The p53-transcriptional target, BTG2 TIS21/PC3 , was previously identified as an antiproliferative gene. However, the precise biological functions of the protein product remain to be elucidated. BTG2 TIS21/PC3 expression is induced in vivo during neurogenesis, and the gene is transiently expressed in vitro in rat pheochromocytoma PC12 cells after induction of neuronal differentiation by addition of nerve growth factor (NGF). These observations suggest that BTG2 TIS21/PC3 is functionally significant during the neuronal differentiation process. To test this hypothesis, a vector that expressed BTG2 TIS21/PC3 under the control of an inducible promoter was introduced into PC12 cells. Growth arrest and differentiation in response to NGF were greatly enhanced by BTG2 TIS21/PC3 overexpression. Furthermore, an antisense oligonucleotide complementary to BTG2 TIS21/PC3 mRNA, which was able to inhibit endogenous BTG2 TIS21/PC3 expression, triggered programmed cell death in differentiated PC12 cells. These observations confirm that BTG2 TIS21/PC3 expression promotes neuronal differentiation and that it is required for survival of terminally differentiated cells.

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Exposure of mammalian cells to genotoxic agents evokes a complex cellular response. An ordered series of molecular events is necessary to sense DNA damage, transduce the signal, and ultimately delay the cell cycle or trigger apoptosis. Recently, we have shown that BTG2/TIS21 gene expression was induced in response to DNA damage through a p53-dependent pathway. This gene belongs to a newly identified family of structurally related genes whose other known human members are BTG1, BTG3, and Tob. To define the respective involvement of these four related genes in the cellular response to DNA damage, we studied their expression in human cell lines after a variety of genotoxic treatments. Our results demonstrated that were BTG1, BTG2/TIS21, and Tob genes the DNA damage--inducible genes. However, BTG2/TIS21 appeared to be the only p53-transcriptional target gene. We speculate that BTG proteins may play a coordinate role in a general transduction pathway that is induced in response to DNA damage. It has been previously described that recombinant BTG1 and BTG2/TIS21 can physically interact with PRMT1, an arginine methyl transferase, suggesting that BTG1 and BTG2/TIS21 induction may lead to posttranslational modifications of cellular proteins. In support of this hypothesis, we showed that the endogenous induction of BTG1 and BTG2 after genotoxic treatment was correlated with a modulation of protein methylation.