p38α: A Suppressor of Cell Proliferation and Tumorigenesis

The mitogen-activated protein kinase (MAPK) p38! is involved in numerous biological processes and is a drug target for inflammation-associated diseases. Genetic analysis in mice demonstrated that fetuses lacking p38! are embryonic lethal owing to impaired placental development. The function of p38! in mice after birth remained unclear until conditional alleles of p38α were used. It was found that p38α is essential for lung functionin both neonatal and adult mice. Increased proliferation and impaired differentiation are the hallmarks of p38α-deficient cells. Moreover, mice deficient in p38α are prone to cancerdevelopment using carcinogen or oncogene-induced cancer models. p38α can suppress cell proliferation by antagonizing the JNK/c-Jun pathway, which is an important regulator of proliferation and apoptosis. These findings suggest that therapeutic inhibition of p38 might lead to unwanted proliferation. Therefore, a combined inhibition of p38 and other pathways, such as the JNK pathway, should be considered for targeting cancer inflammation.

[1]  A. Cuenda,et al.  p38 MAP-kinases pathway regulation, function and role in human diseases. , 2007, Biochimica et biophysica acta.

[2]  Michael Karin,et al.  References and Notes Supporting Online Material Materials and Methods Som Text Figs. S1 to S6 Tables S1 to S4 Gender Disparity in Liver Cancer Due to Sex Differences in Myd88-dependent Il-6 Production , 2022 .

[3]  Wancai Yang,et al.  c-Jun NH2-terminal kinase 1 plays a critical role in intestinal homeostasis and tumor suppression. , 2007, The American journal of pathology.

[4]  P. Muñoz-Cánoves,et al.  Genetic Deficiency of p38α Reveals its Critical Role in Myoblast Cell Cycle Exit:The p38α-JNK Connection , 2007 .

[5]  M. Barbacid,et al.  p38α MAP kinase is essential in lung stem and progenitor cell proliferation and differentiation , 2007, Nature Genetics.

[6]  G. Johnson,et al.  MAPKs: function, regulation, role in cancer and therapeutic targeting , 2007, Oncogene.

[7]  Christian Haslinger,et al.  p38α suppresses normal and cancer cell proliferation by antagonizing the JNK–c-Jun pathway , 2007, Nature Genetics.

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

[9]  Gabriella De Vita,et al.  p38α MAP Kinase as a Sensor of Reactive Oxygen Species in Tumorigenesis , 2007 .

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

[11]  P. Muñoz-Cánoves,et al.  Genetic deficiency of p38alpha reveals its critical role in myoblast cell cycle exit: the p38alpha-JNK connection. , 2007, Cell cycle.

[12]  A. Cuadrado,et al.  p38alpha MAP kinase as a sensor of reactive oxygen species in tumorigenesis. , 2007, Cancer cell.

[13]  M. Barbacid,et al.  p38alpha MAP kinase is essential in lung stem and progenitor cell proliferation and differentiation. , 2007, Nature genetics.

[14]  Rebecca S. Dise,et al.  p38 kinase regulates epidermal growth factor receptor downregulation and cellular migration , 2006, The EMBO journal.

[15]  Y. Yarden,et al.  p38 MAP kinase mediates stress‐induced internalization of EGFR: implications for cancer chemotherapy , 2006, The EMBO journal.

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

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

[18]  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.

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

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

[21]  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.

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

[23]  J. Olson,et al.  p38 MAP kinase: a convergence point in cancer therapy. , 2004, Trends in molecular medicine.

[24]  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.

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

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

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

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

[29]  E. Wagner,et al.  c-Jun regulates eyelid closure and skin tumor development through EGFR signaling. , 2003, Developmental cell.

[30]  Jiahuai Han,et al.  Mitogen‐activated protein kinase p38 defines the common senescence‐signalling pathway , 2003, Genes to cells : devoted to molecular & cellular mechanisms.

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

[32]  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.

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

[34]  A. Bode,et al.  Deficiency of c-Jun-NH(2)-terminal kinase-1 in mice enhances skin tumor development by 12-O-tetradecanoylphorbol-13-acetate. , 2002, Cancer research.

[35]  Weiya Ma,et al.  Suppression of skin tumorigenesis in c-Jun NH(2)-terminal kinase-2-deficient mice. , 2001, Cancer research.

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

[37]  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.

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

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

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

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

[42]  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.

[43]  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.

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