Publication Date:
2009-05-22
Description:
Consistent with the role of microRNAs (miRNAs) in down-regulating gene expression by reducing the translation and/or stability of target messenger RNAs, the levels of specific miRNAs are important for correct embryonic development and have been linked to several forms of cancer. However, the regulatory mechanisms by which primary miRNAs (pri-miRNAs) are processed first to precursor miRNAs (pre-miRNAs) and then to mature miRNAs by the multiprotein Drosha and Dicer complexes, respectively, remain largely unknown. The KH-type splicing regulatory protein (KSRP, also known as KHSRP) interacts with single-strand AU-rich-element-containing mRNAs and is a key mediator of mRNA decay. Here we show in mammalian cells that KSRP also serves as a component of both Drosha and Dicer complexes and regulates the biogenesis of a subset of miRNAs. KSRP binds with high affinity to the terminal loop of the target miRNA precursors and promotes their maturation. This mechanism is required for specific changes in target mRNA expression that affect specific biological programs, including proliferation, apoptosis and differentiation. These findings reveal an unexpected mechanism that links KSRP to the machinery regulating maturation of a cohort of miRNAs that, in addition to its role in promoting mRNA decay, independently serves to integrate specific regulatory programs of protein expression.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2768332/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2768332/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Trabucchi, Michele -- Briata, Paola -- Garcia-Mayoral, Mariaflor -- Haase, Astrid D -- Filipowicz, Witold -- Ramos, Andres -- Gherzi, Roberto -- Rosenfeld, Michael G -- 082088/Wellcome Trust/United Kingdom -- DK018477/DK/NIDDK NIH HHS/ -- DK39949/DK/NIDDK NIH HHS/ -- GFP04003/Telethon/Italy -- HL065445/HL/NHLBI NIH HHS/ -- MC_U117533887/Medical Research Council/United Kingdom -- MC_U117574558/Medical Research Council/United Kingdom -- R37 DK039949/DK/NIDDK NIH HHS/ -- R37 DK039949-26/DK/NIDDK NIH HHS/ -- R37 DK039949-27/DK/NIDDK NIH HHS/ -- WT022088MA/Wellcome Trust/United Kingdom -- Howard Hughes Medical Institute/ -- England -- Nature. 2009 Jun 18;459(7249):1010-4. doi: 10.1038/nature08025. Epub 2009 May 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Department and School of Medicine, University of California, San Diego, 9500 Gilman Drive, Room 345, La Jolla, California 92093-0648, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19458619" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Cell Line
;
Cell Line, Tumor
;
Cell Proliferation
;
Humans
;
Mice
;
MicroRNAs/*biosynthesis/genetics/metabolism
;
RNA Processing, Post-Transcriptional
;
RNA-Binding Proteins/*metabolism
;
Ribonuclease III/chemistry/metabolism
;
Trans-Activators/*metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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