A role for AP-1 in apoptosis: the case for and against.

The nuclear transcription factor AP-1, composed of dimers of Fos and Jun proteins, has been linked to a startling breadth of cellular events including cell transformation, proliferation, differentiation and apoptosis. AP-1 is often portrayed as a general, nuclear decision-maker that determines life or death cell fates in response to extracellular stimuli. However, it is increasingly clear that the cellular context is critical for determining the contribution of AP-1 to cellular fates, and the role of AP-1 in apoptosis should be considered within the context of a complex network of nuclear factors that respond simultaneously to a wide range of signal transduction pathways. We take a closer look at the evidence for and against a role for AP-1 in inducing apoptosis, drawing on examples of studies in neurons, lymphocytes and hepatocytes. Although AP-1 activation is associated with a large number of apoptotic scenarios, its role in ensuring cell survival seems equally important. It is, therefore, difficult to convict AP-1 as a killer without taking into account the cellular and extracellular context within which it is functioning. Defining the target genes regulated by AP-1 in these different contexts will help to decipher the contribution of AP-1 to cell fate decisions.

[1]  D. Green,et al.  DNA damaging agents induce expression of Fas ligand and subsequent apoptosis in T lymphocytes via the activation of NF-kappa B and AP-1. , 1998, Molecular cell.

[2]  E. Wagner,et al.  JunB can substitute for Jun in mouse development and cell proliferation , 2002, Nature Genetics.

[3]  E. Wagner,et al.  Amino-terminal phosphorylation of c-Jun regulates stress-induced apoptosis and cellular proliferation , 1999, Nature Genetics.

[4]  S. Estus,et al.  Altered gene expression in neurons during programmed cell death: identification of c-jun as necessary for neuronal apoptosis , 1994, The Journal of cell biology.

[5]  G. Koretzky,et al.  Stress-Induced Fas Ligand Expression in T Cells Is Mediated through a MEK Kinase 1-Regulated Response Element in the Fas Ligand Promoter , 1998, Molecular and Cellular Biology.

[6]  J. Weitzman,et al.  JunD protects cells from p53-dependent senescence and apoptosis. , 2000, Molecular cell.

[7]  M. Karin,et al.  AP-1 in cell proliferation and survival , 2001, Oncogene.

[8]  L. Rubin,et al.  A c-jun dominant negative mutant protects sympathetic neurons against programmed cell death , 1995, Neuron.

[9]  A. Rao,et al.  Gene expression elicited by NFAT in the presence or absence of cooperative recruitment of Fos and Jun , 2000, The EMBO journal.

[10]  R. Flavell,et al.  The JNK Pathway Regulates the In Vivo Deletion of Immature CD4+CD8+ Thymocytes , 1998, The Journal of experimental medicine.

[11]  P. Krammer,et al.  CD95's deadly mission in the immune system , 2000, Nature.

[12]  Richard A. Flavell,et al.  The Bax Subfamily of Bcl2-Related Proteins Is Essential for Apoptotic Signal Transduction by c-Jun NH2-Terminal Kinase , 2002, Molecular and Cellular Biology.

[13]  D. Israeli,et al.  The c-fos Proto-Oncogene Is a Target for Transactivation by the p53 Tumor Suppressor , 1999, Molecular and Cellular Biology.

[14]  E. Wagner,et al.  The Mammalian UV Response c-Jun Induction Is Required for Exit from p53-Imposed Growth Arrest , 2000, Cell.

[15]  J. Blanks,et al.  Aberrant expression of c-Fos accompanies photoreceptor cell death in the rd mouse. , 1997, Journal of neurobiology.

[16]  E. Wagner,et al.  Impaired postnatal hepatocyte proliferation and liver regeneration in mice lacking c‐jun in the liver , 2002, The EMBO journal.

[17]  J. Weitzman,et al.  Life and death in the JUNgle. , 2001, Trends in molecular medicine.

[18]  L. Greene,et al.  POSH acts as a scaffold for a multiprotein complex that mediates JNK activation in apoptosis , 2003, The EMBO journal.

[19]  E. Wagner,et al.  AP-1 in mouse development and tumorigenesis , 2001, Oncogene.

[20]  Frank Hilberg,et al.  Functions of c-Jun in Liver and Heart Development , 1999, The Journal of cell biology.

[21]  E. Bossy‐Wetzel,et al.  Induction of apoptosis by the transcription factor c‐Jun , 1997, The EMBO journal.

[22]  J. Tsien,et al.  c-fos regulates neuronal excitability and survival , 2002, Nature Genetics.

[23]  S. Ju,et al.  Role of Activator Protein-1 in TCR-Mediated Regulation of the Murine fasl Promoter1 , 2000, The Journal of Immunology.

[24]  D. Levy,et al.  Cooperation between STAT3 and c-jun suppresses Fas transcription. , 2001, Molecular cell.

[25]  C. Grimm,et al.  Retinal photoreceptors are apoptosis-competent in the absence of JunD/AP-1. , 1999, Cell death and differentiation.

[26]  P. Krammer,et al.  An unexpected role for FosB in activation-induced cell death of T cells , 2003, Oncogene.

[27]  Jian Zhang,et al.  Regulation of FAS Ligand Expression during Activation-Induced Cell Death in T Cells by p38 Mitogen-Activated Protein Kinase and C-Jun Nh2-Terminal Kinase , 2000, The Journal of experimental medicine.

[28]  Charles A. Harris,et al.  BH3-only Bcl-2 family members are coordinately regulated by the JNK pathway and require Bax to induce apoptosis in neurons. , 2001, The Journal of biological chemistry.

[29]  E. Wagner,et al.  Control of cell cycle progression by c-Jun is p53 dependent. , 1999, Genes & development.

[30]  D. Green,et al.  Withdrawal of Survival Factors Results in Activation of the JNK Pathway in Neuronal Cells Leading to Fas Ligand Induction and Cell Death , 1999, Molecular and Cellular Biology.

[31]  R. Wisdom,et al.  c-jun is essential for sympathetic neuronal death induced by NGF withdrawal but not by p75 activation , 2002, The Journal of cell biology.

[32]  E. Wagner,et al.  JNK2 is required for efficient T-cell activation and apoptosis but not for normal lymphocyte development , 1999, Current Biology.

[33]  K. Lei,et al.  JNK phosphorylation of Bim-related members of the Bcl2 family induces Bax-dependent apoptosis , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[34]  O. Bernard,et al.  Dominant-Negative c-Jun Promotes Neuronal Survival by Reducing BIM Expression and Inhibiting Mitochondrial Cytochrome c Release , 2001, Neuron.

[35]  M. Yaniv,et al.  The mammalian Jun proteins: redundancy and specificity , 2001, Oncogene.

[36]  E. Wagner,et al.  Jun N-terminal kinase 2 modulates thymocyte apoptosis and T cell activation through c-Jun and nuclear factor of activated T cell (NF-AT). , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[37]  D. Bar-Sagi,et al.  Requirement of JNK for stress-induced activation of the cytochrome c-mediated death pathway. , 2000, Science.

[38]  E. Wagner,et al.  c-Jun-Dependent CD95-L Expression Is a Rate-Limiting Step in the Induction of Apoptosis by Alkylating Agents , 2000, Molecular and Cellular Biology.

[39]  E. Wagner,et al.  Liver Tumor Development c-Jun Antagonizes the Proapoptotic Activity of p53 , 2003, Cell.

[40]  Andrew D. Badley,et al.  Transcriptional Regulation of the Human FasL Promoter-Enhancer Region* , 1998, The Journal of Biological Chemistry.

[41]  M. Karin,et al.  AP-1 as a regulator of cell life and death , 2002, Nature Cell Biology.

[42]  P. Krammer,et al.  A Novel AP-1 Element in the CD95 Ligand Promoter Is Required for Induction of Apoptosis in Hepatocellular Carcinoma Cells upon Treatment with Anticancer Drugs , 2000, Molecular and Cellular Biology.

[43]  P. Rakic,et al.  Absence of excitotoxicity-induced apoptosis in the hippocampus of mice lacking the Jnk3 gene , 1997, Nature.

[44]  D. Nijhawan,et al.  Apoptosis in neural development and disease. , 2000, Annual review of neuroscience.

[45]  J. Lee,et al.  Amyloid-β Induces Smac Release via AP-1/Bim Activation in Cerebral Endothelial Cells , 2002, The Journal of Neuroscience.