title: Involvement of the MAP kinase pathways in induction of GADD45 following UV radiation.
abstract: The p53-regulated stress-inducible gene GADD45 has been shown to participate in cellular response to DNA damage, including cell cycle checkpoint, apoptosis, and DNA repair. However, the regulation of GADD45 expression is complex and may involve both p53-dependent and -independent pathways. Recent findings have demonstrated that the p53-independent induction of GADD45 is mainly regulated by the transcription factors Oct-1 and NF-YA, which directly bind to their consensus motifs located at the GADD45 promoter region. Here, we report that mitogen-activated protein (MAP) kinases are involved in the induction of the GADD45 promoter after DNA damage. Inhibition of JNK1 and ERK kinase activities either by expression of the dominant negative mutant JNK1 or by treatment with a selective chemical inhibitor of ERK (PD098059) substantially abrogates the UV induction of the GADD45 promoter. In contrast, a p38 kinase inhibitor (SB203580) has little effect on GADD45 induction by UV. In addition, the GADD45 promoter is strongly activated following expression of JNK1; Raf-1, which is an upstream activator of the ERK pathway; or MEK1, an upstream activator of both the ERK and the JNK pathways. Activation of the GADD45 promoter by MAP kinases does not require normal p53 function. Interestingly, the MAP kinase-regulatory effect appears to be mediated via OCT-1 and CAAT motifs since disruption of these sites abrogates activation of the GADD45 promoter by MAP kinases. Therefore, these findings indicate that the MAP kinase pathways are involved in the regulation of the p53-independent induction of the GADD45 promoter, probably via interaction with transcription factors that directly bind to OCT-1 and CAAT motifs.
authors.affiliation: Department of Radiation Oncology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: T
authors.initials: T
authors.lastname: Tong
authors.forename: W
authors.initials: W
authors.lastname: Fan
authors.forename: H
authors.initials: H
authors.lastname: Zhao
authors.forename: S
authors.initials: S
authors.lastname: Jin
authors.forename: F
authors.initials: F
authors.lastname: Fan
authors.forename: P
authors.initials: P
authors.lastname: Blanck
authors.forename: I
authors.initials: I
authors.lastname: Alomo
authors.forename: B
authors.initials: B
authors.lastname: Rajasekaran
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.forename: N J
authors.initials: NJ
authors.lastname: Holbrook
authors.forename: Q
authors.initials: Q
authors.lastname: Zhan
mesh_terms: D020816:Amino Acid Motifs / Q000502:physiology / Q000528:radiation effects; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage / Q000502:physiology* / Q000528:radiation effects; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology* / Q000528:radiation effects; D051863:Host Cell Factor C1; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D020935:MAP Kinase Signaling System / Q000502:physiology* / Q000528:radiation effects; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism / Q000528:radiation effects; D050811:Octamer Transcription Factor-1; D011401:Promoter Regions, Genetic / Q000502:physiology* / Q000528:radiation effects; D017434:Protein Structure, Tertiary / Q000235:genetics; D011506:Proteins / Q000235:genetics* / Q000378:metabolism / Q000528:radiation effects; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid / Q000502:physiology; D013312:Stress, Physiological / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism* / Q000528:radiation effects; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism / Q000528:radiation effects; D014466:Ultraviolet Rays / Q000009:adverse effects; D000097642:GADD45 Proteins
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D051863:Host Cell Factor C1; D047908:Intracellular Signaling Peptides and Proteins; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D050811:Octamer Transcription Factor-1; D011506:Proteins; D019908:Proto-Oncogene Proteins c-raf; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D000097642:GADD45 Proteins; C497692:HCFC1 protein, human; C494165:POU2F1 protein, human