p38 MAPK in Development and Cancer

p38 is a MAPK that has been shown to induce a wide variety of biological effects in cell culture,in response to a wide range of stimuli. These effects are dependent not only on the stimuli, butalso on the cellular context, resulting in a bewildering array of possibilites1. For example, p38was shown to induce apoptosis in some cells, but prevent apoptosis in others2. Similarly opposedeffects had been observed with respect to cell cycle regulation2. The role of p38 in inflammatorydisease has been appreciated from the beginning, since it was initially identified as an cytokineinducer3. More recently, p38 function has been evaluated in vivo, and through these studies p38has emerged as an important regulator of both embryonic development and cancer progression.This review will focus on these in vivo studies in an effort to provide perspective on p38biologically and as a pharmacological target.

[1]  S. D'souza,et al.  p38 MAPK signaling during murine preimplantation development. , 2004, Developmental biology.

[2]  Michael Karin,et al.  Macrophage Apoptosis by Anthrax Lethal Factor Through p38 MAP Kinase Inhibition , 2002, Science.

[3]  A. Sater,et al.  Regulation of MAP kinase by the BMP-4/TAK1 pathway in Xenopus ectoderm. , 2001, Developmental biology.

[4]  Jiahuai Han,et al.  Induction of terminal differentiation by constitutive activation of p38 MAP kinase in human rhabdomyosarcoma cells. , 2000, Genes & development.

[5]  T. Lepage,et al.  Nodal and BMP2/4 signaling organizes the oral-aboral axis of the sea urchin embryo. , 2004, Developmental cell.

[6]  D. McClay,et al.  Nuclear beta-catenin is required to specify vegetal cell fates in the sea urchin embryo. , 1999, Development.

[7]  S. Saccani,et al.  p38-Dependent marking of inflammatory genes for increased NF-kappa B recruitment. , 2002, Nature immunology.

[8]  M. Levine,et al.  The graded distribution of the dorsal morphogen is initiated by selective nuclear transport in Drosophila , 1989, Cell.

[9]  C. Nüsslein-Volhard,et al.  A gradient of nuclear localization of the dorsal protein determines dorsoventral pattern in the Drosophila embryo , 1989, Cell.

[10]  Eulàlia de Nadal,et al.  The MAPK Hog1 recruits Rpd3 histone deacetylase to activate osmoresponsive genes , 2004, Nature.

[11]  Nobuyuki Tanaka,et al.  Mechanism of p38 MAP kinase activation in vivo. , 2003, Genes & development.

[12]  M. Dell'Acqua,et al.  Rac–MEKK3–MKK3 scaffolding for p38 MAPK activation during hyperosmotic shock , 2003, Nature Cell Biology.

[13]  J. C. Jones,et al.  Follicle stimulating hormone (FSH) activates the p38 mitogen-activated protein kinase pathway, inducing small heat shock protein phosphorylation and cell rounding in immature rat ovarian granulosa cells. , 1998, Endocrinology.

[14]  P. Rakic,et al.  The Jnk1 and Jnk2 Protein Kinases Are Required for Regional Specific Apoptosis during Early Brain Development , 1999, Neuron.

[15]  C. Der,et al.  Raf-independent Deregulation of p38 and JNK Mitogen-activated Protein Kinases Are Critical for Ras Transformation* , 2002, The Journal of Biological Chemistry.

[16]  N. Hayashi,et al.  Involvement of the p38 mitogen‐activated protein kinase cascade in hepatocellular carcinoma , 2003, Cancer.

[17]  D. Natale,et al.  p38 mitogen‐activated protein kinase (MAPK) first regulates filamentous actin at the 8–16‐cell stage during preimplantation development , 2005, Biology of the cell.

[18]  L. Bardwell,et al.  Inhibitory and activating functions for MAPK Kss1 in the S. cerevisiae filamentous- growth signalling pathway , 1997, Nature.

[19]  M. Gaestel,et al.  In the Cellular Garden of Forking Paths: How p38 MAPKs Signal for Downstream Assistance , 2002, Biological chemistry.

[20]  R. Klein,et al.  Essential role of p38alpha MAP kinase in placental but not embryonic cardiovascular development. , 2000, Molecular cell.

[21]  J. Blank,et al.  p38 Mitogen-activated protein kinase mediates cell death and p21-activated kinase mediates cell survival during chemotherapeutic drug-induced mitotic arrest. , 2003, Molecular biology of the cell.

[22]  R. Flavell,et al.  Defective T cell differentiation in the absence of Jnk1. , 1998, Science.

[23]  Jian Du,et al.  A novel role of p38 alpha MAPK in mitotic progression independent of its kinase activity. , 2005, Cell cycle.

[24]  R. Flavell,et al.  Differentiation of CD4+ T cells to Th1 cells requires MAP kinase JNK2. , 1998, Immunity.

[25]  D. Frank,et al.  p38 MAP kinase regulates the expression of XMyf5 and affects distinct myogenic programs during Xenopus development. , 2005, Developmental biology.

[26]  Jiahuai Han,et al.  The primary structure of p38 gamma: a new member of p38 group of MAP kinases. , 1996, Biochemical and biophysical research communications.

[27]  G. Johnson,et al.  The p38 MAP kinase signaling pathway in Alzheimer’s disease , 2003, Experimental Neurology.

[28]  J. Dean,et al.  Post‐transcriptional regulation of gene expression by mitogen‐activated protein kinase p38 , 2003, FEBS letters.

[29]  H. Steinbeisser,et al.  β-catenin translocation into nuclei demarcates the dorsalizing centers in frog and fish embryos , 1996, Mechanisms of Development.

[30]  M. C. Hu,et al.  Murine p38-δ Mitogen-activated Protein Kinase, a Developmentally Regulated Protein Kinase That Is Activated by Stress and Proinflammatory Cytokines* , 1999, The Journal of Biological Chemistry.

[31]  C. Gabel,et al.  Deficiency of the stress kinase p38alpha results in embryonic lethality: characterization of the kinase dependence of stress responses of enzyme-deficient embryonic stem cells. , 2000, The Journal of experimental medicine.

[32]  H. Ellinger-Ziegelbauer,et al.  Cell Cycle Arrest and Reversion of Ras-Induced Transformation by a Conditionally Activated Form of Mitogen-Activated Protein Kinase Kinase Kinase 3 , 1999, Molecular and Cellular Biology.

[33]  Muffy Calder,et al.  When kinases meet mathematics: the systems biology of MAPK signalling , 2005, FEBS letters.

[34]  O. Timofeev,et al.  A Subtle Change in p38 MAPK Activity is Sufficient to Suppress In Vivo Tumorigenesis , 2005, Cell cycle.

[35]  J. Mudgett,et al.  Essential role for p38alpha mitogen-activated protein kinase in placental angiogenesis. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[36]  J. Ashwell,et al.  Activating p38 MAPK: New Tricks for an Old Kinase , 2005, Cell cycle.

[37]  E. Rassart,et al.  ERK1/2 and p38 regulate trophoblasts differentiation in human term placenta , 2005, The Journal of physiology.

[38]  S. Y. Cajal,et al.  Role of the p38 MAPK pathway in cisplatin-based therapy , 2003, Oncogene.

[39]  George Kollias,et al.  Interleukin‐10 targets p38 MAPK to modulate ARE‐dependent TNF mRNA translation and limit intestinal pathology , 2001, The EMBO journal.

[40]  M. Frödin,et al.  Xp38gamma/SAPK3 promotes meiotic G(2)/M transition in Xenopus oocytes and activates Cdc25C. , 2003, The EMBO journal.

[41]  Jiahuai Han,et al.  MAPKK-independent activation of p38alpha mediated by TAB1-dependent autophosphorylation of p38alpha. , 2002, Science.

[42]  G. Kollias,et al.  MK2 Targets AU-rich Elements and Regulates Biosynthesis of Tumor Necrosis Factor and Interleukin-6 Independently at Different Post-transcriptional Levels* , 2002, The Journal of Biological Chemistry.

[43]  J. Boehm,et al.  p38 MAP kinases: key signalling molecules as therapeutic targets for inflammatory diseases , 2003, Nature Reviews Drug Discovery.

[44]  I. Simon,et al.  Program-Specific Distribution of a Transcription Factor Dependent on Partner Transcription Factor and MAPK Signaling , 2003, Cell.

[45]  J. Landry,et al.  Modulation of actin dynamics during stress and physiological stimulation by a signaling pathway involving p38 MAP kinase and heat-shock protein 27. , 1995, Biochemistry and cell biology = Biochimie et biologie cellulaire.

[46]  A. Hand,et al.  Mechanism of action of bicyclic imidazoles defines a translational regulatory pathway for tumor necrosis factor alpha. , 1995, Journal of inflammation.

[47]  Gerald R. Fink,et al.  MAP Kinases with Distinct Inhibitory Functions Impart Signaling Specificity during Yeast Differentiation , 1997, Cell.

[48]  R. Steward.  Relocalization of the dorsal protein from the cytoplasm to the nucleus correlates with its function , 1989, Cell.

[49]  D. McClay,et al.  p38 MAPK is essential for secondary axis specification and patterning in sea urchin embryos , 2006, Development.

[50]  L. Donehower,et al.  Inactivation of the Wip1 phosphatase inhibits mammary tumorigenesis through p38 MAPK–mediated activation of the p16Ink4a-p19Arf pathway , 2004, Nature Genetics.

[51]  S. Kassis,et al.  Inhibition of p38 mitogen‐activated protein kinase provides neuroprotection in cerebral focal ischemia , 2001, Medicinal research reviews.

[52]  J. Aguirre-Ghiso,et al.  Green Fluorescent Protein Tagging of Extracellular Signal-Regulated Kinase and p38 Pathways Reveals Novel Dynamics of Pathway Activation during Primary and Metastatic Growth , 2004, Cancer Research.

[53]  K. Irie,et al.  The Drosophila p38 MAPK pathway is required during oogenesis for egg asymmetric development. , 1999, Genes & development.

[54]  Steven A. Carr,et al.  Pyridinyl Imidazole Inhibitors of p38 Mitogen-activated Protein Kinase Bind in the ATP Site* , 1997, The Journal of Biological Chemistry.

[55]  Jiahuai Han,et al.  The p38 signal transduction pathway: activation and function. , 2000, Cellular signalling.

[56]  藤井 律子.  Asymmetric p38 activation in zebrafish : Its possible role in symmetric and synchronous cleavage , 2001 .

[57]  Jerry L. Adams,et al.  A protein kinase involved in the regulation of inflammatory cytokine biosynthesis , 1994, Nature.

[58]  J. Laydon,et al.  Pyridinyl imidazoles inhibit IL-1 and TNF production at the protein level , 2005, Agents and Actions.

[59]  J C Lee,et al.  Novel homologues of CSBP/p38 MAP kinase: activation, substrate specificity and sensitivity to inhibition by pyridinyl imidazoles. , 1997, Biochemical and biophysical research communications.

[60]  S. Mackenzie,et al.  Post‐transcriptional regulation of TNF‐α during in vitro differentiation of human monocytes/macrophages in primary culture , 2002, Journal of leukocyte biology.