Molecular mechanisms of monocyte differentiation: impact on vascular smooth muscle cell functional behavior
Zusammenfassung der Projektergebnisse
Through the effort of our current work the new insights have been obtained into the molecular basis of monocyte differentiation, one of the key events contributing to pathogenesis of cardiovascular and inflammatory diseases. The most important finding of our studies covered by this research proposal is the for the first time revealed association of the shuttle protein nucleolin with the transcription factor Stat1, which is required to mediate cell differentiation program specifically in cells of monocytic origin. We have further identified the NLS domain of nucleolin as a sequence mediating Statl nuclear transport. The revealed requirement of nucleolin for Stat1 nuclear translocation was surprising, since the molecular mechanisms of Stat1 nuclear transport have been elucidated. Our findings add to these schemes one novel mechanism for Stat1 nuclear transport, which involves NLS sequence of nucleolin. This mechanism might represent a specialized pathway for the timecoordinated control of Stat1-regulated gene expression in myelopoiesis. Our data support the possibility that the nucleolin-Stat1 complex may regulate both gene transcription and nuclear organization. We provide evidence that formation and activation of nucleolin-Statl complex is mediated via the M-CSFR and that Tyr 708 of M-CSFR serves for docking of this complex through the Stat1 binding. In the second part of our work, we analyzed specific gene expression profiles in VSMC upon interaction with differentiating monocytes. These data point to the phenotypic changes of VSMC mediated by differentiating monocytes. We have found a number of candidate genes to explain the underlying molecular mechanisms. It would be interesting to check in the future studies whether the revealed genes might serve as therapeutic targets upon pathophysiological vascular remodeling in vivo. Finally, we addressed a probable role of uPAR for MMs functional behavior and provide evidence for the uPA-induced accumulation of unesterified cholesterol in macrophages that is a novel pathway by which the uPA/uPAR system may contribute to accelerated atherosclerosis development and vascular remodeling.
