Transcriptional Repressor Activating Transcription Factor 3 Protects Human Umbilical Vein Endothelial Cells from Tumor Necrosis Factor-α-induced Apoptosis through Down-regulation ofp53 Transcription*

Activating transcription factor 3 (ATF3) is a transcriptional repressor that is rapidly induced in cells exposed to a wide range of stress stimuli. To clarify the role of ATF3 in determining cell fate, we overexpressed it in human umbilical vein endothelial cells (HUVECs) by adenovirus-mediated gene transfer. ATF3 protected these cells from tumor necrosis factor (TNF)-α-induced apoptosis, as measured by flow cytometric analysis, trypan blue exclusion assay, and cleavage of procaspase 3 and poly(ADP-ribose) polymerase. Northern blot and nuclear run on assay showed that the transcription of tumor suppressor gene p53 was down-regulated in the ATF3-overexpressing cells. In the transient expression assay, ATF3 suppressed the p53 gene promoter activity through its specific binding to an atypical AP-1 element, PF-1 site, in the p53 gene promoter. Furthermore, the cell-protecting effect of ATF3 was remarkably reduced inp53-deficient cells. These results demonstrate that overexpression of ATF3 suppresses TNF-α-induced cell death of HUVECs, at least in part, through down-regulating the transcription ofp53 gene. ATF3 may function as a cell survival factor of endothelial cells during vascular inflammation and atherogenesis.

[1]  M. Adachi,et al.  Expression of transcriptional repressor ATF3/LRF1 in human atherosclerosis: colocalization and possible involvement in cell death of vascular endothelial cells. , 2002, Atherosclerosis.

[2]  D. Boyd,et al.  ATF3 Represses 72-kDa Type IV Collagenase (MMP-2) Expression by Antagonizing p53-dependent trans-Activation of the Collagenase Promoter* , 2002, The Journal of Biological Chemistry.

[3]  Tsonwin Hai,et al.  The Roles of ATF3 in Glucose Homeostasis , 2001, The Journal of Biological Chemistry.

[4]  K. L. Gardner,et al.  Transgenic mice with cardiac-specific expression of activating transcription factor 3, a stress-inducible gene, have conduction abnormalities and contractile dysfunction. , 2001, The American journal of pathology.

[5]  N. Holbrook,et al.  Protective Role for c-Jun in the Cellular Response to DNA Damage* , 2001, The Journal of Biological Chemistry.

[6]  M. Karin,et al.  AP-1 Repressor Protein JDP-2: Inhibition of UV-Mediated Apoptosis through p53 Down-Regulation , 2001, Molecular and Cellular Biology.

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

[8]  R. Davis,et al.  Signal Transduction by the JNK Group of MAP Kinases , 2000, Cell.

[9]  T. Aso,et al.  Homocysteine-responsive ATF3 gene expression in human vascular endothelial cells: activation of c-Jun NH(2)-terminal kinase and promoter response element. , 2000, Blood.

[10]  B. Metzler,et al.  Increased expression and activation of stress-activated protein kinases/c-Jun NH(2)-terminal protein kinases in atherosclerotic lesions coincide with p53. , 2000, The American journal of pathology.

[11]  A. Noda,et al.  A unique, short sequence determines p53 gene basal and UV-inducible expression in normal human cells , 2000, Oncogene.

[12]  Dirk Bohmann,et al.  Diverse functions of JNK signaling and c-Jun in stress response and apoptosis , 1999, Oncogene.

[13]  M. Bittner,et al.  Fluorescent cDNA microarray hybridization reveals complexity and heterogeneity of cellular genotoxic stress responses , 1999, Oncogene.

[14]  H. Esche,et al.  Expression of human p53 requires synergistic activation of transcription from the p53 promoter by AP-1, NF-κB and Myc/Max , 1999, Oncogene.

[15]  T. W. Fawcett,et al.  Complexes containing activating transcription factor (ATF)/cAMP-responsive-element-binding protein (CREB) interact with the CCAAT/enhancer-binding protein (C/EBP)-ATF composite site to regulate Gadd153 expression during the stress response. , 1999, The Biochemical journal.

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

[17]  S. Berger,et al.  p53 Sites Acetylated In Vitro by PCAF and p300 Are Acetylated In Vivo in Response to DNA Damage , 1999, Molecular and Cellular Biology.

[18]  R. Yu,et al.  Differential regulation of mitogen-activated protein kinases by microtubule-binding agents in human breast cancer cells , 1999, Oncogene.

[19]  Tsonwin Hai,et al.  ATF3 and stress responses. , 1999, Gene expression.

[20]  A. Lau,et al.  Tumor Suppressor p53 as a Component of the Tumor Necrosis Factor-induced, Protein Kinase PKR-mediated Apoptotic Pathway in Human Promonocytic U937 Cells* , 1998, The Journal of Biological Chemistry.

[21]  K. Sakaguchi,et al.  DNA damage activates p53 through a phosphorylation-acetylation cascade. , 1998, Genes & development.

[22]  N. Donato,et al.  Tumor Necrosis Factor-induced Apoptosis Stimulates p53 Accumulation and p21WAF1 Proteolysis in ME-180 Cells* , 1998, The Journal of Biological Chemistry.

[23]  W. Loging,et al.  Transcriptional regulation of the p53 tumor suppressor gene. , 1998, Seminars in cancer biology.

[24]  G. Evan,et al.  Induction of TNF‐sensitive cellular phenotype by c‐Myc involves p53 and impaired NF‐κB activation , 1997, The EMBO journal.

[25]  C. Moyret-Lalle,et al.  Resistance of MCF7 human breast carcinoma cells to TNF-induced cell death is associated with loss of p53 function , 1997, Oncogene.

[26]  Yoichi Taya,et al.  DNA Damage-Induced Phosphorylation of p53 Alleviates Inhibition by MDM2 , 1997, Cell.

[27]  Wei Gu,et al.  Activation of p53 Sequence-Specific DNA Binding by Acetylation of the p53 C-Terminal Domain , 1997, Cell.

[28]  Tsonwin Hai,et al.  Tissue-specific Pattern of Stress Kinase Activation in Ischemic/Reperfused Heart and Kidney* , 1997, The Journal of Biological Chemistry.

[29]  S. Elledge,et al.  Isolation of an AP-1 repressor by a novel method for detecting protein-protein interactions , 1997, Molecular and cellular biology.

[30]  Stephen N. Jones,et al.  Regulation of p53 stability by Mdm2 , 1997, Nature.

[31]  M. Oren,et al.  Mdm2 promotes the rapid degradation of p53 , 1997, Nature.

[32]  S. Nagata,et al.  Apoptosis by Death Factor , 1997, Cell.

[33]  A. Karsan,et al.  Endothelial Cell Death Induced by Tumor Necrosis Factor-α Is Inhibited by the Bcl-2 Family Member, A1* , 1996, The Journal of Biological Chemistry.

[34]  Michael Karin,et al.  Dissection of TNF Receptor 1 Effector Functions: JNK Activation Is Not Linked to Apoptosis While NF-κB Activation Prevents Cell Death , 1996, Cell.

[35]  M. Ewen,et al.  p53 and translational control. , 1996, Biochimica et biophysica acta.

[36]  C. Wolfgang,et al.  Analysis of ATF3, a transcription factor induced by physiological stresses and modulated by gadd153/Chop10 , 1996, Molecular and cellular biology.

[37]  Y. Kanegae,et al.  Efficient generation of recombinant adenoviruses using adenovirus DNA-terminal protein complex and a cosmid bearing the full-length virus genome. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[38]  A. Karsan,et al.  Modulation of endothelial cell apoptosis: mechanisms and pathophysiological roles. , 1996, Journal of atherosclerosis and thrombosis.

[39]  W. Fiers,et al.  Two tumour necrosis factor receptors: structure and function. , 1995, Trends in cell biology.

[40]  M. Peterson,et al.  Induction of Endothelial Cell Apoptosis by TNFα: Modulation by Inhibitors of Protein Synthesis , 1994 .

[41]  Tsonwin Hai,et al.  ATF3 and ATF3 delta Zip. Transcriptional repression versus activation by alternatively spliced isoforms. , 1994, The Journal of biological chemistry.

[42]  G. Pfeifer,et al.  In vivo protein-DNA interactions at the c-jun promoter: preformed complexes mediate the UV response , 1993, Molecular and cellular biology.

[43]  K. Tracey,et al.  Tumor necrosis factor, other cytokines and disease. , 1993, Annual review of cell biology.

[44]  R Taub,et al.  Interactions among LRF-1, JunB, c-Jun, and c-Fos define a regulatory program in the G1 phase of liver regeneration , 1992, Molecular and cellular biology.

[45]  J. Hsu,et al.  Identification of LRF-1, a leucine-zipper protein that is rapidly and highly induced in regenerating liver. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[46]  W. Fiers,et al.  Tumor necrosis factor induces apoptosis (programmed cell death) in normal endothelial cells in vitro. , 1991, The American journal of pathology.

[47]  J. Piette,et al.  Protein-binding elements in the promoter region of the mouse p53 gene. , 1990, Oncogene.

[48]  O. H. Lowry,et al.  Protein measurement with the Folin phenol reagent. , 1951, The Journal of biological chemistry.