The LDL receptor is a ubiquitous cell surface receptor which functions to internalize LDL particles. The cholesterol thus internalized, in non- hepatic and non-steroidogenic cells, is primarily utilized as a structural component of cellular membranes, especially the plasma membrane. In addition, this free cholesterol exerts a number of regulatory effects in the cell. Chief among these are suppression of LDL receptor and HMG CoA reductase activities and stimulation of ACAT activity. Regulation of LDL receptor expression by sterols has been intensively studied and reported in great detail. In addition to sterols, peptide hormones and mitogens have been shown to be important in the regulation of LDL receptor expression. Interestingly, the response of the LDL receptor gene to mitogens is extremely rapid (enhanced gene transcription can be observed within 60 minutes) suggesting that this gene be considered among the """"""""early response genes"""""""" to growth activators. In support of this concept, increased LDL receptor gene expression, after growth stimulation, is independent of ongoing protein synthesis. In fact, expression of the LDL receptor gene is superinduced by translational inhibitors, such as cycloheximide. In this application, we propose a set of studies to carefully characterize the relationship between cell growth and LDL receptor expression. Specifically we plan: a) to characterize the genetic mechanism for the PDGF response of the LDL receptor gene; b) to explore the regulatory mechanism restraining LDL receptor gene expression which is dependent on ongoing protein synthesis; c) to determine how the PDGF signal is transduced to the LDL receptor gene; and d) to study potential sites for post-transcriptional regulation of the LDL receptor pathway. These studies will provide insight into the processes which regulate LDL receptor expression as a function of cell growth state. Such insight could directly bear on the atherogenic process in an much as the vessel wall lesion is characterized by proliferating smooth muscle cells and an excess LDL-derived cholesterol.
| Tsao, R; Jones, S A; Giddens, D P et al. (1995) An automated three-dimensional particle tracking technique for the study of modeled arterial flow fields. J Biomech Eng 117:211-8 |
