Transcription factor AP-2gamma stimulates proliferation and apoptosis and impairs differentiation in a transgenic model.
AP-2 transcription factors play pivotal roles in orchestrating embryonic development by influencing the differentiation, proliferation, and survival of cells. Furthermore, AP-2 transcription factors have been implicated in carcinogenesis, a process where the normal growth and differentiation program of cells is disturbed. To experimentally address the potential involvement of AP-2 in mammary gland tumorigenesis, we generated mice overexpressing AP-2gamma by transgenesis using the mouse mammary tumor virus-long terminal repeat as the transgene-driving promoter unit. In the mammary gland, transgene expression elicited a hyperproliferation that, however, was counterbalanced by the enhanced apoptosis of epithelial cells leading to a hypoplasia of the alveolar epithelium during late pregnancy. In addition, secretory differentiation was impaired, resulting in a lactation failure. In male transgenic mice, the seminal vesicles were sites of strong transgene expression. There the effects of AP-2gamma on proliferation and apoptosis were even more pronounced, and differentiation was impaired, too, as revealed by the absence of androgen receptor immunoreactivity. In both tissues, the mammary gland and the seminal vesicles, enhanced steady-state transcript levels of the AP-2 target gene IGFBP-5 were detected, revealing a potential mechanism of AP-2-induced apoptosis. Our results suggest a role of AP-2 transcription factors in the maintenance of a proliferative and undifferentiated state of cells, characteristics not only important during embryonic development but also in tumorigenesis.
Institute for Pathology, Department of Developmental Pathology, University of Bonn Medical School, Bonn, Germany.
Richard
R
Jäger
Uwe
U
Werling
Stephan
S
Rimpf
Andrea
A
Jacob
Hubert
H
Schorle
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D015152:Blotting, Northern; D002454:Cell Differentiation / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D015972:Gene Expression Regulation, Neoplastic; D008297:Male; D008321:Mammary Glands, Animal / Q000378:metabolism* / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism*; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D011247:Pregnancy; D050656:Transcription Factor AP-2; D014157:Transcription Factors / Q000378:metabolism*; D015854:Up-Regulation
D004268:DNA-Binding Proteins; C583890:Tfap2c protein, mouse; D050656:Transcription Factor AP-2; D014157:Transcription Factors