The long term goals of this project are to elucidate the molecular mechanisms underlying the abnormal liferation and migration of vascular smooth muscle (VSM) cells that is induced by acute arterial injury and leads to restenosis. The striking morphological similarities between cells in restenosis injury and cancer cells suggest that many of the same mechanisms may be responsible for abnormal growth of both types of cells. We have recently obtained evidence that overexpression of the transcription factor Yin Yang 1(YY1) in G0/G1-arrested coronary artery smooth muscle cells (CASMC) activates DNA synthesis. In cells that overexpress both YY1 and Rb, however, level of DNA synthesis falls back to normal levels. We also found that in growth arrested CASMC a significant portion of YY1 is in a complex with Rb but not in S-phase cultures and that recombinant Rb physically, directly interacts with YY1, destabilizing YY1's interaction with DNA. Moreover we found that Rb inhibits YY1 dependent transcription in vitro. The preliminary data suggest that YY1 is an important downstream target of the Rb pathway in CASMC and that the interaction of Rb and YY1 is likely to be cell cycle specific in vivo. It suggests that, as part of a complex with Rb, YY1 may participate in checkpoint functions that regulate the transition from a contractile to a """"""""proliferative"""""""" phenotype at the level of transcription. We hypothesize that overexpression of YY1 induced by inflammatory cytokines and growth factors and/or disruption of the interaction between Rb and YY1 may alter gene expression and perhaps even cause abnormal CASMC growth after arterial injury.
The Specific Aims of this proposal are: 1.0. To characterize the Rb-YY1 interaction and the effect of the YY1-Rb interaction on YY1's transcription factor function in the context of cellular promoters. 2.0 to study the functional consequences of the deregulated expression of YY1 in human CASMC. At present, understanding of and potential strategies to prevent the abnormal growth and migration of VSM cells are directly extrapolated from knowledge obtained from other cell systems, particularly from cancer cells in which cell cycle checkpoints are abrogated and normal cell cycle progression is lost. Little if any experimental evidence is available elucidating the mechanisms by which VSM cells themselves escape from G0 arrest and begin active proliferation. Therefore, it is essential to define the molecular mechanisms of VSM cell proliferation before one can consider specific strategies to prevent restenosis.
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