RECEPTOR-C-K-DEPENDENT REGULATION OF GENES INVOLVED IN THE CELL-CYCLE

The present study was addressed to understand the interrelationship be tween Receptor-C-k activation, mevalonate pathway and primary response genes such as c-fos, c-myc and cyclin 'D' involved in the cell cycle. The results reported here unambiguously revealed that the phosphatidi c acid (generated through the activation of Receptor-C-k by cholestero l) regulates mevalonate pathway, DNA synthesis as well as expression o f genes coding for c-fos, c-myc and cyclin 'D'. By using the specific blockers of ras farnesylation as well as phospholipase D, it became ap parent that phosphatidic acid regulates two processes: (a) activation of Gapras pathway leading to the expression of c-fos, c-myc proto-onco genes probably through the activation of NF1 transcription factor; (b) cleavage of 125 kDa endoplasmic reticulum protein leading to the gene ration of 47 kDa protein factor which not only regulates mevalonate pa thway but also has an ability to heterodimerize with Receptor-C-k prot ein and this heterodimer may be responsible for the regulation of cycl in 'D' expression probably by binding to the SRE like sequence present in the promoter region of this gene. On the basis of these findings, we propose a pathway through which Receptor-C-k upon endocytosis regul ate these primary response genes (c-fos, c-myc, cyclin 'D') involved i n the cell cycle.