The regulation of ATF3 gene expression by mitogen-activated protein kinases.

Abstract

ATF3 (activating transcription factor 3) gene encodes a member of the ATF/CREB (cAMP-response-element-binding protein) family of transcription factors. Its expression is induced by a wide range of signals, including stress signals and signals that promote cell proliferation and motility. Thus the ATF3 gene can be characterized as an 'adaptive response' gene for the cells to cope with extra- and/or intra-cellular changes. In the present study, we demonstrate that the p38 signalling pathway is involved in the induction of ATF3 by stress signals. Ectopic expression of CA (constitutively active) MKK6 [MAPK (mitogen-activated protein kinase) kinase 6], a kinase upstream of p38, indicated that activation of the p38 pathway is sufficient to induce the expression of the ATF3 gene. Inhibition of the pathway indicated that the p38 pathway is necessary for various signals to induce ATF3, including anisomycin, IL-1beta (interleukin 1beta), TNFalpha (tumour necrosis factor alpha) and H2O2. Analysis of the endogenous ATF3 gene indicates that the regulation is at least in part at the transcription level. Specifically, CREB, a transcription factor known to be phosphorylated by p38, plays a role in this induction. Interestingly, the ERK (extracellular-signal-regulated kinase) and JNK (c-Jun N-terminal kinase)/SAPK (stress-activated protein kinase) signalling pathways are neither necessary nor sufficient to induce ATF3 in the anisomycin stress paradigm. Furthermore, analysis of caspase 3 activation indicated that knocking down ATF3 reduced the ability of MKK6(CA) to exert its pro-apoptotic effect. Taken together, our results indicate that a major signalling pathway, the p38 pathway, plays a critical role in the induction of ATF3 by stress signals, and that ATF3 is functionally important to mediate the pro-apoptotic effects of p38.

• Authors: Dan Lu, Jingchun Chen, Tsonwin Hai
• Journal: The Biochemical journal (Biochem J) Vol. 401 Issue 2 Pg. 559-67 (Jan 15 2007) ISSN: 1470-8728 [Electronic] England
• PMID: 17014422 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Activating Transcription Factor 3
• Flavonoids
• Imidazoles
• Pyridines
• Transcription Factors
• Anisomycin
• JNK Mitogen-Activated Protein Kinases
• Mitogen-Activated Protein Kinases
• p38 Mitogen-Activated Protein Kinases
• MAP Kinase Kinase 7
• SB 203580
• 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one

Topics

• Activating Transcription Factor 3 (biosynthesis, genetics)
• Animals
• Anisomycin (pharmacology)
• COS Cells
• Chlorocebus aethiops
• Enzyme Activation
• Enzyme Induction (drug effects)
• Flavonoids (pharmacology)
• Gene Expression Regulation
• HeLa Cells
• Humans
• Imidazoles (pharmacology)
• JNK Mitogen-Activated Protein Kinases (antagonists & inhibitors, metabolism)
• MAP Kinase Kinase 7 (metabolism)
• Mitogen-Activated Protein Kinases (physiology)
• Pyridines (pharmacology)
• Transcription Factors (metabolism)
• p38 Mitogen-Activated Protein Kinases (antagonists & inhibitors, metabolism)