AMP-Activated Kinase Regulates Cytoplasmic HuR

ABSTRACT While transport of RNA-binding protein HuR from nucleus to cytoplasm is emerging as a key regulatory step for HuR function, the mechanisms underlying this process remain poorly understood. Here, we report that the AMP-activated kinase (AMPK), an enzyme involved in responding to metabolic stresses, potently regulates the levels of cytoplasmic HuR. Inhibition of AMPK, accomplished either through cell treatment or by adenovirus infection to express dominant-negative AMPK, was found to increase the level of HuR in the cytoplasm and to enhance the binding of HuR to p21, cyclin B1, and cyclin A mRNA transcripts and elevate their expression and half-lives. Conversely, AMPK activation, achieved by means including infection to express constitutively active AMPK, resulted in reduced cytoplasmic HuR; decreased levels and half-lives of mRNAs encoding p21, cyclin A, and cyclin B1; and diminished HuR association with the corresponding transcripts. We therefore propose a novel function for AMPK as a regulator of cytoplasmic HuR levels, which in turn influences the mRNA-stabilizing function of HuR and the expression of HuR target transcripts.

[1]  D. Hardie,et al.  AMP‐activated protein kinase: the energy charge hypothesis revisited , 2001, BioEssays : news and reviews in molecular, cellular and developmental biology.

[2]  M. Kaminishi,et al.  Cell cycle regulation via p53 phosphorylation by a 5'-AMP activated protein kinase activator, 5-aminoimidazole- 4-carboxamide-1-beta-D-ribofuranoside, in a human hepatocellular carcinoma cell line. , 2001, Biochemical and biophysical research communications.

[3]  J. Steitz,et al.  Protein ligands mediate the CRM1-dependent export of HuR in response to heat shock. , 2001, RNA.

[4]  Myriam Gorospe,et al.  Loss of HuR Is Linked to Reduced Expression of Proliferative Genes during Replicative Senescence , 2001, Molecular and Cellular Biology.

[5]  J. Malter,et al.  Extracellular-regulated kinase controls β-amyloid precursor protein mRNA decay , 2001 .

[6]  J. A. Steitz,et al.  HuR and mRNA stability , 2001, Cellular and Molecular Life Sciences CMLS.

[7]  J. Malter,et al.  Up-regulation of Nucleolin mRNA and Protein in Peripheral Blood Mononuclear Cells by Extracellular-regulated Kinase* , 2001, The Journal of Biological Chemistry.

[8]  A. Passaniti,et al.  p53-independent elevation of p21 expression by PMA results from PKC-mediated mRNA stabilization. , 2001, Biochemical and biophysical research communications.

[9]  G. M. Wilson,et al.  Down-Regulation of Cyclin D1 Expression by Prostaglandin A2 Is Mediated by Enhanced Cyclin D1 mRNA Turnover , 2000, Molecular and Cellular Biology.

[10]  D. Carling,et al.  Characterization of the Role of AMP-Activated Protein Kinase in the Regulation of Glucose-Activated Gene Expression Using Constitutively Active and Dominant Negative Forms of the Kinase , 2000, Molecular and Cellular Biology.

[11]  J. Pouysségur,et al.  Stress-activated Protein Kinases (JNK and p38/HOG) Are Essential for Vascular Endothelial Growth Factor mRNA Stability* , 2000, The Journal of Biological Chemistry.

[12]  Myriam Gorospe,et al.  HuR regulates cyclin A and cyclin B1 mRNA stability during cell proliferation , 2000, The EMBO journal.

[13]  J. Steitz,et al.  HuR binding to cytoplasmic mRNA is perturbed by heat shock. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[14]  Myriam Gorospe,et al.  HuR Regulates p21 mRNA Stabilization by UV Light , 2000, Molecular and Cellular Biology.

[15]  Klaus Resch,et al.  The p38 MAP kinase pathway signals for cytokine‐induced mRNA stabilization via MAP kinase‐activated protein kinase 2 and an AU‐rich region‐targeted mechanism , 1999, The EMBO journal.

[16]  C. Y. Chen,et al.  Unraveling a cytoplasmic role for hnRNP D in the in vivo mRNA destabilization directed by the AU-rich element. , 1999, Genes & development.

[17]  M. Gaestel,et al.  MAPKAP kinase 2 is essential for LPS-induced TNF-α biosynthesis , 1999, Nature Cell Biology.

[18]  R. Cuesta,et al.  Control of mRNA decay by heat shock-ubiquitin-proteasome pathway. , 1999, Science.

[19]  Georges Huez,et al.  Identification of TIAR as a Protein Binding to the Translational Regulatory AU-rich Element of Tumor Necrosis Factor α mRNA* , 1999, The Journal of Biological Chemistry.

[20]  J. Keene.  Why is Hu where? Shuttling of early-response-gene messenger RNA subsets. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[21]  J. Dean,et al.  p38 Mitogen-activated Protein Kinase Regulates Cyclooxygenase-2 mRNA Stability and Transcription in Lipopolysaccharide-treated Human Monocytes* , 1999, The Journal of Biological Chemistry.

[22]  J. Steitz,et al.  HNS, a nuclear-cytoplasmic shuttling sequence in HuR. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[23]  D. Hardie,et al.  AMP-activated protein kinase is activated by low glucose in cell lines derived from pancreatic beta cells, and may regulate insulin release. , 1998, The Biochemical journal.

[24]  U. Atasoy,et al.  ELAV protein HuA (HuR) can redistribute between nucleus and cytoplasm and is upregulated during serum stimulation and T cell activation. , 1998, Journal of cell science.

[25]  C. Moroni,et al.  c‐jun N‐terminal kinase is involved in AUUUA‐mediated interleukin‐3 mRNA turnover in mast cells , 1998, The EMBO journal.

[26]  P. Blackshear,et al.  Feedback Inhibition of Macrophage Tumor Necrosis Factor-α Production by Tristetraprolin , 1998 .

[27]  B. Joseph,et al.  p21waf1 mRNA Contains a Conserved Element in Its 3′-Untranslated Region That Is Bound by the Elav-like mRNA-stabilizing Proteins* , 1998, The Journal of Biological Chemistry.

[28]  M. Karin,et al.  Stabilization of interleukin-2 mRNA by the c-Jun NH2-terminal kinase pathway. , 1998, Science.

[29]  A. Shyu,et al.  RNA stabilization by the AU‐rich element binding protein, HuR, an ELAV protein , 1998, The EMBO journal.

[30]  J. Steitz,et al.  Overexpression of HuR, a nuclear–cytoplasmic shuttling protein, increases the in vivo stability of ARE‐containing mRNAs , 1998, The EMBO journal.

[31]  M. Gorospe,et al.  p53-Dependent Elevation of p21Waf1Expression by UV Light Is Mediated through mRNA Stabilization and Involves a Vanadate-Sensitive Regulatory System , 1998, Molecular and Cellular Biology.

[32]  G. Crabtree,et al.  Architectural DNA binding by a high-mobility-group/kinesin-like subunit in mammalian SWI/SNF-related complexes. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[33]  D. Mercola,et al.  The JUN Kinase/Stress-activated Protein Kinase Pathway Is Required for Epidermal Growth Factor Stimulation of Growth of Human A549 Lung Carcinoma Cells* , 1997, The Journal of Biological Chemistry.

[34]  H. Furneaux,et al.  The Elav-like proteins bind to AU-rich elements and to the poly(A) tail of mRNA. , 1997, Nucleic acids research.

[35]  C. Y. Chen,et al.  Modulation of the fate of cytoplasmic mRNA by AU-rich elements: key sequence features controlling mRNA deadenylation and decay , 1997, Molecular and cellular biology.

[36]  E. Appella,et al.  Redox-mediated regulation of p21(waf1/cip1) expression involves a post-transcriptional mechanism and activation of the mitogen-activated protein kinase pathway. , 1997, European journal of biochemistry.

[37]  J. LaBaer,et al.  New functional activities for the p21 family of CDK inhibitors. , 1997, Genes & development.

[38]  K. McGowan,et al.  Ectopic expression of Hel-N1, an RNA-binding protein, increases glucose transporter (GLUT1) expression in 3T3-L1 adipocytes , 1997, Molecular and cellular biology.

[39]  M. Gorospe,et al.  Protective role of p21(Waf1/Cip1) against prostaglandin A2-mediated apoptosis of human colorectal carcinoma cells , 1996, Molecular and cellular biology.

[40]  Anne Wright,et al.  Cloning and Characterization of HuR, a Ubiquitously Expressed Elav-like Protein (*) , 1996, The Journal of Biological Chemistry.

[41]  D. Hardie,et al.  5′‐AMP inhibits dephosphorylation, as well as promoting phosphorylation, of the AMP‐activated protein kinase. Studies using bacterially expressed human protein phosphatase‐2Cα and native bovine protein phosphatase‐2Ac , 1995, FEBS letters.

[42]  C. Y. Chen,et al.  AU-rich elements: characterization and importance in mRNA degradation. , 1995, Trends in biochemical sciences.

[43]  J. Ross,et al.  mRNA stability in mammalian cells. , 1995, Microbiological reviews.

[44]  P. Good.  A conserved family of elav-like genes in vertebrates. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[45]  J. Steitz,et al.  Isolation and characterization of a novel, low abundance hnRNP protein: A0. , 1995, RNA.

[46]  G. Hannon,et al.  p21-containing cyclin kinases exist in both active and inactive states. , 1994, Genes & development.

[47]  H. Hirsch,et al.  Cyclosporin A inhibits growth of autocrine tumour cell lines by destabilizing interleukin-3 mRNA , 1994, Nature.

[48]  C Baglioni,et al.  Degradation of unstable interleukin-1 alpha mRNA in a rabbit reticulocyte cell-free system. Localization of an instability determinant to a cluster of AUUUA motifs. , 1994, The Journal of biological chemistry.

[49]  David Beach,et al.  p21 is a universal inhibitor of cyclin kinases , 1993, Nature.

[50]  W Zhang,et al.  Purification, characterization, and cDNA cloning of an AU-rich element RNA-binding protein, AUF1 , 1993, Molecular and cellular biology.

[51]  A. Sachs,et al.  Messenger RNA degradation in eukaryotes , 1993, Cell.

[52]  J. Malter,et al.  Association of heterogeneous nuclear ribonucleoprotein A1 and C proteins with reiterated AUUUA sequences. , 1993, The Journal of biological chemistry.

[53]  Susheel Kumar,et al.  Tumor necrosis factor increases stability of interleukin-1 mRNA by activating protein kinase C. , 1993, The Journal of biological chemistry.

[54]  C. Thompson,et al.  AU RNA-binding factors differ in their binding specificities and affinities. , 1992, The Journal of biological chemistry.

[55]  D. Hardie,et al.  Evidence that AMP triggers phosphorylation as well as direct allosteric activation of rat liver AMP-activated protein kinase. A sensitive mechanism to protect the cell against ATP depletion. , 1991, European journal of biochemistry.

[56]  J. Malter,et al.  A redox switch and phosphorylation are involved in the post-translational up-regulation of the adenosine-uridine binding factor by phorbol ester and ionophore. , 1991, The Journal of biological chemistry.

[57]  C. Thompson,et al.  Regulation of lymphokine messenger RNA stability by a surface-mediated T cell activation pathway. , 1989, Science.

[58]  G. Dreyfuss,et al.  Monoclonal antibody characterization of the C proteins of heterogeneous nuclear ribonucleoprotein complexes in vertebrate cells , 1984, The Journal of cell biology.

[59]  J. Malter,et al.  Extracellular-regulated kinase controls beta-amyloid precursor protein mRNA decay. , 2001, Brain research. Molecular brain research.

[60]  J. Steitz,et al.  Protein ligands mediate the CRM1-dependent export of HuR in response to heat shock. , 2001, RNA.

[61]  D. Hardie,et al.  Analysis of the role of the AMP-activated protein kinase in the response to cellular stress. , 2000, Methods in molecular biology.

[62]  M. Czyzyk-Krzeska,et al.  Hypoxia-induced regulation of mRNA stability. , 2000, Advances in experimental medicine and biology.

[63]  D. Hardie,et al.  Roles of the AMP-activated/SNF1 protein kinase family in the response to cellular stress. , 1999, Biochemical Society symposium.

[64]  M. Carlson,et al.  The AMP-activated/SNF1 protein kinase subfamily: metabolic sensors of the eukaryotic cell? , 1998, Annual review of biochemistry.

[65]  D. Hardie,et al.  The AMP-activated protein kinase--fuel gauge of the mammalian cell? , 1997, European journal of biochemistry.

[66]  G. Hannon,et al.  p21 is a component of active cell cycle kinases. , 1994, Cold Spring Harbor symposia on quantitative biology.