HuR-dependent loading of miRNA RISC to the mRNA encoding the Ras-related small GTPase RhoB controls its translation during UV-induced apoptosis

Of critical importance in the stress response is the post-transcriptional control of the expression of important genes involved in the control of cell survival and apoptosis. Here we report that miR-19, an oncogenic component of the miR-17-92/Oncomir-1 microRNA polycistron, regulates the expression of Ras homolog B (RhoB) in keratinocytes upon exposure to ultraviolet (UV) radiation. Strikingly, we could not find any evidence for deregulated expression of miR-19 during UV treatment. However, we show that miR-19-mediated regulation of antiapoptotic RhoB expression requires the binding of human antigen R (HuR), an AU-rich element binding protein, to the 3′-untranslated region of the rhoB mRNA. We propose that the loss of the interdependent binding between HuR and miR-19 to the rhoB mRNA upon UV exposure relieves this mRNA from miR-19-dependent inhibition of translation and contributes to the apoptotic response.

[1]  Petra Schwille,et al.  Importin 8 Is a Gene Silencing Factor that Targets Argonaute Proteins to Distinct mRNAs , 2009, Cell.

[2]  Kotb Abdelmohsen,et al.  Posttranscriptional Orchestration of an Anti-Apoptotic Program by HuR , 2007, Cell cycle.

[3]  H. Schwalbe,et al.  Tandem Phosphorylation of Serines 221 and 318 by Protein Kinase Cδ Coordinates mRNA Binding and Nucleocytoplasmic Shuttling of HuR , 2010, Molecular and Cellular Biology.

[4]  M. Bushell,et al.  Translational regulation of gene expression during conditions of cell stress. , 2010, Molecular cell.

[5]  D. Ron,et al.  Translation reinitiation at alternative open reading frames regulates gene expression in an integrated stress response , 2004, The Journal of cell biology.

[6]  E. Izaurralde,et al.  Getting to the Root of miRNA-Mediated Gene Silencing , 2008, Cell.

[7]  M. Gorospe,et al.  The RNA binding protein HuR differentially regulates unique subsets of mRNAs in estrogen receptor negative and estrogen receptor positive breast cancer , 2010, BMC Cancer.

[8]  W. Filipowicz,et al.  Relief of microRNA-Mediated Translational Repression in Human Cells Subjected to Stress , 2006, Cell.

[9]  Guihua Sun,et al.  Sequence context outside the target region influences the effectiveness of miR-223 target sites in the RhoB 3′UTR , 2009, Nucleic acids research.

[10]  P. Ongusaha,et al.  Prolyl 4-hydroxylation regulates Argonaute 2 stability , 2008, Nature.

[11]  Shuang Huang,et al.  Involvement of MicroRNA in AU-Rich Element-Mediated mRNA Instability , 2005, Cell.

[12]  V. Beneš,et al.  Widespread estrogen-dependent repression of micrornas involved in breast tumor cell growth. , 2009, Cancer research.

[13]  Jung-Chun Lin,et al.  Cell stress modulates the function of splicing regulatory protein RBM4 in translation control , 2007, Proceedings of the National Academy of Sciences.

[14]  Kotb Abdelmohsen,et al.  MKP-1 mRNA Stabilization and Translational Control by RNA-Binding Proteins HuR and NF90 , 2008, Molecular and Cellular Biology.

[15]  Kotb Abdelmohsen,et al.  Phosphorylation of HuR by Chk2 regulates SIRT1 expression. , 2007, Molecular cell.

[16]  P. Graves,et al.  Phosphorylation of Argonaute 2 at serine-387 facilitates its localization to processing bodies. , 2008, The Biochemical journal.

[17]  R. Paules,et al.  An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. , 2003, Molecular cell.

[18]  George A. Calin,et al.  A MicroRNA Signature of Hypoxia , 2006, Molecular and Cellular Biology.

[19]  J. Malter,et al.  RhoB mRNA is stabilized by HuR after UV light , 2005, Oncogene.

[20]  G. Favre,et al.  RhoB Protects Human Keratinocytes from UVB-induced Apoptosis through Epidermal Growth Factor Receptor Signaling* , 2005, Journal of Biological Chemistry.

[21]  M. Gorospe,et al.  RNA-binding protein HuR enhances p53 translation in response to ultraviolet light irradiation , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[22]  Jun O. Liu,et al.  RNA-Binding Proteins HuR and PTB Promote the Translation of Hypoxia-Inducible Factor 1α , 2007, Molecular and Cellular Biology.

[23]  M. Holcik,et al.  Cytoplasmic relocalization of heterogeneous nuclear ribonucleoprotein A1 controls translation initiation of specific mRNAs. , 2007, Molecular biology of the cell.

[24]  S. Srikantan,et al.  HuR recruits let-7/RISC to repress c-Myc expression. , 2009, Genes & development.

[25]  Lin He,et al.  The guardian's little helper: microRNAs in the p53 tumor suppressor network. , 2007, Cancer research.

[26]  Phillip A. Sharp,et al.  microRNAs: A Safeguard against Turmoil? , 2007, Cell.

[27]  M. Rosenfeld,et al.  Akt2-mediated phosphorylation of Pitx2 controls Ccnd1 mRNA decay during muscle cell differentiation , 2010, Cell Death and Differentiation.

[28]  R. Karlsson,et al.  Rho GTPase function in tumorigenesis. , 2009, Biochimica et biophysica acta.

[29]  J. Steitz,et al.  AU-Rich-Element-Mediated Upregulation of Translation by FXR1 and Argonaute 2 , 2007, Cell.

[30]  Jun O. Liu,et al.  RNA-binding proteins HuR and PTB promote the translation of hypoxia-inducible factor 1alpha. , 2008, Molecular and cellular biology.

[31]  C. Rogler,et al.  Overexpression of miR-21 Promotes an In vitro Metastatic Phenotype by Targeting the Tumor Suppressor RHOB , 2010, Molecular Cancer Research.

[32]  Alexander Kondrashov,et al.  Translational reprogramming following UVB irradiation is mediated by DNA-PKcs and allows selective recruitment to the polysomes of mRNAs encoding DNA repair enzymes. , 2009, Genes & development.

[33]  Xiaoxia Qi,et al.  Control of Stress-Dependent Cardiac Growth and Gene Expression by a MicroRNA , 2007, Science.

[34]  B. Kaina,et al.  Ras-related GTPase RhoB forces alkylation-induced apoptotic cell death. , 2000, Biochemical and biophysical research communications.

[35]  A. Komar,et al.  The hnRNA-Binding Proteins hnRNP L and PTB Are Required for Efficient Translation of the Cat-1 Arginine/Lysine Transporter mRNA during Amino Acid Starvation , 2009, Molecular and Cellular Biology.

[36]  M. Holcik,et al.  Subcellular relocalization of a trans-acting factor regulates XIAP IRES-dependent translation. , 2007, Molecular biology of the cell.

[37]  W. V. van IJcken,et al.  MicroRNA‐mediated gene silencing modulates the UV‐induced DNA‐damage response , 2009, The EMBO journal.

[38]  Kotb Abdelmohsen,et al.  Regulation of HuR by DNA Damage Response Kinases , 2010, Journal of nucleic acids.