Voz Marianne L, Mathys Janick, Hensen Karen, Pendeville Hélène, Van Valckenborgh Isabelle, Van Huffel Christophe, Chavez Marcela, Van Damme Boudewijn, De Moor Bart, Moreau Yves, Van de Ven Wim J M
Laboratory for Molecular Oncology, Center for Human Genetics, KU Leuven & Flanders Interuniversity Institute for Biotechnology, Herestraat 49, Leuven B-3000, Belgium.
Oncogene. 2004 Jan 8;23(1):179-91. doi: 10.1038/sj.onc.1207013.
PLAG1 is a proto-oncogene whose ectopic expression can trigger the development of pleomorphic adenomas of the salivary glands and of lipoblastomas. As PLAG1 is a transcription factor, able to activate transcription through the binding to the consensus sequence GRGGC(N)(6-8)GGG, its ectopic expression presumably results in the deregulation of target genes, leading to uncontrolled cell proliferation. The identification of PLAG1 target genes is therefore a crucial step in understanding the molecular mechanisms involved in PLAG1-induced tumorigenesis. To this end, we analysed the changes in gene expression caused by the conditional induction of PLAG1 expression in fetal kidney 293 cell lines. Using oligonucleotide microarray analyses of about 12 000 genes, we consistently identified 47 genes induced and 12 genes repressed by PLAG1. One of the largest classes identified as upregulated PLAG1 targets consists of growth factors such as the insulin-like growth factor II and the cytokine-like factor 1. The in silico search for PLAG1 consensus sequences in the promoter of the upregulated genes reveals that a large proportion of them harbor several copies of the PLAG1-binding motif, suggesting that they represent direct PLAG1 targets. Our approach was complemented by the comparison of the expression profiles of pleomorphic adenomas induced by PLAG1 versus normal salivary glands. Concordance between these two sets of experiments pinpointed 12 genes that were significantly and consistently upregulated in pleomorphic adenomas and in PLAG1-expressing cells, identifying them as putative PLAG1 targets in these tumors.
PLAG1是一种原癌基因，其异位表达可引发涎腺多形性腺瘤和成脂细胞瘤的发生。由于PLAG1是一种转录因子，能够通过与共有序列GRGGC(N)(6 - 8)GGG结合来激活转录，其异位表达可能导致靶基因失调，进而导致细胞增殖失控。因此，鉴定PLAG1靶基因是理解PLAG1诱导肿瘤发生所涉及分子机制的关键步骤。为此，我们分析了胎儿肾293细胞系中PLAG1表达的条件性诱导所引起的基因表达变化。通过对约12000个基因进行寡核苷酸微阵列分析，我们一致鉴定出47个被PLAG1诱导的基因和12个被PLAG1抑制的基因。被鉴定为上调的PLAG1靶基因中最大的一类包括生长因子，如胰岛素样生长因子II和细胞因子样因子1。对上调基因启动子中PLAG1共有序列的计算机搜索显示，其中很大一部分含有多个PLAG1结合基序拷贝，这表明它们代表直接的PLAG1靶基因。通过比较PLAG1诱导的多形性腺瘤与正常涎腺的表达谱，对我们的方法进行了补充。这两组实验之间的一致性确定了12个在多形性腺瘤和表达PLAG1的细胞中显著且一致上调的基因，将它们鉴定为这些肿瘤中假定的PLAG1靶基因。
