Non-Classical P38 Map Kinase Functions: Cell Cycle Checkpoints and Survival

The p38 MAPK kinase pathway is activated in response to a wide range of cellular stress stimuli and cytokines. Our understanding of the important functions of p38 MAPK in the process of differentiation and cell death has grown considerably in the recent years and is now relatively established. Here we discuss the role of p38 MAPK in the mediation of cell cycle checkpoints and cell survival, processes that have received less attention. We describe how p38 MAPK regulates both the G2/M as well as a G1/S cell cycle checkpoint in response to cellular stress such as DNA damage. While p38 MAPK has classically been associated with the induction of apoptosis, we discuss that p38 MAPK can also mediate cell survival in specific situations, such as in response to DNA damage. It is important to recognize these less appreciated functions of p38 MAPK when considering the potential use of pharmacological inhibitors of p38 MAPK in therapeutic treatments for disease.

[1]  J. Gutkind,et al.  Faculty Opinions recommendation of Phosphorylation by p38 MAPK as an alternative pathway for GSK3beta inactivation. , 2008 .

[2]  Gustavo Pedraza-Alva,et al.  Phosphorylation by p38 MAPK as an Alternative Pathway for GSK3β Inactivation , 2008, Science.

[3]  C. Simone.  Signal-dependent control of autophagy and cell death in colorectal cancer cell: the role of the p38 pathway. , 2008, Autophagy.

[4]  Peiqing Sun,et al.  The pathways to tumor suppression via route p38. , 2007, Trends in biochemical sciences.

[5]  Wei Chen,et al.  Differential regulation and properties of MAPKs , 2007, Oncogene.

[6]  Yingming Zhao,et al.  TAO kinases mediate activation of p38 in response to DNA damage , 2007, The EMBO journal.

[7]  J. Castro,et al.  Ionizing radiation activates IGF-1R triggering a cytoprotective signaling by interfering with Ku-DNA binding and by modulating Ku86 expression via a p38 kinase-dependent mechanism , 2007, Oncogene.

[8]  B. Nico,et al.  A novel cell type-specific role of p38α in the control of autophagy and cell death in colorectal cancer cells , 2007, Cell Death and Differentiation.

[9]  Michael B Yaffe,et al.  p53-deficient cells rely on ATM- and ATR-mediated checkpoint signaling through the p38MAPK/MK2 pathway for survival after DNA damage. , 2007, Cancer cell.

[10]  Chandan K Sen,et al.  The role of the NADPH oxidase complex, p38 MAPK, and Akt in regulating human monocyte/macrophage survival. , 2007, American journal of respiratory cell and molecular biology.

[11]  E. Wagner,et al.  p38alpha: a suppressor of cell proliferation and tumorigenesis. , 2007, Cell cycle.

[12]  B. Monsarrat,et al.  CDC25B Phosphorylation by p38 and MK-2 , 2006, Cell cycle.

[13]  J. Ashwell.  The many paths to p38 mitogen-activated protein kinase activation in the immune system , 2006, Nature Reviews Immunology.

[14]  L. Heasley,et al.  JNK regulation of oncogenesis. , 2006, Molecules and cells.

[15]  Keisuke Ito,et al.  Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells , 2006, Nature Medicine.

[16]  M. Schlissel,et al.  Activation of p38 MAP kinase by DNA double‐strand breaks in V(D)J recombination induces a G2/M cell cycle checkpoint , 2006, The EMBO journal.

[17]  T. Koyama,et al.  p38 MAP kinase plays a role in G2 checkpoint activation and inhibits apoptosis of human B cell lymphoma cells treated with etoposide , 2005, Apoptosis.

[18]  E. Appella,et al.  Alternative p38 activation pathway mediated by T cell receptor–proximal tyrosine kinases , 2005, Nature Immunology.

[19]  Michael B Yaffe,et al.  MAPKAP kinase-2 is a cell cycle checkpoint kinase that regulates the G2/M transition and S phase progression in response to UV irradiation. , 2005, Molecular cell.

[20]  F. Oesch,et al.  p38alpha MAPK is required for contact inhibition. , 2005, Oncogene.

[21]  Jiahuai Han,et al.  Activation and signaling of the p38 MAP kinase pathway , 2005, Cell Research.

[22]  P. Tazzari,et al.  Antiapoptotic role of p38 mitogen activated protein kinase in Jurkat T cells and normal human T lymphocytes treated with 8-methoxypsoralen and ultraviolet-A radiation , 2005, Apoptosis.

[23]  C. Peschel,et al.  Constitutive activation of the MAPkinase p38 is critical for MMP-9 production and survival of B-CLL cells on bone marrow stromal cells , 2004, Leukemia.

[24]  A. Mikhailov,et al.  Topoisomerase II and histone deacetylase inhibitors delay the G2/M transition by triggering the p38 MAPK checkpoint pathway , 2004, The Journal of cell biology.

[25]  M. McDevitt,et al.  The HBP1 transcriptional repressor and the p38 MAP kinase: unlikely partners in G1 regulation and tumor suppression. , 2004, Gene.

[26]  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.

[27]  Fredrik Melander,et al.  p38-MAPK Signals Survival by Phosphorylation of Caspase-8 and Caspase-3 in Human Neutrophils , 2004, The Journal of experimental medicine.

[28]  A. Fornace,et al.  Gadd45a regulates matrix metalloproteinases by suppressing DeltaNp63alpha and beta-catenin via p38 MAP kinase and APC complex activation. , 2004, Oncogene.

[29]  E. Rosenthal,et al.  Breast cancer cells with inhibition of p38α have decreased MMP-9 activity and exhibit decreased bone metastasis in mice , 2004, Clinical & Experimental Metastasis.

[30]  Tong Tong,et al.  Gadd45a contributes to p53 stabilization in response to DNA damage , 2003, Oncogene.

[31]  M. Berger,et al.  The p38 Mitogen-Activated Protein Kinase Pathway Links the DNA Mismatch Repair System to the G2 Checkpoint and to Resistance to Chemotherapeutic DNA-Methylating Agents , 2003, Molecular and Cellular Biology.

[32]  E. Appella,et al.  Regulation of Human Cdc25A Stability by Serine 75 Phosphorylation Is Not Sufficient to Activate a S-phase Checkpoint , 2003, Cell cycle.

[33]  A. Fornace,et al.  Loss of Oncogenic H-ras-Induced Cell Cycle Arrest and p38 Mitogen-Activated Protein Kinase Activation by Disruption of Gadd45a , 2003, Molecular and Cellular Biology.

[34]  B. Doble,et al.  GSK-3: tricks of the trade for a multi-tasking kinase , 2003, Journal of Cell Science.

[35]  C. Weston,et al.  The JNK signal transduction pathway. , 2007, Current opinion in genetics & development.

[36]  Hui Zhao,et al.  Disruption of the checkpoint kinase 1/cell division cycle 25A pathway abrogates ionizing radiation-induced S and G2 checkpoints , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[37]  E. Friedman,et al.  The Stress-activated Protein Kinases p38α and JNK1 Stabilize p21Cip1 by Phosphorylation* , 2002, The Journal of Biological Chemistry.

[38]  Xi He,et al.  Control of β-Catenin Phosphorylation/Degradation by a Dual-Kinase Mechanism , 2002, Cell.

[39]  Jiahuai Han,et al.  MAPKK-Independent Activation of p38α Mediated by TAB1-Dependent Autophosphorylation of p38α , 2002, Science.

[40]  A. Fornace,et al.  p38 and Chk1 kinases: different conductors for the G(2)/M checkpoint symphony. , 2002, Current opinion in genetics & development.

[41]  T. Andersson,et al.  p38 Mitogen‐activated protein kinase and phosphatidylinositol 3‐kinase activities have opposite effects on human neutrophil apoptosis , 2002, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[42]  Xi He,et al.  Control of beta-catenin phosphorylation/degradation by a dual-kinase mechanism. , 2002, Cell.

[43]  E. Friedman,et al.  The stress-activated protein kinases p38 alpha and JNK1 stabilize p21(Cip1) by phosphorylation. , 2002, The Journal of biological chemistry.

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

[45]  Y. Taya,et al.  Osmotic Shock Induces G1 Arrest through p53 Phosphorylation at Ser33 by Activated p38MAPK without Phosphorylation at Ser15 and Ser20 * , 2001, The Journal of Biological Chemistry.

[46]  E. Appella,et al.  Initiation of a G2/M checkpoint after ultraviolet radiation requires p38 kinase , 2001, Nature.

[47]  Peipei Ping,et al.  p38 Kinase-dependent MAPKAPK-2 Activation Functions as 3-Phosphoinositide-dependent Kinase-2 for Akt in Human Neutrophils* , 2001, The Journal of Biological Chemistry.

[48]  Weiya Ma,et al.  Resveratrol-induced activation of p53 and apoptosis is mediated by extracellular-signal-regulated protein kinases and p38 kinase. , 2001, Cancer research.

[49]  S. Elledge,et al.  The DNA damage response: putting checkpoints in perspective , 2000, Nature.

[50]  F. Miró,et al.  Osmotic Stress Regulates the Stability of Cyclin D1 in a p38SAPK2-dependent Manner* , 2000, The Journal of Biological Chemistry.

[51]  M. Morris,et al.  An Essential Phosphorylation-site Domain of Human cdc25C Interacts with Both 14-3-3 and Cyclins* , 2000, The Journal of Biological Chemistry.

[52]  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.

[53]  M. Karin,et al.  Requirement for p38α in Erythropoietin Expression A Role for Stress Kinases in Erythropoiesis , 2000, Cell.

[54]  Z. Dong,et al.  ERKs and p38 Kinase Phosphorylate p53 Protein at Serine 15 in Response to UV Radiation* , 2000, The Journal of Biological Chemistry.

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

[56]  Melanie Allen,et al.  Deficiency of the Stress Kinase P38α Results in Embryonic Lethality , 2000, The Journal of Experimental Medicine.

[57]  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.

[58]  K. Sakaguchi,et al.  Phosphorylation of human p53 by p38 kinase coordinates N‐terminal phosphorylation and apoptosis in response to UV radiation , 1999, The EMBO journal.

[59]  Z. Mao,et al.  Calcineurin Enhances MEF2 DNA Binding Activity in Calcium-dependent Survival of Cerebellar Granule Neurons* , 1999, The Journal of Biological Chemistry.

[60]  M. Roussel.  The INK4 family of cell cycle inhibitors in cancer , 1999, Oncogene.

[61]  I. Hoffmann,et al.  Ectopic Expression of Cdc25A Accelerates the G1/S Transition and Leads to Premature Activation of Cyclin E- and Cyclin A-Dependent Kinases , 1999, Molecular and Cellular Biology.

[62]  M. Lindsay,et al.  SB 203580, an inhibitor of p38 mitogen-activated protein kinase, enhances constitutive apoptosis of cytokine-deprived human eosinophils. , 1999, The Journal of pharmacology and experimental therapeutics.

[63]  A. Levine,et al.  P19(ARF) stabilizes p53 by blocking nucleo-cytoplasmic shuttling of Mdm2. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[64]  X. Wang,et al.  Association with Cdc2 and inhibition of Cdc2/Cyclin B1 kinase activity by the p53-regulated protein Gadd45 , 1999, Oncogene.

[65]  Charles J. Sherr,et al.  Nucleolar Arf sequesters Mdm2 and activates p53 , 1999, Nature Cell Biology.

[66]  Weiya Ma,et al.  p38 Kinase Mediates UV-induced Phosphorylation of p53 Protein at Serine 389* , 1999, The Journal of Biological Chemistry.

[67]  P. Russell,et al.  Nuclear localization of Cdc25 is regulated by DNA damage and a 14-3-3 protein , 1999, Nature.

[68]  A. Sparks,et al.  Identification of c-MYC as a target of the APC pathway. , 1998, Science.

[69]  D. Zechner,et al.  MKK6 Activates Myocardial Cell NF-κB and Inhibits Apoptosis in a p38 Mitogen-activated Protein Kinase-dependent Manner* , 1998, The Journal of Biological Chemistry.

[70]  K. Kinzler,et al.  14-3-3σ Is a p53-Regulated Inhibitor of G2/M Progression , 1997 .

[71]  K. Kinzler,et al.  14-3-3sigma is a p53-regulated inhibitor of G2/M progression. , 1997, Molecular cell.

[72]  J. Pouysségur,et al.  Cyclin D1 Expression Is Regulated Positively by the p42/p44MAPK and Negatively by the p38/HOGMAPK Pathway* , 1996, The Journal of Biological Chemistry.

[73]  P. Cohen,et al.  Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B , 1995, Nature.

[74]  Michael E. Greenberg,et al.  Opposing Effects of ERK and JNK-p38 MAP Kinases on Apoptosis , 1995, Science.

[75]  H Nojima,et al.  Cdc25A is a novel phosphatase functioning early in the cell cycle. , 1994, The EMBO journal.

[76]  J. Trent,et al.  WAF1, a potential mediator of p53 tumor suppression , 1993, Cell.