Abstract
Recently, we demonstrated that the function of ATF3, a stress-inducible transcriptional repressor, is negatively regulated by a bZip protein, gadd153/Chop10. In this report, we present evidence that ATF3 can repress the expression of its own inhibitor, gadd153/Chop10. First, ATF3 represses a chloramphenicol acetyltransferase reporter gene driven by the gadd153/Chop10 promoter when assayed by a transfection assay in vivo and a transcription assay in vitro. Second, the gadd153/Chop10 promoter contains two functionally important binding sites for ATF3: an AP-1 site and a C/EBP-ATF composite site, a previously unidentified binding site for ATF3. The absence of either site reduces the ability of ATF3 to repress the promoter. Third, overexpression of ATF3 by transient transfection results in a reduction of the endogenous gadd153/Chop10 mRNA level. Fourth, as described previously, ATF3 is induced in the liver upon CCl4 treatment. Intriguingly, we show in this report that gadd153/Chop10 mRNA is not present in areas where ATF3 is induced. Taken together, these results strongly suggest that ATF3 represses the expression of gadd153/Chop10. The mutual negative regulation between ATF3 and gadd153/Chop10 is discussed.
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- Baeuerle P. A., Baltimore D. NF-kappa B: ten years after. Cell. 1996 Oct 4;87(1):13–20. doi: 10.1016/s0092-8674(00)81318-5. [DOI] [PubMed] [Google Scholar]
- Barak Y., Juven T., Haffner R., Oren M. mdm2 expression is induced by wild type p53 activity. EMBO J. 1993 Feb;12(2):461–468. doi: 10.1002/j.1460-2075.1993.tb05678.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bartlett J. D., Luethy J. D., Carlson S. G., Sollott S. J., Holbrook N. J. Calcium ionophore A23187 induces expression of the growth arrest and DNA damage inducible CCAAT/enhancer-binding protein (C/EBP)-related gene, gadd153. Ca2+ increases transcriptional activity and mRNA stability. J Biol Chem. 1992 Oct 5;267(28):20465–20470. [PubMed] [Google Scholar]
- Carlson S. G., Fawcett T. W., Bartlett J. D., Bernier M., Holbrook N. J. Regulation of the C/EBP-related gene gadd153 by glucose deprivation. Mol Cell Biol. 1993 Aug;13(8):4736–4744. doi: 10.1128/mcb.13.8.4736. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chen B. P., Liang G., Whelan J., Hai T. ATF3 and ATF3 delta Zip. Transcriptional repression versus activation by alternatively spliced isoforms. J Biol Chem. 1994 Jun 3;269(22):15819–15826. [PubMed] [Google Scholar]
- Chen B. P., Wolfgang C. D., Hai T. Analysis of ATF3, a transcription factor induced by physiological stresses and modulated by gadd153/Chop10. Mol Cell Biol. 1996 Mar;16(3):1157–1168. doi: 10.1128/mcb.16.3.1157. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Coni P., Simbula G., de Prati A. C., Menegazzi M., Suzuki H., Sarma D. S., Ledda-Columbano G. M., Columbano A. Differences in the steady-state levels of c-fos, c-jun and c-myc messenger RNA during mitogen-induced liver growth and compensatory regeneration. Hepatology. 1993 Jun;17(6):1109–1116. [PubMed] [Google Scholar]
- Das D. K., Maulik N., Moraru I. I. Gene expression in acute myocardial stress. Induction by hypoxia, ischemia, reperfusion, hyperthermia and oxidative stress. J Mol Cell Cardiol. 1995 Jan;27(1):181–193. doi: 10.1016/s0022-2828(08)80017-x. [DOI] [PubMed] [Google Scholar]
- Dignam J. D., Lebovitz R. M., Roeder R. G. Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Res. 1983 Mar 11;11(5):1475–1489. doi: 10.1093/nar/11.5.1475. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dragunow M., Beilharz E., Sirimanne E., Lawlor P., Williams C., Bravo R., Gluckman P. Immediate-early gene protein expression in neurons undergoing delayed death, but not necrosis, following hypoxic-ischaemic injury to the young rat brain. Brain Res Mol Brain Res. 1994 Aug;25(1-2):19–33. doi: 10.1016/0169-328x(94)90274-7. [DOI] [PubMed] [Google Scholar]
- Fawcett T. W., Eastman H. B., Martindale J. L., Holbrook N. J. Physical and functional association between GADD153 and CCAAT/enhancer-binding protein beta during cellular stress. J Biol Chem. 1996 Jun 14;271(24):14285–14289. doi: 10.1074/jbc.271.24.14285. [DOI] [PubMed] [Google Scholar]
- Fiallos-Estrada C. E., Kummer W., Mayer B., Bravo R., Zimmermann M., Herdegen T. Long-lasting increase of nitric oxide synthase immunoreactivity, NADPH-diaphorase reaction and c-JUN co-expression in rat dorsal root ganglion neurons following sciatic nerve transection. Neurosci Lett. 1993 Feb 19;150(2):169–173. doi: 10.1016/0304-3940(93)90528-s. [DOI] [PubMed] [Google Scholar]
- Fornace A. J., Jr, Alamo I., Jr, Hollander M. C. DNA damage-inducible transcripts in mammalian cells. Proc Natl Acad Sci U S A. 1988 Dec;85(23):8800–8804. doi: 10.1073/pnas.85.23.8800. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Fornace A. J., Jr, Nebert D. W., Hollander M. C., Luethy J. D., Papathanasiou M., Fargnoli J., Holbrook N. J. Mammalian genes coordinately regulated by growth arrest signals and DNA-damaging agents. Mol Cell Biol. 1989 Oct;9(10):4196–4203. doi: 10.1128/mcb.9.10.4196. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Guyton K. Z., Xu Q., Holbrook N. J. Induction of the mammalian stress response gene GADD153 by oxidative stress: role of AP-1 element. Biochem J. 1996 Mar 1;314(Pt 2):547–554. doi: 10.1042/bj3140547. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hai T. W., Horikoshi M., Roeder R. G., Green M. R. Analysis of the role of the transcription factor ATF in the assembly of a functional preinitiation complex. Cell. 1988 Sep 23;54(7):1043–1051. doi: 10.1016/0092-8674(88)90119-5. [DOI] [PubMed] [Google Scholar]
- Hai T. W., Liu F., Coukos W. J., Green M. R. Transcription factor ATF cDNA clones: an extensive family of leucine zipper proteins able to selectively form DNA-binding heterodimers. Genes Dev. 1989 Dec;3(12B):2083–2090. doi: 10.1101/gad.3.12b.2083. [DOI] [PubMed] [Google Scholar]
- Hai T., Curran T. Cross-family dimerization of transcription factors Fos/Jun and ATF/CREB alters DNA binding specificity. Proc Natl Acad Sci U S A. 1991 May 1;88(9):3720–3724. doi: 10.1073/pnas.88.9.3720. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Haupt Y., Maya R., Kazaz A., Oren M. Mdm2 promotes the rapid degradation of p53. Nature. 1997 May 15;387(6630):296–299. doi: 10.1038/387296a0. [DOI] [PubMed] [Google Scholar]
- Hill C. S., Treisman R. Transcriptional regulation by extracellular signals: mechanisms and specificity. Cell. 1995 Jan 27;80(2):199–211. doi: 10.1016/0092-8674(95)90403-4. [DOI] [PubMed] [Google Scholar]
- Karin M. Signal transduction from the cell surface to the nucleus through the phosphorylation of transcription factors. Curr Opin Cell Biol. 1994 Jun;6(3):415–424. doi: 10.1016/0955-0674(94)90035-3. [DOI] [PubMed] [Google Scholar]
- Kubbutat M. H., Jones S. N., Vousden K. H. Regulation of p53 stability by Mdm2. Nature. 1997 May 15;387(6630):299–303. doi: 10.1038/387299a0. [DOI] [PubMed] [Google Scholar]
- Le Bail O., Schmidt-Ullrich R., Israël A. Promoter analysis of the gene encoding the I kappa B-alpha/MAD3 inhibitor of NF-kappa B: positive regulation by members of the rel/NF-kappa B family. EMBO J. 1993 Dec 15;12(13):5043–5049. doi: 10.1002/j.1460-2075.1993.tb06197.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lee K. A., Hai T. Y., SivaRaman L., Thimmappaya B., Hurst H. C., Jones N. C., Green M. R. A cellular protein, activating transcription factor, activates transcription of multiple E1A-inducible adenovirus early promoters. Proc Natl Acad Sci U S A. 1987 Dec;84(23):8355–8359. doi: 10.1073/pnas.84.23.8355. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Liang G., Wolfgang C. D., Chen B. P., Chen T. H., Hai T. ATF3 gene. Genomic organization, promoter, and regulation. J Biol Chem. 1996 Jan 19;271(3):1695–1701. doi: 10.1074/jbc.271.3.1695. [DOI] [PubMed] [Google Scholar]
- Luethy J. D., Fargnoli J., Park J. S., Fornace A. J., Jr, Holbrook N. J. Isolation and characterization of the hamster gadd153 gene. Activation of promoter activity by agents that damage DNA. J Biol Chem. 1990 Sep 25;265(27):16521–16526. [PubMed] [Google Scholar]
- Moss B., Elroy-Stein O., Mizukami T., Alexander W. A., Fuerst T. R. Product review. New mammalian expression vectors. Nature. 1990 Nov 1;348(6296):91–92. doi: 10.1038/348091a0. [DOI] [PubMed] [Google Scholar]
- Proctor E., Chatamra K. High yield micronodular cirrhosis in the rat. Gastroenterology. 1982 Dec;83(6):1183–1190. [PubMed] [Google Scholar]
- Robinson G. A. Immediate early gene expression in axotomized and regenerating retinal ganglion cells of the adult rat. Brain Res Mol Brain Res. 1994 Jul;24(1-4):43–54. doi: 10.1016/0169-328x(94)90116-3. [DOI] [PubMed] [Google Scholar]
- Ron D., Habener J. F. CHOP, a novel developmentally regulated nuclear protein that dimerizes with transcription factors C/EBP and LAP and functions as a dominant-negative inhibitor of gene transcription. Genes Dev. 1992 Mar;6(3):439–453. doi: 10.1101/gad.6.3.439. [DOI] [PubMed] [Google Scholar]
- Sagar S. M., Sharp F. R., Curran T. Expression of c-fos protein in brain: metabolic mapping at the cellular level. Science. 1988 Jun 3;240(4857):1328–1331. doi: 10.1126/science.3131879. [DOI] [PubMed] [Google Scholar]
- Scott M. L., Fujita T., Liou H. C., Nolan G. P., Baltimore D. The p65 subunit of NF-kappa B regulates I kappa B by two distinct mechanisms. Genes Dev. 1993 Jul;7(7A):1266–1276. doi: 10.1101/gad.7.7a.1266. [DOI] [PubMed] [Google Scholar]
- Sun S. C., Ganchi P. A., Ballard D. W., Greene W. C. NF-kappa B controls expression of inhibitor I kappa B alpha: evidence for an inducible autoregulatory pathway. Science. 1993 Mar 26;259(5103):1912–1915. doi: 10.1126/science.8096091. [DOI] [PubMed] [Google Scholar]
- Sylvester S. L., ap Rhys C. M., Luethy-Martindale J. D., Holbrook N. J. Induction of GADD153, a CCAAT/enhancer-binding protein (C/EBP)-related gene, during the acute phase response in rats. Evidence for the involvement of C/EBPs in regulating its expression. J Biol Chem. 1994 Aug 5;269(31):20119–20125. [PubMed] [Google Scholar]
- Tanaka M., Herr W. Differential transcriptional activation by Oct-1 and Oct-2: interdependent activation domains induce Oct-2 phosphorylation. Cell. 1990 Feb 9;60(3):375–386. doi: 10.1016/0092-8674(90)90589-7. [DOI] [PubMed] [Google Scholar]
- Vallejo M., Gosse M. E., Beckman W., Habener J. F. Impaired cyclic AMP-dependent phosphorylation renders CREB a repressor of C/EBP-induced transcription of the somatostatin gene in an insulinoma cell line. Mol Cell Biol. 1995 Jan;15(1):415–424. doi: 10.1128/mcb.15.1.415. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Vallejo M., Ron D., Miller C. P., Habener J. F. C/ATF, a member of the activating transcription factor family of DNA-binding proteins, dimerizes with CAAT/enhancer-binding proteins and directs their binding to cAMP response elements. Proc Natl Acad Sci U S A. 1993 May 15;90(10):4679–4683. doi: 10.1073/pnas.90.10.4679. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Vinson C. R., Hai T., Boyd S. M. Dimerization specificity of the leucine zipper-containing bZIP motif on DNA binding: prediction and rational design. Genes Dev. 1993 Jun;7(6):1047–1058. doi: 10.1101/gad.7.6.1047. [DOI] [PubMed] [Google Scholar]
- Wang X. Z., Lawson B., Brewer J. W., Zinszner H., Sanjay A., Mi L. J., Boorstein R., Kreibich G., Hendershot L. M., Ron D. Signals from the stressed endoplasmic reticulum induce C/EBP-homologous protein (CHOP/GADD153). Mol Cell Biol. 1996 Aug;16(8):4273–4280. doi: 10.1128/mcb.16.8.4273. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wu W., Li Y., Schinco F. P. Expression of c-jun and neuronal nitric oxide synthase in rat spinal motoneurons following axonal injury. Neurosci Lett. 1994 Sep 26;179(1-2):157–161. doi: 10.1016/0304-3940(94)90958-x. [DOI] [PubMed] [Google Scholar]
- Wu X., Bayle J. H., Olson D., Levine A. J. The p53-mdm-2 autoregulatory feedback loop. Genes Dev. 1993 Jul;7(7A):1126–1132. doi: 10.1101/gad.7.7a.1126. [DOI] [PubMed] [Google Scholar]
- Yin T., Sandhu G., Wolfgang C. D., Burrier A., Webb R. L., Rigel D. F., Hai T., Whelan J. Tissue-specific pattern of stress kinase activation in ischemic/reperfused heart and kidney. J Biol Chem. 1997 Aug 8;272(32):19943–19950. doi: 10.1074/jbc.272.32.19943. [DOI] [PubMed] [Google Scholar]