The tumorigenic diversity of the three PLAG family members is associated with different DNA binding capacities.
Pleomorphic adenoma gene (PLAG) 1, the main translocation target in pleomorphic adenomas of the salivary glands, is a member of a new subfamily of zinc finger proteins comprising the tumor suppressor candidate PLAG-like1 (also called ZAC1 or lost on transformation 1) and PLAGL2. In this report, we show that NIH3T3 cells overexpressing PLAG1 or PLAGL2 display the typical markers of neoplastic transformation: (a) the cells lose cell-cell contact inhibition; (b) show anchorage-independent growth; and (c) are able to induce tumors in nude mice. In contrast, PLAGL1 has been shown to prevent the proliferation of tumor cells by inducing cell cycle arrest and apoptosis. This difference in function is also reflected in their DNA binding, as we show here that the three PLAG proteins, although highly homologous in their DNA-binding domain, bind different DNA sequences in a distinct fashion. Interestingly, the PLAG1- and PLAGL2-induced transformation is accompanied by a drastic up-regulation of insulin-like growth factor-II, which we prove is a target of PLAG1 and PLAGL2. This strongly suggests that the oncogenic capacity of PLAG1 and PLAGL2 is mediated at least partly by activating the insulin-like growth factor-II mitogenic pathway.
Hensen
Karen
K
Laboratory for Molecular Oncology, Center for Human Genetics, University of Leuven (KUL) and Flanders Interuniversity Institute for Biotechnology (VIB), Herestraat 49 B-3000 Leuven, Belgium. karen.hensen@med.kuleuven.ac.be
Van Valckenborgh
Isabelle C C
IC
Kas
Koen
K
Van de Ven
Wim J M
WJ
Voz
Marianne L
ML
D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D004247:DNA / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000502:physiology; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D011519:Proto-Oncogenes; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000502:physiology; D014157:Transcription Factors; D015854:Up-Regulation
D004268:DNA-Binding Proteins; C104382:PLAG1 protein, human; C114598:PLAGL2 protein, human; C491264:Plag1 protein, mouse; C485426:Plagl2 protein, mouse; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D007335:Insulin-Like Growth Factor II; D004247:DNA