High levels of phosphorylated c-Jun, Fra-1, Fra-2 and ATF-2 proteins correlate with malignant phenotypes in the multistage mouse skin carcinogenesis model.
Analysis of the functions of AP-1 transcription factor in cellular systems has shown its key role as a mediator of oncogenic signals. The employment of suitable animal model systems greatly facilitates the study of changes in the composition and activity of the AP-1 complex. Here, we have analysed the quantitative and qualitative changes of AP-1 at different stages of carcinogenesis in mouse skin cell lines, derived from tumours induced by chemical mutagens. The findings of this study suggest that elevated AP-1 DNA binding and transactivation activity characterize the carcinoma cell lines, most notably the highly malignant spindle carcinomas. In addition, increased amounts and post-translational modifications of c-Jun, Fra-1, Fra-2 and ATF-2 proteins account for a high percentage of the increased AP-1 activity. Remarkably, high levels of phosphorylated ATF-2 protein were detected in malignant cell lines, indicating a novel role of ATF-2 in tumour progression. c-Jun and ATF-2 proteins are phosphorylated by highly active JNK kinases present in tumour cells. Finally, our results indicate distinct functions for different AP-1 components in the promotion and progression of mouse skin tumours. Oncogene (2000) 19, 4011 - 4021.
Zoumpourlis
V
V
Institute of Biological Research and Biotechnology, National Hellenic Research Foundation, 48 Vas. Constantinou Ave., 116 35 Athens, Greece.
Papassava
P
P
Linardopoulos
S
S
Gillespie
D
D
Balmain
A
A
Pintzas
A
A
D051698:Activating Transcription Factor 2; D000818:Animals; D002277:Carcinoma / Q000139:chemically induced / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology; D017362:Cyclic AMP Response Element-Binding Protein / Q000032:analysis* / Q000737:chemistry; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000032:analysis* / Q000737:chemistry; D051921:Fos-Related Antigen-2; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras; D048031:JNK Mitogen-Activated Protein Kinases; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009363:Neoplasm Proteins / Q000032:analysis / Q000737:chemistry / Q000502:physiology*; D010212:Papilloma / Q000139:chemically induced / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D010766:Phosphorylation; D011230:Precancerous Conditions / Q000139:chemically induced / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational; D016760:Proto-Oncogene Proteins c-fos / Q000032:analysis* / Q000737:chemistry; D016755:Proto-Oncogene Proteins c-jun / Q000032:analysis* / Q000737:chemistry; D016283:Proto-Oncogene Proteins p21(ras) / Q000096:biosynthesis; D012878:Skin Neoplasms / Q000139:chemically induced / Q000737:chemistry* / Q000378:metabolism / Q000473:pathology; D018808:Transcription Factor AP-1 / Q000502:physiology*; D014157:Transcription Factors / Q000032:analysis* / Q000737:chemistry; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D000099169:Fos-Related Antigen 1
D051698:Activating Transcription Factor 2; D017362:Cyclic AMP Response Element-Binding Protein; D004247:DNA; D004268:DNA-Binding Proteins; D051921:Fos-Related Antigen-2; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D009363:Neoplasm Proteins; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D016283:Proto-Oncogene Proteins p21(ras); D018808:Transcription Factor AP-1; D014157:Transcription Factors; D000099169:Fos-Related Antigen 1; C497106:Atf2 protein, mouse; C497873:Fosl2 protein, mouse