Overexpression of activating transcription factor-2 is required for tumor growth and progression in mouse skin tumors.
Activating transcription factor (ATF)-2 is a member of the ATF/cyclic AMP-responsive element binding protein family of transcription factors. It has been shown, in vitro, to possess growth factor-independent proliferation and transformation capacity. The information concerning the involvement of ATF-2 in carcinogenesis is rather limited. In a previous report, we showed a progressive increase in the levels of various activator protein (AP)-1 components, including phosphorylated ATF-2, in a series of mouse skin cell lines that represented developmental stages of the mouse skin carcinogenesis system. In the present study, we examined in detail the role of ATF-2 in the development of mouse skin spindle cells A5 and CarB, which correspond to the late and most aggressive stage of the mouse skin carcinogenesis model. To address this issue, we overexpressed a dominant negative form of ATF-2 in the A5 and CarB cell lines and examined their behavior in vitro and in vivo at the molecular and cellular level. The stable transfectants expressed decreased levels of phosphorylated ATF-2 and c-Jun. Subsequently, we observed that dominant negative ATF-2 affected the composition and reduced the activity of AP-1. The above biochemical changes were followed, both in vitro and in vivo in BALB/c severe combined immunodeficient mice, by suppression of the aggressive characteristics of the A5 and CarB mouse skin spindle cells. We attributed this behavior to the significant down-regulation of cyclin D1, cyclin A, and ATF-3, known AP-1 targets implicated in cell cycle control and promotion. In conclusion, our findings underscore a key regulatory role of ATF-2 in tumor growth and progression of mouse skin tumors.
Papassava
Paraskevi
P
Unit of Biomedical Applications, Institute of Biological Research and Biotechnology, National Hellenic Research Foundation, Athens, Greece.
Gorgoulis
Vassilis G
VG
Papaevangeliou
Dimitra
D
Vlahopoulos
Spiros
S
van Dam
Hans
H
Zoumpourlis
Vassilis
V
D015127:9,10-Dimethyl-1,2-benzanthracene; D051698:Activating Transcription Factor 2; D051700:Activating Transcription Factor 3; D000818:Animals; D002273:Carcinogens; D002277:Carcinoma / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002453:Cell Cycle / Q000235:genetics; D048708:Cell Growth Processes / Q000502:physiology; D017362:Cyclic AMP Response Element-Binding Protein / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D019925:Cyclin A / Q000096:biosynthesis / Q000235:genetics; D019938:Cyclin D1 / Q000096:biosynthesis / Q000235:genetics; D018450:Disease Progression; D016758:Genes, jun; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D010766:Phosphorylation; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis / Q000235:genetics; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D018808:Transcription Factor AP-1 / Q000502:physiology; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014162:Transfection; D015854:Up-Regulation
D051698:Activating Transcription Factor 2; D051700:Activating Transcription Factor 3; C497106:Atf2 protein, mouse; D002273:Carcinogens; D017362:Cyclic AMP Response Element-Binding Protein; D019925:Cyclin A; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D019938:Cyclin D1; D015127:9,10-Dimethyl-1,2-benzanthracene