Dataset Information

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

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 14-3-3?, 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-? 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.

SUBMITTER: Kasinski A

PROVIDER: S-EPMC3972145 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Kasinski Andrea A Dong Xueyuan X Khuri Fadlo R FR Boss Jeremy J Fu Haian H

PloS one 20140401 4

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 identificatio ...[more]

PMID: 24690670

Similar Datasets

Project description:ObjectiveMetabolic stress primes monocytes for accelerated chemokine-mediated adhesion, migration, and recruitment into vascular lesions by increasing actin remodeling. The mechanism linking metabolic stress to accelerated actin turnover and enhanced monocyte migration was not known. We tested the hypothesis that in metabolically primed monocytes, the acceleration of monocyte chemoattractant protein-1-induced chemotaxis is mediated by the hyperactivation of cofilin.Approach and resultsMetabolic priming was induced by exposing human THP-1 monocytes to diabetic conditions, that is, human native low-density lipoprotein plus high glucose concentrations. In healthy monocytes, monocyte chemoattractant protein-1 induced the phosphorylation and inactivation of cofilin. This response was completely blocked in metabolically primed monocytes but restored by overexpression of the thiol transferase, glutaredoxin 1. Cofilin kinase, LIM kinase 1, and cofilin phosphatase, Slingshot-1L, were not affected by metabolic stress. However, metabolic priming increased 3.8-fold the S-glutathionylation of the Slingshot-1L-binding protein 14-3-3ζ (zeta), resulting in its caspase-dependent degradation. Glutaredoxin 1 overexpression inhibited low-density lipoprotein plus high glucose-induced S-glutathionylation and degradation of 14-3-3ζ. The C25S mutant of 14-3-3ζ was resistant to both S-glutathionylation and degradation induced by low-density lipoprotein plus high glucose. Overexpression of the C25S mutant restored monocyte chemoattractant protein-1-induced cofilin phosphorylation and prevented accelerated migration of metabolically stressed monocytes, suggesting that loss of 14-3-3ζ increases the pool of free Slingshot-1L phosphatase, thereby preventing the phosphorylation and deactivation of cofilin in response to chemokine activation.ConclusionsBy preventing the inactivation of cofilin, metabolic stress-induced degradation of 14-3-3ζ promotes the conversion of blood monocytes into a hypermigratory, proatherogenic phenotype.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets