Abstract
Apoptosis is essential for retinal development but it is also a major mode of cell loss in many human retinal dystrophies. High levels of visible light induce retinal apoptosis in mice and rats. This process is dependent on the induction of the transcription factor AP-1, a dimeric complex composed of c-Fos and c-Jun/JunD phosphoproteins. While c-Fos is essential, JunD is dispensable for light-induced photoreceptor apoptosis. Here we show that N-terminal phosphorylation of c-Jun, the other main partner of c-Fos in induced AP-1 complexes is not required for programmed cell death during retinal development in vivo and is also dispensable for photoreceptor apoptosis induced by the exogenous stimuli ‘excessive light’ and N-nitroso-N-methylurea (MNU). Mice expressing a mutant c-Jun protein (JunAA) that cannot be phosphorylated at its N-terminus are apoptosis competent and their retina is not distinguishable from wild-type mice. Accordingly, Jun kinase, responsible for phosphorylation of wild-type c-Jun protein is at best only marginally induced by the apoptotic stimuli ‘light’ and MNU. Complex composition of light-induced AP-1 complexes is similar in wild-type and JunAA mice. This shows that the mutant c-Jun protein can be part of the DNA binding complex AP-1 and demonstrates that induction of the DNA binding activity of AP-1 after light insult does not depend on N-terminal phosphorylation of c-Jun. Our results suggest that transactivation of target genes by phosphorylated c-jun/AP-1 is not required for MNU- or light-induced apoptosis of photoreceptor cells. Cell Death and Differentiation (2001) 8, 859–867
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
Abbreviations
- AP-1:
-
activator protein-1
- ONL:
-
outer nuclear layer
- ROS:
-
rod outer segment
- RIS:
-
rod inner segment
- PE:
-
pigment epithelium
- JNK:
-
Jun kinase
- TUNEL:
-
Terminal transferase-mediated dUTP nick end labeling
- JNP:
-
c-Jun N-terminal phosphorylation
- MNU:
-
N-methyl-N-nitrosourea
References
Young RW . 1984 Cell death during differentiation of the retina in the mouse J. Comp. Neurol. 229: 362–373
Thompson CB . 1995 Apoptosis in the pathogenesis and treatment of disease Science 267: 1456–1462
Gorman AM, McGowan A, Oneill C, Cotter T . 1996 Oxidative Stress and Apoptosis In Neurodegeneration J. Neurol. Sci. 139: 45–52
Reme CE, Grimm C, Hafezi F, Marti A, Wenzel A . 1998 Apoptotic cell death in retinal degenerations Prog. Retin. Eye Res. 17: 443–464
LaVail MM, Gorrin GM, Yasumura D, Matthes MT . 1999 Increased susceptibility to constant light in nr and pcd mice with inherited retinal degenerations Invest. Ophthalmol. Vis. Sci. 40: 1020–1024
Naash ML, Peachey NS, Li ZY, Gryczan CC, Goto Y, Blanks J, Milam AH, Ripps H . 1996 Light-induced acceleration of photoreceptor degeneration in transgenic mice expressing mutant rhodopsin Invest. Ophthalmol. Vis. Sci. 37: 775–782
Simons K . 1993 Artificial light and early-life exposure in age-related macular degeneration and in cataractogenic phototoxicity Arch. Ophthalmol. 111: 297–298
Taylor HR, Munoz B, West S, Bressler NM, Bressler SB, Rosenthal FS . 1990 Visible light and risk of age-related macular degeneration Trans. Am. Ophthalmol. Soc. 88: 163–173
Cideciyan AV, Hood DC, Huang Y, Banin E, Li ZY, Stone EM, Milam AH, Jacobson SG . 1998 Disease sequence from mutant rhodopsin allele to rod and cone photoreceptor degeneration in man Proc. Natl. Acad. Sci. USA. 95: 7103–7108
Cruickshanks KJ, Klein R, Klein BE . 1993 Sunlight and age-related macular degeneration. The Beaver Dam Eye Study Arch. Ophthalmol. 111: 514–518
Xu GZ, Li WW, Tso MO . 1996 Apoptosis in human retinal degenerations Trans. Am. Ophthalmol. Soc. 94: 411–430
Wong P . 1994 Apoptosis, retinitis pigmentosa, and degeneration Biochem. Cell. Biol. 72: 489–498
Noell WK, Walker VS, Kang BS, Berman S . 1966 Retinal damage by light in rats Invest. Ophthalmol. 5: 450–473
Organisciak DT, Darrow RM, Barsalou L, Darrow RA, Kutty RK, Kutty G, Wiggert B . 1998 Light history and age-related changes in retinal light damage Invest. Ophthalmol. Vis. Sci. 39: 1107–1116
LaVail MM, Gorrin GM, Repaci MA . 1987 Strain differences in sensitivity to light-induced photoreceptor degeneration in albino mice Curr. Eye Res. 6: 825–834
Gorgels TG, van Norren D . 1995 Ultraviolet and green light cause different types of damage in rat retina Invest. Ophthalmol. Vis. Sci. 36: 851–863
Grimm C, Wenzel A, Hafezi F, Yu S, Redmond TM, Remé CE . 2000 Protection of Rpe65-deficient mice identifies rhodopsin as mediator of light-induced retinal degeneration Nature Genet. 25: 63–66
Hafezi F, Marti A, Grimm C, Wenzel A, Remé CE . 1999 Differential DNA binding activities of the transcription factors AP-1 and Oct-1 during light-induced apoptosis of photoreceptors Vision Res. 39: 2511–2518
Wenzel A, Grimm C, Marti A, Kueng-Hitz N, Hafezi F, Niemeyer G, Remé CE . 2000 c-fos controls the ‘private pathway’ of light-induced apoptosis of retinal photoreceptors J. Neurosci. 20: 81–88
Curran T, Franza Jr BR . 1988 Fos and Jun: the AP-1 connection Cell 55: 395–397
Ham J, Babij C, Whitfield J, Pfarr CM, Lallemand D, Yaniv M, Rubin LL . 1995 A c-Jun dominant negative mutant protects sympathetic neurons against programmed cell death Neuron. 14: 927–939
Bossy-Wetzel E, Bakiri L, Yaniv M . 1997 Induction of apoptosis by the transcription factor c-Jun EMBO J. 16: 1695–1709
Hafezi F, Grimm C, Wenzel A, Abegg M, Yaniv M, Reme CE . 1999 Retinal photoreceptors are apoptosis-competent in the absence of JunD/AP-1 Cell Death Differ. 6: 934–936
Hafezi F, Steinbach JP, Marti A, Munz K, Wang ZQ, Wagner EF, Aguzzi A, Reme CE . 1997 The absence of c-fos prevents light-induced apoptotic cell death of photoreceptors in retinal degeneration in vivo Nat. Med. 3: 346–349
Kyriakis JM, Banerjee P, Nikolakaki E, Dai T, Rubie EA, Ahmad MF, Avruch J, Woodgett JR . 1994 The stress-activated protein kinase subfamily of c-Jun kinases Nature 369: 156–160
Derijard B, Hibi M, Wu IH, Barrett T, Su B, Deng T, Karin M, Davis RJ . 1994 JNK1: a protein kinase stimulated by UV light and Ha-Ras that binds and phosphorylates the c-Jun activation domain Cell 76: 1025–1037
Johnson RS, van Lingen B, Papaioannou VE, Spiegelman BM . 1993 A null mutation at the c-jun locus causes embryonic lethality and retarded cell growth in culture Genes Dev. 7: 1309–1317
Hilberg F, Aguzzi A, Howells N, Wagner EF . 1993 c-jun is essential for normal mouse development and hepatogenesis Nature 365: 179–181
Behrens A, Sibilia M, Wagner EF . 1999 Amino-terminal phosphorylation of c-Jun regulates stress-induced apoptosis and cellular proliferation Nat. Genet. 21: 326–329
Karin M . 1995 The regulation of AP-1 activity by mitogen-activated protein kinases J. Biol. Chem. 270: 16483–16486
Tominaga Y, Tsuzuki T, Shiraishi A, Kawate H, Sekiguchi M . 1997 Alkylation-induced apoptosis of embryonic stem cells in which the gene for DNA-repair, methyltransferase, had been disrupted by gene targeting Carcinogenesis 18: 889–896
Wurdeman RL, Douskey MC, Gold B . 1993 DNA methylation by N-methyl-N-nitrosourea: methylation pattern changes in single- and double-stranded DNA, and in DNA with mismatched or bulged guanines Nucleic Acids Research 21: 4975–4980
Nambu H, Yuge K, Nakajima M, Shikata N, Takahashi K, Miki H, Uyama M, Tsubura A . 1997 Morphologic Characteristics Of N Methyl N Nitrosourea Induced Retinal Degeneration In C57bl Mice Pathology International 47 6: 377–383
Nakajima M, Yuge K, Senzaki H, Shikata N, Miki H, Uyama M, Tsubura A . 1996 Photoreceptor apoptosis induced by a single systemic administration of N-methyl-N-nitrosourea in the rat retina Am. J. Pathol. 148: 631–641
Nikolakaki E, Coffer PJ, Hemelsoet R, Woodgett JR, Defize LH . 1993 Glycogen synthase kinase 3 phosphorylates Jun family members in vitro and negatively regulates their transactivating potential in intact cells Oncogene 8: 833–840
Boyle WJ, Smeal T, Defize LH, Angel P, Woodgett JR, Karin M, Hunter T . 1991 Activation of protein kinase C decreases phosphorylation of c-Jun at sites that negatively regulate its DNA-binding activity Cell 64: 573–584
Smeal T, Binetruy B, Mercola DA, Birrer M, Karin M . 1991 Oncogenic and transcriptional cooperation with Ha-Ras requires phosphorylation of c-Jun on serines 63 and 73 Nature 354: 494–496
Pulverer BJ, Kyriakis JM, Avruch J, Nikolakaki E, Woodgett JR . 1991 Phosphorylation of c-jun mediated by MAP kinases Nature 353: 670–674
Leppa S, Bohmann D . 1999 Diverse functions of JNK signaling and c-Jun in stress response and apoptosis Oncogene 18: 6158–6162
Eferl R, Sibilia M, Hilberg F, Fuchsbichler A, Kufferath I, Guertl B, Zenz R, Wagner EF, Zatloukal K . 1999 Functions of c-Jun in liver and heart development J. Cell Biol. 145: 1049–1061
Herzog KH, Chen SC, Morgan JI . 1999 c-jun Is dispensable for developmental cell death and axogenesis in the retina J. Neurosci. 19: 4349–4359
Kueng-Hitz N, Grimm C, Lansel N, Hafezi F, He L, Fox DA, Reme CE, Niemeyer G, Wenzel A . 2000 The retina of c-fos-/- mice: electrophysiologic, morphologic and biochemical aspects Invest. Ophthalmol Vis. Sci. 41: 909–916
Rich KA, Zhan Y, Blanks JC . 1997 Aberrant expression of c-Fos accompanies photoreceptor cell death in the rd mouse J. Neurobiol. 32: 593–612
Otori Y, Shimada S, Morimura H, Ishimoto I, Tohyama M, Tano Y . 1997 Expression of c-fos and c-jun mRNA following transient retinal ischemia: an approach using ligation of the retinal central artery in the rat Surv. Ophthalmol. 42: S96–S104
Grimm C, Wenzel A, Hafezi F, Reme CE . 2000 Gene expression in the mouse retina: the effect of damaging light Mol. Vis. 6: 252–260
Ivanov VN, Nikolic-Zugic J . 1997 Transcription factor activation during signal-induced apoptosis of immature CD4(+)CD8(+) thymocytes. A protective role of c-Fos J. Biol. Chem. 272: 8558–8566
Dosch J, Kaina B . 1996 Induction of c-fos, c-jun, junB and junD mRNA and AP-1 by alkylating mutagens in cells deficient and proficient for the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) and its relationship to cell death, mutation induction and chromosomal instability Oncogene 13: 1927–1935
Gupta S, Campbell D, Derijard B, Davis RJ . 1995 Transcription factor ATF2 regulation by the JNK signal transduction pathway Science 267: 389–393
Whitmarsh AJ, Shore P, Sharrocks AD, Davis RJ . 1995 Integration of MAP kinase signal transduction pathways at the serum response element Science 269: 403–407
Aguirre V, Uchida T, Yenush L, Davis R, White MF . 2000 The c-Jun NH(2)-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser(307) J. Biol. Chem. 275: 9047–9054
Yamamoto K, Ichijo H, Korsmeyer SJ . 1999 BCL-2 is phosphorylated and inactivated by an ASK1/Jun N-terminal protein kinase pathway normally activated at G(2)/M Mol. Cell Biol. 19: 8469–8478
Tournier C, Hess P, Yang DD, Xu J, Turner TK, Nimnual A, Bar-Sagi D, Jones SN, Flavell RA, Davis RJ . 2000 Requirement of JNK for stress-induced activation of the cytochrome c-mediated death pathway Science 288: 870–874
Fleischmann A, Hafezi F, Elliott C, Reme CE, Ruther U, Wagner EF . 2000 Fra-1 replaces c-fos-dependent functions in mice Genes Dev. 14: 2695–2700
Matsuo K, Owens JM, Tonko M, Elliott C, Chambers TJ, Wagner EF . 2000 Fosl1 is a transcriptional target of c-Fos during osteoclast differentiation Nat. Genet. 24: 184–187
Marti A, Jehn B, Costello E, Keon N, Ke G, Martin F, Jaggi R . 1994 Protein kinase A and AP-1 (c-Fos/JunD) are induced during apoptosis of mouse mammary epithelial cells Oncogene 9: 1213–1223
Wenzel A, Grimm C, Seeliger N, Jaissle G, Hafezi F, Kretschmer R, Zreuuer E, Remé CE . 2001 Photoreceptor apoptosis prevented by activation of the glucocorticoid receptor Invest. Ophthalmol. Vis. Sci. in press
Acknowledgements
This work was supported by the Velux Foundation, Glarus, Switzerland, the Deutsche Forschungs Gemeinschaft and the Swiss National Science Foundation.
Author information
Authors and Affiliations
Corresponding author
Additional information
Edited by T Cotter
Rights and permissions
About this article
Cite this article
Grimm, C., Wenzel, A., Behrens, A. et al. AP-1 mediated retinal photoreceptor apoptosis is independent of N-terminal phosphorylation of c-Jun. Cell Death Differ 8, 859–867 (2001). https://doi.org/10.1038/sj.cdd.4400871
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/sj.cdd.4400871
Keywords
This article is cited by
-
Photoreceptor protection by mesenchymal stem cell transplantation identifies exosomal MiR-21 as a therapeutic for retinal degeneration
Cell Death & Differentiation (2021)
-
Inhibitory role of TGIF in the As2O3-regulated p21 WAF1/CIP1 expression
Journal of Biomedical Science (2008)
-
Prognostic significance of loss of c-fos protein in gastric carcinoma
Pathology & Oncology Research (2007)
-
Mutual regulation of c-Jun and ATF2 by transcriptional activation and subcellular localization
The EMBO Journal (2006)
