Activation of Raf-1/MEK-1/2/p42/44MAPK cascade alone is sufficient to uncouple LDL receptor expression from cell growth

Our previous observation that induction of low density lipoprotein (LDL) receptor expression by a variety of extracellular signals is blocked by PD98059, a specific mitogen-activated protein kinase kinase inhibitor, led to the suggestion that the growth-responsive p42/44^sup MAPK^ cascade plays a critical role in regulating LDL receptor transcription. To analyze the specific contribution of the p42/44^sup MAPK^ cascade in regulating cell growth and LDL receptor induction, we established a HepG2-derived cell line that stably expresses an inducible form of oncogenic human Raf-1 kinase. Using this system, we provide direct evidence that specific activation of this cascade alone is not only required but is sufficient to fully induce LDL receptor expression. Interestingly, degree of p42/44^sup MAPK^ activation determines the extent of LDL receptor induction. However, activation of p42/44^sup MAPK^ in the above cells led to the inhibition of DNA synthesis, caused growth arrest, decrease in cyclin A and upregulation of p21^sup Cip^ expression in a time-dependent manner. These results suggest that each of these two processes can be regulated independently of each other in response to p42/44^sup MAPK^ activation. Thus, extent of p42/44^sup MAPK^ activation may be important in transducing divergent cellular responses in human cells with implications for altered signaling resulting in hypercholesterolemia.[PUBLICATION ABSTRACT]