ISOLATION OF 10 DIFFERENTIALLY EXPRESSED CDNAS IN P53-INDUCED APOPTOSIS - ACTIVATION OF THE VERTEBRATE HOMOLOG OF THE DROSOPHILA-7 IN-ABSENTIA GENE

We report the isolation of 10 differentially expressed cDNAs in the pr ocess of apoptosis induced by the p53 tumor suppressor. As a global an alytical method, we performed a differential display of mRNA between m ouse M1 myeloid leukemia cells and derived clone LTR6 cells, which con tain a stably transfected temperature-sensitive mutant of p53. At 32 d egrees C wild-type p53 function is activated in LTR6 cells, resulting in programmed cell death. Eight genes are activated (TSAP; tumor suppr essor activated pathway), and two are inhibited (TSIP, tumor suppresso r inhibited pathway) in their expression. None of the 10 sequences has hitherto been recognized as part of the p53 signaling pathway. Three TSAPs are homologous to known genes. TSAP1 corresponds to phospholipas e C beta 4. TSAP2 has a conserved domain homologous to a multiple endo crine neoplasia I (ZFM1) candidate gene. TSAP3 is the mouse homologue of the Drosophila seven in absentia gene. These data provide novel mol ecules involved in the pathway of wild-type p53 activation. They estab lish a functional link between a homologue of a conserved developmenta l Drosophila gene and signal transduction in tumor suppression leading to programmed cell death.