Tristetraprolin and other CCCH tandem zinc-finger proteins in the regulation of mRNA turnover.
The tristetraprolin (TTP) family of CCCH tandem zinc-finger proteins is composed of three known members in mammals, with a fourth member recently identified in frogs and fish. Although TTP was first cloned more than 10 years ago as a growth factor-induced gene, a physiological function for the protein has been discovered only within the last few years. TTP is now known to bind to so-called class II AU-rich elements within the mRNAs that encode tumour necrosis factor-alpha and granulocyte/macrophage colony-stimulating factor. In both cases, this binding results in destabilization of the mRNA and decreased secretion of the protein. Recent evidence suggests that TTP can accomplish this accelerated mRNA degradation by first promoting removal of the polyadenylated tail from the mRNA (deadenylation). In functional assays in cells, the other family members have similar activities, but are expressed differently in tissues and in response to stimuli, suggesting that they may control the stability of mRNAs under different circumstances from those in which TTP affects mRNA. All of these proteins are phosphoproteins and nucleocytoplasmic shuttling proteins, suggesting that their activities can be regulated in ways other than regulating gene transcription. Together, the TTP family members should be capable of complex regulation of short-lived mRNAs containing this type of AU-rich instability motif.
Blackshear
P J
PJ
Office of Clinical Research and the Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA. black009@niehs.nih.gov
D001854:Bone Marrow Cells / Q000166:cytology; D004268:DNA-Binding Proteins; D005786:Gene Expression Regulation; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D017874:Immediate-Early Proteins / Q000737:chemistry*; D008264:Macrophages / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism*; D013997:Time Factors; D051816:Tristetraprolin; D016335:Zinc Fingers
D004268:DNA-Binding Proteins; D017874:Immediate-Early Proteins; D012333:RNA, Messenger; D051816:Tristetraprolin; C497552:ZFP36 protein, human; D016178:Granulocyte-Macrophage Colony-Stimulating Factor