Global microRNA elevation by inducible Exportin 5 regulates cell cycle entry.

Proper regulation of gene expression during cell cycle entry ensures the successful completion of proliferation, avoiding risks such as carcinogenesis. The microRNA (miRNA) network is an emerging molecular system regulating multiple genetic pathways. We demonstrate here that the global elevation of miRNAs is critical for proper control of gene expression program during cell cycle entry. Strikingly, Exportin 5 (XPO5) is promptly induced during cell cycle entry by a PI3K-dependent post-transcriptional mechanism. Inhibition of XPO5 induction interfered with global miRNA elevation and resulted in a proliferation defect associated with delayed G1/S transition. During cell cycle entry, XPO5 therefore plays a paramount role as a critical molecular hub controlling the gene expression program through global regulation of miRNAs. Our data suggest that XPO5-mediated global miRNA elevation might be involved in a broad range of cellular events associated with cell cycle control.

[1]  M. Ashburner,et al.  Gene Ontology: tool for the unification of biology , 2000, Nature Genetics.

[2]  W. Kaelin.  Alterations in G1/S Cell‐Cycle Control Contributing to Carcinogenesis , 1997, Annals of the New York Academy of Sciences.

[3]  Jan-Fang Cheng,et al.  Dicer, Drosha, and outcomes in patients with ovarian cancer. , 2008, The New England journal of medicine.

[4]  L. Hartwell,et al.  Cell cycle control and cancer. , 1994, Science.

[5]  Michael Kertesz,et al.  The role of site accessibility in microRNA target recognition , 2007, Nature Genetics.

[6]  Hiroyuki Yamamoto,et al.  A genetic defect in exportin-5 traps precursor microRNAs in the nucleus of cancer cells. , 2010, Cancer cell.

[7]  K Y Hui,et al.  A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). , 1994, The Journal of biological chemistry.

[8]  C. Burge,et al.  Conserved Seed Pairing, Often Flanked by Adenosines, Indicates that Thousands of Human Genes are MicroRNA Targets , 2005, Cell.

[9]  Keara M. Lane,et al.  Dicer1 functions as a haploinsufficient tumor suppressor. , 2009, Genes & development.

[10]  Li Zhao,et al.  Oncogenic PI3K deregulates transcription and translation , 2005, Nature Reviews Cancer.

[11]  B. Cullen,et al.  Overexpression of exportin 5 enhances RNA interference mediated by short hairpin RNAs and microRNAs. , 2005, RNA.

[12]  M. Siomi,et al.  Posttranscriptional regulation of microRNA biogenesis in animals. , 2010, Molecular cell.

[13]  Carla Oliveira,et al.  A TARBP2 mutation in human cancer impairs microRNA processing and DICER1 function , 2009, Nature Genetics.

[14]  Ramin Massoumi,et al.  Cyld Inhibits Tumor Cell Proliferation by Blocking Bcl-3-Dependent NF-κB Signaling , 2006, Cell.

[15]  D. Bartel.  MicroRNAs Genomics, Biogenesis, Mechanism, and Function , 2004, Cell.

[16]  R. Weinberg,et al.  Control of the cell cycle and apoptosis. , 1999, European journal of cancer.

[17]  Peter Horvath,et al.  A Protein Inventory of Human Ribosome Biogenesis Reveals an Essential Function of Exportin 5 in 60S Subunit Export , 2010, PLoS biology.

[18]  Teng Ma,et al.  DCUN1D3, a novel UVC‐responsive gene that is involved in cell cycle progression and cell growth , 2008, Cancer science.

[19]  Chunxiang Zhang,et al.  MicroRNomics: a newly emerging approach for disease biology. , 2008, Physiological genomics.

[20]  M. Prætorius-Ibba,et al.  Linking tRNA localization with activation of nutritional stress responses , 2010, Cell cycle.

[21]  G. Tsujimoto,et al.  Role of Dbl's big sister in the anti-mitogenic pathway from alpha1B-adrenergic receptor to c-Jun N-terminal kinase. , 2002, Biochemical and biophysical research communications.

[22]  H. Horvitz,et al.  MicroRNA expression profiles classify human cancers , 2005, Nature.

[23]  Chyung-Ru Wang,et al.  Helper T cell differentiation is controlled by the cell cycle. , 1998, Immunity.

[24]  Susumu Goto,et al.  KEGG: Kyoto Encyclopedia of Genes and Genomes , 2000, Nucleic Acids Res..

[25]  M. Loda,et al.  The oncogenic properties of mutant p110α and p110β phosphatidylinositol 3-kinases in human mammary epithelial cells , 2005 .

[26]  Pier Paolo Pandolfi,et al.  Tenets of PTEN Tumor Suppression , 2008, Cell.

[27]  Stephen J. Elledge,et al.  Cell Cycle Checkpoints: Preventing an Identity Crisis , 1996, Science.

[28]  K. Kinzler,et al.  The multistep nature of cancer. , 1993, Trends in genetics : TIG.

[29]  Yoko Fukuda,et al.  An Evolutionarily Conserved Mechanism for MicroRNA-223 Expression Revealed by MicroRNA Gene Profiling , 2007, Cell.