title: A novel role for proline- and acid-rich basic region leucine zipper (PAR bZIP) proteins in the transcriptional regulation of a BH3-only proapoptotic gene.
abstract: Proline- and acid-rich (PAR) basic region leucine zipper (bZIP) proteins thyrotroph embryonic factor (TEF), D-site-binding protein (DBP), and hepatic leukemia factor have been involved in neurotransmitter homeostasis and amino acid metabolism. Here we demonstrate a novel role for these proteins in the transcriptional control of a BH3-only gene. PAR bZIP proteins are able to transactivate the promoter of bcl-gS. This promoter is particularly responsive to TEF activation and is silenced by NFIL3, a repressor that shares the consensus binding site with PAR bZIP proteins. Consistently, transfection of TEF induces the expression of endogenous bcl-gS in cancer cells, and this induction is independent of p53. A naturally occurring variant of DBP (tDBP), lacking the transactivation domain, has been identified and shown to impede the formation of active TEF dimers in a competitive manner and to reduce the TEF-dependent induction of bcl-gS. Of note, treatment of cancer cells with etoposide induces TEF activation and promotes the expression of bcl-gS. Furthermore, blockade of bcl-gS or TEF expression by a small interfering RNA strategy or transfection with tDBP significantly reduces the etoposide-mediated apoptotic cell death. These findings represent the first described role for PAR bZIP proteins in the regulation of a gene involved in the execution of apoptosis.
authors.affiliation: Unidad de Genetica Molecular, Hospital Universitario Marques de Valdecilla, Servicio Cantabro de Salud, 39008 Santander, Spain.
authors.forename: Adalberto
authors.initials: A
authors.lastname: Benito
authors.forename: Olga
authors.initials: O
authors.lastname: Gutierrez
authors.forename: Carlos
authors.initials: C
authors.lastname: Pipaon
authors.forename: Pedro J
authors.initials: PJ
authors.lastname: Real
authors.forename: Frederic
authors.initials: F
authors.lastname: Gachon
authors.forename: Alistair E
authors.initials: AE
authors.lastname: Ritchie
authors.forename: Jose L
authors.initials: JL
authors.lastname: Fernandez-Luna
mesh_terms: D017209:Apoptosis / Q000235:genetics*; D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers; D005786:Gene Expression Regulation; D006801:Humans; D016350:Leucine Zippers / Q000502:physiology*; D011392:Proline / Q000502:physiology*; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic
chemical_list: D017931:DNA Primers; D011392:Proline