CHRONIC TREATMENT OF HUMAN FIBROBLASTS CULTURES WITH DIACYLGLYCEROL INDUCES DOWN-REGULATION OF P53 FUNCTIONAL-ACTIVITY

We found that many spontaneous human tumors exhibit increased levels o f endocellular diacylglycerol (DAG;) which is synthesized de novo as a byproduct of glycolysis. It has been shown that DAG mimics phorbol es ters as a full tumor promoter in mouse skin carcinogenesis, A short te rm DAG treatment activates protein kinase C (PKC), while a long term ' 'chronic'' treatment down-regulates PKC, We show here that chronic tre atment of human fibroblast with DAG induces p53 downregulation and inh ibition of p53 functional activity, and protection from W-induced apop tosis, As PKC phosphorylation is necessary for p53 functional activity , we propose that chronic DAG treatment mimics the same event occurrin g in vivo for the effect of glycolysis in tumor progression. (C) 1998 Academic Press.