Regulation of eukaryotic messenger RNA turnover.
We have demonstrated the existence of multiple mRNA binding proteins that interact specifically with defined regions in posttranscriptionally regulated mRNAs. These domains appear to be destabilizers whose function can be attenuated by the interaction with the specific binding proteins. Thus, the ability to alter mRNA decay rates on demand, given different environmental or intracellular conditions, appears to be mediated by controlling the localization, activity, and overall function of the cognate binding protein. Based on our limited experience, we predict that most, if not all, of similarly regulated mRNAs will ultimately be found to interact with regulatory mRNA binding proteins. Under conditions whereby the mRNA binding proteins are constitutively active (e.g., tumor cell lines), abnormal mRNA decay will result, with accumulation and overtranslation. Such appears to be the case for cytokines and possibly amyloid protein precursor mRNAs in cancer and Alzheimer's disease, respectively. Conversely, mutagenesis of these critical 3' untranslated region elements will likely have comparable deleterious effects on the regulation of gene expression. To the extent that such derangements exist in human disease, attention to understanding the mechanistic detail at this level may provide insights into the development of appropriate therapeutics or treatment strategies.
Rajagopalan
L E
LE
Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison Hospitals and Clinics 53792, USA.
Malter
J S
JS
D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D016207:Cytokines / Q000235:genetics; D005057:Eukaryotic Cells; D015316:Genetic Therapy / Q000379:methods; D005914:Globins / Q000235:genetics; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics; D006207:Half-Life; D006801:Humans; D009690:Nucleic Acid Conformation; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism*
D016564:Amyloid beta-Protein Precursor; D016207:Cytokines; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D005914:Globins