Regulation of Eukaryotic Messenger RNA Turnover1

Department of Pathology and Laboratory Medicine, University of Wisconsin–Madison, Madison, Wisconsin, United States
Progress in Nucleic Acid Research and Molecular Biology (Impact Factor: 4.14). 02/1997; 56:257-86. DOI: 10.1016/S0079-6603(08)61007-7
Source: PubMed


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.

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    • "It is noteworthy to consider that there is not a direct correlation between mRNA transcripts and protein levels. Gene expression is also regulated by the control of mRNA degradation, since the steady-state concentration of mRNA is determined both by its rates of synthesis and decay (Rajagopalan and Malter 1997; Meyer et al. 2004). Changes in mRNA half-life do not reflect changes in transcription (Ross 1996). "
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    • "The use of an in vitro protocol under highly controlled and reproducible conditions is warranted since our preliminary work revealed that measuring the stability of transcripts in skeletal muscle of living animals using transcription inhibitors such as actinomycin D, is unreliable and fraught with difficulties (data not shown). In fact, limitations of this approach have been discussed previously (34,36) and they include: (i) the toxicity of the drug which kills the animals in a few hours making extrapolations of half-life of relatively stable mRNAs questionable and (ii) the direct effect of these drugs on the mRNA decay process which may artificially alter the rate of degradation of specific cellular transcripts. "
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    Nucleic Acids Research 03/2008; 36(3):826-38. DOI:10.1093/nar/gkm1107 · 9.11 Impact Factor
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    • "However, the potential hairpin loop sequence was not present in all reported mammalian -subunit mRNA sequences; a G in the horse 3 UTR removes a potential base pair in the hairpin stem reducing the predicted G value to 1·0 kcal/mol, while the rat and mouse transcripts entirely lack the sequence (Chin et al. 1981, Godine et al. 1982). Conservation of mRNA secondary structure may indicate functional significance, and a role for hairpin loop structures in regulating mRNA stability in some transcripts is well established (Rajagopalan & Malter 1997). It is noteworthy that the position of the possum -subunit putative hairpin loop with respect to the translation termination codon was also conserved, varying between 177 and 188 nucleotides in the six -subunit 3 UTR sequences shown in Fig. 3. Furthermore, in five of the six 3 UTR sequences in Fig. 3, the putative hairpin sequence was located six or eight nucleotides 5 to the sequence AUUUA (AUUUUA in horse) which itself was positioned approximately 30 nucleotides 5 to the polyadenylation signal AAUAAA. "
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