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Diverse roles of the nucleic acid‐binding protein KHSRP in cell differentiation and disease

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The single‐stranded nucleic acid‐binding protein KHSRP (KH‐type splicing regulatory protein) modulates RNA life and gene expression at various levels. KHSRP controls important cellular functions as different as proliferation, differentiation, metabolism, and response to infectious agents. We summarize and discuss experimental evidence providing a potential link between changes in KHSRP expression/function and human diseases including neuromuscular disorders, obesity, type II diabetes, and cancer. WIREs RNA 2016, 7:227–240. doi: 10.1002/wrna.1327 This article is categorized under: RNA Interactions with Proteins and Other Molecules > RNA–Protein Complexes RNA Turnover and Surveillance > Regulation of RNA Stability RNA in Disease and Development > RNA in Disease
KSRP decreases GAP‐43 mRNA stability and axonal outgrowth. (a) As shown by Bird et al., addition of recombinant KSRP to S100 extracts from Ksrp −/− mouse brains decreases the half‐life of the GAP‐43 mRNA. Decay curves show the average results of three separate decay experiments fitted with a single‐rate exponential decay curve. *p < 0.05. The effect of KSRP required both the presence of the KH4 domain in the protein and the ARE in the GAP‐43 3′ UTR. (b) Overexpression (OE) of KSRP in primary hippocampal neuron cultures impairs axonal elongation. This process is reversed by either KSRP knockdown (KD) or by OE of a GAP‐43 mRNA with a 3′ UTR targeting sequence for axonal localization.
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Missense point mutations in KHSRP. The primary sequence of KHSRP is represented as a straight line in the center, with the positions of the known missense point mutations indicated by blue bars. The position of the KH domains and that of the two domains of unknown function (DUF, as from Pfam) is shown. The region spanning amino acids 90–120 containing a cluster of nine distinct mutations and putatively involved in nuclear localization is highlighted with a dotted box. The three‐dimensional structures of the four KH domains are also represented as ribbon diagrams in the same orientation with respect to the RNA‐binding groove, with the position of the mutated residues highlighted in red. The experimentally determined position of the bound RNA is shown for KH3 and KH4. The Protein Data Bank codes for the four KH domains are 2opu (KH1), 2opv (KH2), and 1j4w (KH3, KH4).
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RNA Interactions with Proteins and Other Molecules > RNA–Protein Complexes
RNA in Disease and Development > RNA in Disease
RNA Turnover and Surveillance > Regulation of RNA Stability

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