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0031-6997/08/6003-261-310$7.00
Pharmacol Rev 60:261-310, 2008

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Mitogen-Activated Protein (MAP) Kinase/MAP Kinase Phosphatase Regulation: Roles in Cell Growth, Death, and Cancer

Tarek Boutros, Eric Chevet and Peter Metrakos

Departments of Surgery (T.B., E.C., P.M.) and Anatomy and Cell Biology (T.B.), McGill University, Montreal, Quebec, Canada; Team Avenir, Institut National de la Santé et de la Recherche Médicale, U889, Bordeaux, France (E.C.); and Université Bordeaux 2, Bordeaux, France (E.C.)

Abstract
I. Introduction
II. Mitogen-Activated Protein Kinase Family: An Overview
    A. Ras-Raf-Mitogen-Activated Protein Kinase Kinase/Extracellular-Regulated Kinase Kinase Kinase-Extracellular-Regulated Kinase Interactions
    B. Extracellular-Regulated Kinases
    C. c-Jun NH2-Terminal Kinases
    D. p38 Mitogen-Activated Protein Kinases
    E. Mitogen-Activated Protein Kinase Cross-Talk
III. Regulation of Mitogen-Activated Protein Kinase Phosphatase-1 Expression and Activity
    A. mkp-1 Gene Structure, Promoter, and Enhancer
    B. mkp-1 mRNA
        1. Regulation of mkp-1 mRNA Expression Levels.
        2. mRNA Stability.
        3. De Novo Transcription.
        4. mRNA Elongation.
    C. Mitogen-Activated Protein Kinase Phosphatase-1 Protein Function and Affinity
        1. Regulation of Mitogen-Activated Protein Kinase Phosphatase-1 Protein Expression Levels.
        2. Protein Stability and De Novo Protein Synthesis.
        3. Protein Activity.
IV. Overview of the Dual-Specificity Phosphatase Family
V. Mitogen-Activated Protein Kinase Phosphatase-1, Animal Models, and Cancer
    A. mkp-1 Transgenic Mice
    B. mkp-1 Knockout Mice
        1. Phenotype.
        2. Immunological Consequences.
        3. Diet-Induced Obesity.
    C. Mitogen-Activated Protein Kinase and Cancer: An Overview
        1. Ras-Raf Cancer Connection.
        2. Extracellular-Regulated Kinases.
        3. c-Jun NH2-Terminal Kinases.
        4. p38 Mitogen-Activated Protein Kinases.
    D. Cancer-Related Mechanisms
        1. Apoptosis.
            a. Platinum.
            b. Deacetylation/demethylation.
            c. Glucocorticoids.
            d. Fas/Fas ligand.
            e. Mitogen-activated protein kinase phosphatase-1 and the proteasome.
            f. (Z)-1-[N-(2-Aminoethyl)-N-(2-ammonioethyl) amino]diazen-1-ium-1,2-diolate.
            g. Radiation.
        2. Antiapoptosis.
        3. Differentiation.
        4. Proliferation.
        5. Anchorage-Independent Growth.
        6. Metastasis.
        7. Hypoxia.
        8. Angiogenesis and Vasculogenesis.
VI. Mitogen-Activated Protein Kinase Phosphatase, Cancer in Humans, and Relevant Models
    A. Breast Cancer
    B. Gastrointestinal Cancers
        1. Colon Cancer.
        2. Gastric Cancer.
        3. Hepatocellular Carcinoma.
    C. Lung Cancer
    D. Urogenital Cancers
        1. Renal Cell Carcinomas.
        2. Bladder Cancer.
        3. Prostate Cancer.
        4. Uterine Leiomyoma Cells.
        5. Ovarian Carcinomas.
VII. Conclusion
Mitogen-activated protein kinase dual-specificity phosphatase-1 (also called MKP-1, DUSP1, ERP, CL100, HVH1, PTPN10, and 3CH134) is a member of the threonine-tyrosine dual-specificity phosphatases, one of more than 100 protein tyrosine phosphatases. It was first identified approximately 20 years ago, and since that time extensive investigations into both mkp-1 mRNA and protein regulation and function in different cells, tissues, and organs have been conducted. However, no general review on the topic of MKP-1 exists. As the subject matter pertaining to MKP-1 encompasses many branches of the biomedical field, we focus on the role of this protein in cancer development and progression, highlighting the potential role of the mitogen-activated protein kinase (MAPK) family. Section II of this article elucidates the MAPK family cross-talk. Section III reviews the structure of the mkp-1 encoding gene, and the known mechanisms regulating the expression and activity of the protein. Section IV is an overview of the MAPK-specific dual-specificity phosphatases and their role in cancer. In sections V and VI, mkp-1 mRNA and protein are examined in relation to cancer biology, therapeutics, and clinical studies, including a discussion of the potential role of the MAPK family. We conclude by proposing an integrated scheme for MKP-1 and MAPK in cancer.

Address correspondence to: Tarek Boutros, Department of Surgery, Royal Victoria Hospital, McGill University, 687 Pine Ave. W., Montreal, QC, Canada H3A 1A1. E-mail: tarek.boutros{at}mail.mcgill.ca






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