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PLoS One. 2014 Apr 1;9(4):e93480. doi: 10.1371/journal.pone.0093480. eCollection 2014.

Transcriptional regulation of YWHAZ, the gene encoding 14-3-3ζ.

Author information

1
Program in Genetics and Molecular Biology, Emory University, Atlanta, Georgia, United States of America; Department of Pharmacology, Emory University, Atlanta, Georgia, United States of America.
2
Department of Pharmacology, Emory University, Atlanta, Georgia, United States of America.
3
Department of Hematology and Medical Oncology, Emory University, Atlanta, Georgia, United States of America.
4
Department of Microbiology and Immunology, Emory University, Atlanta, Georgia, United States of America.

Abstract

Aberrant expression of oncogenic 14-3-3 proteins is correlated with poor survival of cancer patients. While the underlying mechanism of the abnormal expression in tumors remains elusive for the six oncogenic 14-3-3 isoforms; the potential involvement of a transcriptional component has been suggested. Unfortunately, little experimental data has been reported to support this hypothesis. In this study we describe the genetic structure of YWHAZ, the gene encoding 14-3-3ζ, including the identification of previously unreported transcript variants. In total, five transcript variants were revealed and their expressions confirmed in a panel of cell lines. Expressed sequence tag (EST) database mining and in vitro rapid-amplification of cDNA ends (RACE) confirmed that one variant, 1c, represents >80% of the expressed transcripts, which is also the most efficiently translated. An analysis of the proximal promoter of this variant revealed a functional Cyclic-AMP Response Element (CRE). Factors that bound to the CRE element were recognized through fractionation and subsequent EMSAs. This analysis identified CREB and ATF-1 as the trans-interacting factors. Cell-based assays confirm that ATF-1, and to a lesser extent CREB, bind the endogenous YWHAZ promoter especially under TNF-α stimulating conditions. In support of a role of ATF-1 in the regulation of YWHAZ, silencing of ATF-1 resulted in a marked reduction in two of the five YWHAZ transcripts. These data suggest a novel mechanism for the transcriptional regulation of a major pro-survival gene, YWHAZ, by ATF-1.

PMID:
24690670
PMCID:
PMC3972145
DOI:
10.1371/journal.pone.0093480
[Indexed for MEDLINE]
Free PMC Article
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