as cofactors for ZEB1, forming a P300/PCAF/ZEB1 complex on the miR200c/141 promoter. This binding results in lysine acetylation of ZEB1 and a release of ZEB1 suppression on miR-200c/141 transcription. Furthermore, disruption of P300 and PCAF interactions dramatically down regulates miR-200c/141 promoter activity, indicating a PCAF/P300 cooperative function in regulating the transcriptional suppressor/activator role of ZEB1. These data demonstrate a novel mechanism of miRNA regulation in mediating cell phenotype. © 2012 Mizuguchi et al.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Mizuguchi, Y
Specht, S
Lunz, JGjlunz@pitt.eduJLUNZ
Isse, K
Corbitt, N
Takizawa, T
Demetris, AJdemetris@pitt.eduDEMETRIS
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorEl-Rifai, WaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Centers: Other Centers, Institutes, or Units > Thomas E. Starzl Transplantation Institute
Date: 22 February 2012
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 7
Number: 2
DOI or Unique Handle: 10.1371/journal.pone.0032449
Schools and Programs: School of Medicine > Pathology
Refereed: Yes
MeSH Headings: Animals; Cell Line, Tumor; Cornified Envelope Proline-Rich Proteins--metabolism; Epithelial-Mesenchymal Transition; Epithelium--metabolism; Humans; Mice; MicroRNAs--biosynthesis; Models, Genetic; Phenotype; Promoter Regions, Genetic; Protein Biosynthesis; Transcription, Genetic; Up-Regulation; p300-CBP Transcription Factors--metabolism
Other ID: NLM PMC3284570
PubMed Central ID: PMC3284570
PubMed ID: 22384255
Date Deposited: 13 Sep 2012 18:04
Last Modified: 01 Jul 2018 01:55
URI: http://d-scholarship.pitt.edu/id/eprint/14143

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