p38α suppresses normal and cancer cell proliferation by antagonizing the JNK–c-Jun pathway

The mitogen-activated protein kinase (MAPK) p38α controls inflammatory responses and cell proliferation. Using mice carrying conditional Mapk14 (also known as p38α) alleles, we investigated its function in postnatal development and tumorigenesis. When we specifically deleted Mapk14 in the mouse embryo, fetuses developed to term but died shortly after birth, probably owing to lung dysfunction. Fetal hematopoietic cells and embryonic fibroblasts deficient in p38α showed increased proliferation resulting from sustained activation of the c-Jun N-terminal kinase (JNK)–c-Jun pathway. Notably, in chemical-induced liver cancer development, mice with liver-specific deletion of Mapk14 showed enhanced hepatocyte proliferation and tumor development that correlated with upregulation of the JNK–c-Jun pathway. Furthermore, inactivation of JNK or c-Jun suppressed the increased proliferation of Mapk14-deficient hepatocytes and tumor cells. These results demonstrate a new mechanism whereby p38α negatively regulates cell proliferation by antagonizing the JNK–c-Jun pathway in multiple cell types and in liver cancer development.

[1]  Chao Zhang,et al.  JNK2 is a positive regulator of the cJun transcription factor. , 2006, Molecular cell.

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

[3]  Michael Karin,et al.  IKKβ Couples Hepatocyte Death to Cytokine-Driven Compensatory Proliferation that Promotes Chemical Hepatocarcinogenesis , 2005, Cell.

[4]  E. Wagner,et al.  Amino-terminal phosphorylation of c-Jun regulates stress-induced apoptosis and cellular proliferation , 1999, Nature Genetics.

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

[6]  J. Pollack,et al.  c-Jun N-terminal kinase is activated in non-small-cell lung cancer and promotes neoplastic transformation in human bronchial epithelial cells , 2007, Oncogene.

[7]  A. Vercelli,et al.  A peptide inhibitor of c-Jun N-terminal kinase protects against excitotoxicity and cerebral ischemia , 2003, Nature Medicine.

[8]  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.

[9]  L. Glimcher,et al.  Mouse ATF-2 Null Mutants Display Features of a Severe Type of Meconium Aspiration Syndrome* , 1999, The Journal of Biological Chemistry.

[10]  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.

[11]  T. Pawson,et al.  HPK1, a hematopoietic protein kinase activating the SAPK/JNK pathway. , 1996, The EMBO journal.

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

[13]  J. Kyriakis.  Faculty Opinions recommendation of Genetic analysis of p38 MAP kinases in myogenesis: fundamental role of p38alpha in abrogating myoblast proliferation. , 2007 .

[14]  Michael Karin,et al.  Reactive Oxygen Species Promote TNFα-Induced Death and Sustained JNK Activation by Inhibiting MAP Kinase Phosphatases , 2005, Cell.

[15]  Shuang Huang,et al.  Sequential Activation of the MEK-Extracellular Signal-Regulated Kinase and MKK3/6-p38 Mitogen-Activated Protein Kinase Pathways Mediates Oncogenic ras-Induced Premature Senescence , 2002, Molecular and Cellular Biology.

[16]  E. Wagner,et al.  Distinct roles for JNK1 and JNK2 in regulating JNK activity and c-Jun-dependent cell proliferation. , 2004, Molecular cell.

[17]  E. Wagner,et al.  MKK7 couples stress signalling to G2/M cell-cycle progression and cellular senescence , 2004, Nature Cell Biology.

[18]  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.

[19]  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.

[20]  V. Nizet,et al.  Innate Immunity Gone Awry: Linking Microbial Infections to Chronic Inflammation and Cancer , 2006, Cell.

[21]  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.

[22]  M. Karin,et al.  Loss of hepatic NF-kappa B activity enhances chemical hepatocarcinogenesis through sustained c-Jun N-terminal kinase 1 activation. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[23]  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.

[24]  M. Karin,et al.  Mammalian MAP kinase signalling cascades , 2001, Nature.

[25]  J. Yates,et al.  PRAK Is Essential for ras-Induced Senescence and Tumor Suppression , 2007, Cell.

[26]  A. Fornace,et al.  p38 MAP kinase's emerging role as a tumor suppressor. , 2004, Advances in cancer research.

[27]  R. Schwabe,et al.  c‐Jun‐N‐terminal kinase drives cyclin D1 expression and proliferation during liver regeneration , 2003, Hepatology.

[28]  C. Kellendonk,et al.  Hepatocyte‐specific expression of Cre recombinase , 2000, Genesis.

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

[30]  G. Sumara,et al.  c-Jun/AP-1 controls liver regeneration by repressing p53/p21 and p38 MAPK activity. , 2006, Genes & development.

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

[32]  E. Bossy‐Wetzel,et al.  Cell cycle‐dependent variations in c‐Jun and JunB phosphorylation: a role in the control of cyclin D1 expression , 2000, The EMBO journal.

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

[34]  P. Ling,et al.  Leukocyte-specific adaptor protein Grap2 interacts with hematopoietic progenitor kinase 1 (HPK1) to activate JNK signaling pathway in T lymphocytes , 2001, Oncogene.

[35]  E. Wagner,et al.  Control of cell cycle progression by c-Jun is p53 dependent. , 1999, Genes & development.

[36]  E. Wagner,et al.  Differential effects of JNK1 and JNK2 on signal specific induction of apoptosis , 2002, Oncogene.

[37]  M Aguet,et al.  Inducible gene targeting in mice , 1995, Science.

[38]  J. D. Di Santo,et al.  c-Jun NH2-terminal kinase/c-Jun signaling promotes survival and metastasis of B lymphocytes transformed by Theileria. , 2006, Cancer research.

[39]  J. Ihle.  The Challenges of Translating Knockout Phenotypes into Gene Function , 2000, Cell.

[40]  E. Wagner,et al.  Genetic analysis of p38 MAP kinases in myogenesis: fundamental role of p38α in abrogating myoblast proliferation , 2007, The EMBO journal.

[41]  E. Wagner,et al.  Liver Tumor Development c-Jun Antagonizes the Proapoptotic Activity of p53 , 2003, Cell.

[42]  Francesca Zazzeroni,et al.  Gadd45β mediates the NF-κB suppression of JNK signalling by targeting MKK7/JNKK2 , 2004, Nature Cell Biology.

[43]  Wei-Jen Tang,et al.  Gadd45 beta mediates the NF-kappa B suppression of JNK signalling by targeting MKK7/JNKK2. , 2004, Nature cell biology.

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

[45]  Yibin Wang,et al.  p38 MAP kinase inhibition enables proliferation of adult mammalian cardiomyocytes. , 2005, Genes & development.

[46]  H. Beug,et al.  Leukemic transformation of normal murine erythroid progenitors: v- and c-ErbB act through signaling pathways activated by the EpoR and c-Kit in stress erythropoiesis , 2001, Oncogene.