In response to signals of either endogenous and exogenous origin, mammalian cells activate a series of events leading to changes in gene expression and to the implementation of a global cellular response. While the transcriptional events regulating such changes in gene expression have been thoroughly studied, it is becoming increasingly clear that posttranscriptional regulatory mechanisms, which are less well understood, are also critically involved. These posttranscriptional events include mRNA processing, transport, stability and translation, as well as protein processing, phosphorylation and degradation. With respect to mRNA stability, we are investigating the mechanisms regulating the expression of various cell cycle regulatory molecules. Expression of p21, an inhibitor of cyclin-dependent kinases, is induced by various stresses (such as ultraviolet light) through stabilization of its mRNA by the RNA-binding protein HuR. Likewise, the expression of cyclins A and B1 throughout the cell division cycle is regulated through the cyclic association of their respective mRNAs with HuR, which results in transcript stabilization. Conversely, the decreased expression of cyclin D1 following treatment with the stress agent prostaglandin A2 is accomplished through cyclin D1 mRNA destabilization and is likely to involve the RNA-binding protein AUF1. Our efforts are focused on searching for RNA-binding proteins, target mRNA regions and signaling pathways involved in regulating the stability of mRNAs encoding growth control and cell cycle regulatory genes.The product of the tumor suppressor gene von Hippel-Lindau (pVHL) is believed to modulate gene expression at the levels of transcription elongation, mRNA stability and protein degradation. However, the mechanisms whereby pVHL exerts its tumor suppressive function remain to be determined. We are currently investigating pVHL's influence on gene expression by using SAGE analysis, and are seeking to identify proteins that interact with pVHL. We anticipate that these studies will help elucidate pVHL's function and its tumor suppressor properties.
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