Stressful signals are transduced through various signalling pathways, ultimately resulting in the altered expression of critical genes, including cycle regulatory genes. While transcriptional events regulating gene expression has been thoroughly studied, it is becoming increasingly clear that post-transcriptional regulatory mechanisms also play a critical role in gene regulation by stress. These post- transcriptional processes, still poorly understood, include mRNA processing, transport, stability and translation, as well as post- translational events such 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. Expression of various cyclins throughout the cell division cycle and in response to stress agents is likewise regulated through alterations in the half-life of their respective mRNA. Much effort is focused on searching for RNA regions and proteins involved in regulating the stability of p21, cyclins and other cell cycle regulatory genes. This analysis involves both in vitro and in vivo determinations of RNA binding and RNA degradation, the identification of the RNA-binding proteins involved and the signalling pathways that modulate their activity. We are also studying the function of the tumor suppressor gene von Hippel-Lindau (VHL) as it is believed to modulate gene expression at the levels of transcription elongation, mRNA stability and protein degradation. We are examining the function of the VHL tumor suppressor gene within the stress response. - cyclins, p21, mRNA stability, mRNA-binding proteins, apoptosis, growth arrest, VHL
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