Receptor-Ck-dependent regulation of genes involved in the cell cycle.

The present study was addressed to understand the interrelationship between Receptor-Ck 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 phosphatidic acid (generated through the activation of Receptor-Ck by cholesterol) regulates mevalonate pathway, DNA synthesis as well as expression of 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 apparent that phosphatidic acid regulates two processes: (a) activation of Gap-ras pathway leading to the expression of c-fos, c-myc proto-oncogenes probably through the activation of NF1 transcription factor; (b) cleavage of 125 kDa endoplasmic reticulum protein leading to the generation of 47 kDa protein factor which not only regulates mevalonate pathway but also has an ability to heterodimerize with Receptor-Ck protein and this heterodimer may be responsible for the regulation of cyclin '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-Ck upon endocytosis regulate these primary response genes (c-fos, c-myc, cyclin 'D') involved in the cell cycle.