“…Members of the ATF/CREB family of transcription factors are downstream e ectors of the PKA pathway, but are also a ected by PKC-mediated signaling (see review by Karin and Hunter, 1995). ATF-4 and Par-4 both seem to be negative regulators of transcription by interfering with ATF1/2 (Shimizu et al, 1998) or WT1-mediated transcription (Johnstone et al, 1996), respectively. It is conceivable that these negative activities of ATF-4 and Par-4 can be regulated through phosphorylation by Dlk/ZIP kinase.…”
Section: The Leucine Zipper As Interaction Domain In Transcription Famentioning
Dlk/ZIP kinase is a newly discovered serine/threonine kinase which, due to its homology to DAP kinase, was named DAP like kinase, Dlk. This kinase is tightly associated with nuclear structures, it undergoes extensive autophosphorylation and phosphorylates myosin light chain and core histones H3, H2A and H4 in vitro. Moreover, it possesses a leucine zipper which mediates interaction with transcription factor ATF-4, therefore it was called ZIP kinase. We employed the yeast twohybrid system to identify interaction partners of Dlk that might serve as regulators or targets. Besides ATF-4 and others we found Par-4, a modulator of transcription factor WT1 and mediator of apoptosis. Complex formation between Dlk and Par-4 was con®rmed by GST pull-down experiments and kinase reactions in vitro and coexpression experiments in vivo. The interaction domain within Dlk was mapped to an arginine-rich region between residues 338 ± 417, rather than to the leucine zipper. Strikingly, coexpression of Dlk and Par-4 lead to relocation of Dlk from the nucleus to the cytoplasm, particularly to actin ®laments. These interactions provoked a dramatic reorganization of the cytoskeleton and morphological symptoms of apoptosis, thus suggesting a functional relationship between Dlk and Par-4 in the control of apoptosis.
“…Members of the ATF/CREB family of transcription factors are downstream e ectors of the PKA pathway, but are also a ected by PKC-mediated signaling (see review by Karin and Hunter, 1995). ATF-4 and Par-4 both seem to be negative regulators of transcription by interfering with ATF1/2 (Shimizu et al, 1998) or WT1-mediated transcription (Johnstone et al, 1996), respectively. It is conceivable that these negative activities of ATF-4 and Par-4 can be regulated through phosphorylation by Dlk/ZIP kinase.…”
Section: The Leucine Zipper As Interaction Domain In Transcription Famentioning
Dlk/ZIP kinase is a newly discovered serine/threonine kinase which, due to its homology to DAP kinase, was named DAP like kinase, Dlk. This kinase is tightly associated with nuclear structures, it undergoes extensive autophosphorylation and phosphorylates myosin light chain and core histones H3, H2A and H4 in vitro. Moreover, it possesses a leucine zipper which mediates interaction with transcription factor ATF-4, therefore it was called ZIP kinase. We employed the yeast twohybrid system to identify interaction partners of Dlk that might serve as regulators or targets. Besides ATF-4 and others we found Par-4, a modulator of transcription factor WT1 and mediator of apoptosis. Complex formation between Dlk and Par-4 was con®rmed by GST pull-down experiments and kinase reactions in vitro and coexpression experiments in vivo. The interaction domain within Dlk was mapped to an arginine-rich region between residues 338 ± 417, rather than to the leucine zipper. Strikingly, coexpression of Dlk and Par-4 lead to relocation of Dlk from the nucleus to the cytoplasm, particularly to actin ®laments. These interactions provoked a dramatic reorganization of the cytoskeleton and morphological symptoms of apoptosis, thus suggesting a functional relationship between Dlk and Par-4 in the control of apoptosis.
“…ATF4 has been demonstrated to activate transcription through interactions at ATF\CRE sites [39,46,48], and also through the interleukin-2 CD28 response element [51]. While there are reports showing that ATF4 can suppress promoter activity [52], others describe ' apparent ' transcriptional repression by ATF4 due to ' squelching ' under certain conditions [46]. ATF4 can interact with several general transcription factors [46] and can dimerize with C\EBP family members, including C\EBPβ [50] and IgEBP [53,54].…”
Gadd153, also known as chop, encodes a member of the CCAAT/enhancer-binding protein (C/EBP) transcription factor family and is transcriptionally activated by cellular stress signals. We recently demonstrated that arsenite treatment of rat pheochromocytoma PC12 cells results in the biphasic induction of Gadd153 mRNA expression, controlled in part through binding of C/EBPβ and two uncharacterized protein complexes to the C/EBP–ATF (activating transcription factor) composite site in the Gadd153 promoter. In this report, we identified components of these additional complexes as two ATF/CREB (cAMP-responsive-element-binding protein) transcription factors having differential binding activities dependent upon the time of arsenite exposure. During arsenite treatment of PC12 cells, we observed enhanced binding of ATF4 to the C/EBP–ATF site at 2 h as Gadd153 mRNA levels increased, and enhanced binding of ATF3 complexes at 6 h as Gadd153 expression declined. We further demonstrated that ATF4 activates, while ATF3 represses, Gadd153 promoter activity through the C/EBP–ATF site. ATF3 also repressed ATF4-mediated transactivation and arsenite-induced activation of the Gadd153 promoter. Our results suggest that numerous members of the ATF/CREB family are involved in the cellular stress response, and that regulation of stress-induced biphasic Gadd153 expression in PC12 cells involves the ordered, sequential binding of multiple transcription factor complexes to the C/EBP–ATF composite site.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.