INHIBITION OF PRESENILIN-1 EXPRESSION IS PROMOTED BY P53 AND P21(WAF-1) AND RESULTS IN APOPTOSIS AND TUMOR SUPPRESSION

Previously, we cloned a cDNA fragment, TSIP 2 (tumor suppressor inhibi ted pathway clone 2), that detects by northern blot analysis of M1-LTR 6 cells a 3-kb mRNA downregulated during p53-induced apoptosis(1). Clo ning the full-length TSIP 2 cDNA showed that it corresponds to the pre senilin 1 (PS1) gene, in which mutations have been reported in early-o nset familial Alzheimer's disease(2-4). Here we demonstrate that PS1 i s downregulated in a series of model systems for p53-dependent and p53 -independent apoptosis and tumor suppression. To investigate the biolo gical relevance of this downregulation, we stably transfected U937 cel ls with antisense PS1 cDNA. The downregulation of PS1 in these U937 tr ansfectants results in reduced growth with an increased fraction of th e cells in apoptosis. When injected into mice homozygous for severe co mbined immunodeficiency disease (scid/scid mice), these cells show a s uppression of their malignant phenotype. Our results indicate that PS1 , initially identified in a neurodegenerative disease, may also be inv olved in the regulation of cancer-related pathways.