Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04141 (granulocyte-macrophage colony-stimulating factor)
 6,790 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Members of the tristetraprolin (TTP) family of CCCH tandem zinc finger proteins can bind directly to certain types of AU-rich elements (AREs) in mRNA. Experiments in TTP-deficient mice have shown that TTP is involved in the physiological destabilization of at least two cytokine mRNAs, those encoding tumor necrosis factor alpha and granulocyte-macrophage colony-stimulating factor. The two other known mammalian members of the TTP family, CMG1 and TIS11D, also contain ARE-binding CCCH tandem zinc finger domains and can also destabilize ARE-containing mRNAs. To investigate the effects of primary sequence on the subcellular localization of these proteins, we constructed green fluorescent protein fusions with TTP, CMG1, and TIS11D; these were predominantly cytoplasmic when expressed in 293 or HeLa cells. Deletion and mutation analyses revealed functional nuclear export signals in the amino terminus of TTP and in the carboxyl termini of CMG1 and TIS11D. This type of leucine-rich nuclear export signal interacts with the nuclear export receptor CRM1; abrogation of CRM1 activity resulted in nuclear accumulation of TTP, CMG1, and TIS11D. These proteins are thus nucleocytoplasmic shuttling proteins and rely on CRM1 for their export from the nucleus. Although TTP, CMG1, and TIS11D lack known nuclear import sequences, mapping experiments revealed that their nuclear accumulation required an intact tandem zinc finger domain but did not require RNA binding ability. These findings suggest possible roles for nuclear import and export in the regulation of cellular TTP, CMG1, and TIS11D activity.
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PMID:Members of the tristetraprolin family of tandem CCCH zinc finger proteins exhibit CRM1-dependent nucleocytoplasmic shuttling. 1179 23

The three known mammalian CCCH tandem zinc finger proteins of the tristetraprolin (TTP) class have recently been demonstrated to be mRNA-binding proteins. The prototype, TTP, functions in normal physiology to promote the instability of the tumor necrosis factor alpha (TNFalpha) and granulocyte-macrophage colony-stimulating factor mRNAs. Conversely, these mRNAs are stabilized in TTP-deficient mice, leading to an inflammatory phenotype characterized by overproduction of these cytokines. To explore sequence variations in TTP and its two related proteins, we sequenced genomic DNA encoding the TTP protein (ZFP36) and those of its two known mammalian relatives, ZFP36L1 and ZFP36L2, from 72 to 92 anonymous human subjects from various geographical and ethnic backgrounds. We also sequenced ZFP36 in genomic DNA from 92 subjects exhibiting evidence of excessive TNFalpha action. The resequencing strategy identified 13 polymorphisms in the protein-coding regions of these three genes, of which six would result in amino acid changes; other putative polymorphisms were identified by EST searches. One mutation in ZFP36L1 was a dinucleotide substitution that would prevent splicing of the single intron. This mutation was identified in only one allele of the original 144 sequenced from an adult female Aka Pygmy from the Central African Republic; a second individual with the same variant allele was found by genotyping 58 additional Aka DNA samples. Analysis of mRNA from one of these subject's lymphoblasts confirmed that ZFP36L1 mRNA levels were approximately 50% of those in a comparable sample without the mutation. The functional significance of this and the other polymorphisms identified remains to be determined by both biochemical and population linkage studies.
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PMID:Polymorphisms in the genes encoding members of the tristetraprolin family of human tandem CCCH zinc finger proteins. 1460 9