Posttranscriptional Regulation Of Genes Cell Growth

Aging

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Abstract

In response to signals of either endogenous or exogenous origin, mammalian cells activate a series of events leading to changes in gene expression. These alterations in gene expression, in turn, directly participate in 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 events, which are less well understood, are also major regulatory mechanisms that profoundly modify gene expression. Posttranscriptional events of gene regulation 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 and growth regulatory genes. We have shown that induction of the cyclin-dependent kinase inhibitor p21 by ultraviolet light and other stresses occurs through stabilization of its mRNA by the RNA-binding protein HuR. Likewise, the expression of cyclins A and B1 throughout the cell division cycle was shown to be regulated through the cyclic association of their respective mRNAs with HuR, which results in transcript stabilization during the S phase. We have recently reported that high levels of HuR expression in young human fibroblasts contributes to the heightened presence of cyclins A and B1, as HuR stabilizes their mRNAs. Conversely, in senescent human fibroblasts, lower HuR levels directly results in reduced stability, and hence expression, of cyclin A and cyclin B1 mRNAs. Other studies have shown that decreased expression of cyclin D1 following treatment with the stress agent prostaglandin A2 was accomplished through cyclin D1 mRNA destabilization and likely involved the RNA-binding protein AUF1. Our long-term efforts are thus 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. We are currently investigating pVHL's global influence on gene expression using SAGE analysis, as well as its influence on TNF-alpha mRNA expression specifically. We anticipate that these studies will help elucidate pVHL's function and its tumor suppressor properties.