title: Transcriptional regulation of YWHAZ, the gene encoding 14-3-3ζ.
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.
authors.affiliation: 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.
authors.forename: Andrea
authors.initials: A
authors.lastname: Kasinski
authors.affiliation: Department of Pharmacology, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Xueyuan
authors.initials: X
authors.lastname: Dong
authors.affiliation: Department of Hematology and Medical Oncology, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Fadlo R
authors.initials: FR
authors.lastname: Khuri
authors.affiliation: Department of Microbiology and Immunology, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Boss
authors.affiliation: Department of Pharmacology, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Haian
authors.initials: H
authors.lastname: Fu
mesh_terms: D048948:14-3-3 Proteins / Q000737:chemistry / Q000235:genetics*; D020121:5' Untranslated Regions; D051697:Activating Transcription Factor 1 / Q000378:metabolism; D017398:Alternative Splicing; D001483:Base Sequence; D002460:Cell Line; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D005091:Exons; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D014176:Protein Biosynthesis; D059368:RNA Isoforms; D012333:RNA, Messenger / Q000235:genetics; D012045:Regulatory Sequences, Nucleic Acid; D016415:Sequence Alignment; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D048948:14-3-3 Proteins; D020121:5' Untranslated Regions; D051697:Activating Transcription Factor 1; D017362:Cyclic AMP Response Element-Binding Protein; D009687:Nuclear Proteins; D059368:RNA Isoforms; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha