Posttranscriptional Gene Regulation Of 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. In turn, these alterations in gene expression directly influence the global response of the cell. While the transcriptional events regulating such changes in gene expression have been thoroughly studied, posttranscriptional events, which are less well understood, are emerging as major gene regulatory mechanisms. Posttranscriptional gene regulation includes mRNA processing, transport, stability and translation, as well as protein processing, modification and degradation. With respect to mRNA stability, we are investigating the mechanisms that regulate the expression of various cell cycle regulatory and proliferation-associated genes. We have shown that the function of the RNA-binding protein HuR, which stabilizes transcripts encoding proliferative genes, is strongly regulated by the AMP-activated kinase (AMPK). AMPK promotes the nuclear localization of HuR and thus prevents the stabilization of HuR targets. With respect to translation, we have recently demonstrated that HuR also participates in enhancing protein synthesis from target mRNAs, such as that encoding the tumor suppressor p53. Our long-term efforts are focused on investigating RNA-binding proteins, target mRNA regions, and signaling pathways effecting post-transcriptional gene regulation on growth control and cell cycle regulatory factors.