CHOP, a basic leucine zipper transcriptional factor, contributes to the antiproliferative effect of IL-1 on A375 human melanoma cells through augmenting transcription of IL-6.
Interleukin-1 (IL-1) inhibits the proliferation of A375 human melanoma cells. We have demonstrated previously that p38 mitrogen-activated protein kinase (MAPK) mediated the antiproliferative effect of IL-1 partially through the downregulation of activity and protein level of ornithine decarboxylase (ODC). In this study, we investigated the role of CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP), one of the p38 MAPK target transcriptional factors. The mRNA level of CHOP was not affected by IL-1 treatment in A375-6 cells. Unexpectedly, CHOP was constitutively phosphorylated, and IL-1 or p38 MAPK inhibitor, SB203580, did not affect the phosphorylation level. However, A375-6 cells exhibited enhanced sensitivity to IL-1 by transfecting CHOP expression plasmid and reduced sensitivity to IL-1 by antisense CHOP mRNA expression plasmid. Furthermore, CHOP appeared to regulate positively IL-6 production at the transcriptional level. The experiments using CHOP muteins revealed that dimerization ability - but not p38 MAPK-dependent phosphorylation or DNA binding activity - is important for the IL-6 inducing activity of CHOP. These results indicate that CHOP contributes to the IL-1 growth-inhibitory signal through augmenting IL-6 production.
Hattori
T
T
Department of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Nagoya City University, Mizuho, Nagoya 467-8603, Japan.
Itoh
S
S
Hayashi
H
H
Chiba
T
T
Takii
T
T
Yoshizaki
K
K
Onozaki
K
K
D000276:Adjuvants, Immunologic / Q000037:antagonists & inhibitors / Q000502:physiology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D022762:CCAAT-Enhancer-Binding Proteins / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D006131:Growth Inhibitors / Q000037:antagonists & inhibitors / Q000502:physiology*; D006801:Humans; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D016350:Leucine Zippers / Q000235:genetics / Q000276:immunology*; D008545:Melanoma / Q000276:immunology / Q000473:pathology*; D016376:Oligonucleotides, Antisense / Q000235:genetics; D010766:Phosphorylation; D011700:Putrescine / Q000494:pharmacology; D051742:Transcription Factor CHOP; D014157:Transcription Factors / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
D000276:Adjuvants, Immunologic; D000970:Antineoplastic Agents; D022762:CCAAT-Enhancer-Binding Proteins; C497249:DDIT3 protein, human; D006131:Growth Inhibitors; D007375:Interleukin-1; D015850:Interleukin-6; D016376:Oligonucleotides, Antisense; D014157:Transcription Factors; D051742:Transcription Factor CHOP; D011700:Putrescine