Salivary gland tumors in transgenic mice with PLAG1 proto-oncogene overexpression

Objectives:Activation and overexpression of PLAG1 gene due to t(3;8)(p21;q12) translocation are associated with the development of human pleomorphic adenomas of the salivary glands. To elucidate the role of PLAG1 gene in tumorigenesis in vivo, ubiquitously-expressed or tissue-specific expressed PLAG1 transgenic mice were generated. Methods:Human PLAG1 cDNA was cloned from salivary gland tumor or placenta tissues by RT-PCR. Ubiquitous expression vector pCMV-EGFP/PLAG1 driven by CMV promoter and tissue-specific expression vector pMMTV-PLAG1 driven by MMTV LTR were constructed. NIH3T3 cells transiently transfected with pCMV-EGFP/PLAG1 show high expression of PLAG1 in nucleus. Transgenes were microinjected into pronucleus of zygotes to generate transgenic mice. Results:Human PLAG1 cDNA cloned from several salivary gland tumor and normal placenta tissues consistently show a variation of a single nucleotide at same position compared with the human PLAG1 cDNA sequence in Genbank (Accession No. U65002), which leads to T458P at aminophenol level. It might be a Single Nucleotide Polymorphism (SNP) locus . Fusion EGFP/PLAG1 protein is localized in nucleus of NIH3T3 cells transiently transfected with pCMV-EGFP/PLAG1. We got several pCMV-EGFP/PLAG1 and pMMTV-PLAG1 transgenic mouse lines, respectively. As we expected, pMMTV-PLAG1 transgenic mice spontaneously develop salivary gland tumors in three independent lines. Among them, line 42 shows tumorigenic phenotype in almost 100% of transgenic mice within three months after birth. Conclusions:Overexpression of PLAG1 gene plays a crucial role in tumorigenesis of salivary gland tumors. Key words pleomorphic adenoma gene 1(PLAG1); transgenic mice; salivary gland tumors