Mitogen-activated protein kinase phosphatase 1 is overexpressed in prostate cancers and is inversely related to apoptosis

Lab Invest. 1997 Jan;76(1):37-51.


Several oncogenes involved in prostate carcinogenesis activate mitogen-activated protein (MAP) kinases, which can relay both proliferative (via extracellular regulated kinases (ERK)) and apoptotic signals (via jun N-terminal protein kinases (JNK)) to the nucleus. Mitogen-activated protein kinase phosphatase 1 (MKP-1) is induced by several oncogenes in the ras-dependent pathway and can inactivate both MAP kinase pathways. The role of MKP-1 in proliferation and apoptosis is, however, still controversial. A series of 51 prostate cancers, including a subset (n = 13) that had been previously treated by androgen ablation, was used to examine whether MKP-1 mRNA and protein expression correlated with that of ERK-1, JNK-1, bcl-2, which confers resistance to apoptosis, and apoptotic index measured by in situ end-labeling of fragmented DNA. In a subset of tumors, MKP-1 expression was assessed by semiquantitative RT-PCR and was compared with both ERK-1 and JNK-1 enzymatic activity. In cases not treated by androgen ablation, MKP-1 was overexpressed in the preinvasive stage of prostate cancer, but its expression decreased with higher histologic grade and advanced disease stage. There was coexpression of MKP-1, ERK-1, and JNK-1 proteins. In addition, MKP-1 expression was inversely correlated to JNK-1 but not to ERK-1 enzymatic activity. Finally, MKP-1 and bcl-2 were inversely related to apoptotic indices. In cases treated by total androgen ablation, MKP-1 and bcl-2 were both down-regulated, whereas JNK-1 was up-regulated. Subpopulations of cells that did not undergo apoptosis maintained expression of both MKP-1 and bcl-2. These results suggest that MKP-1 overexpression is associated with the early phases of neoplastic transformation in prostate tissue. The enzymatic data on MKP-1 kinase substrates and the inverse correlation between MKP-1 and parameters of programmed cell death support the hypothesis that MKP-1 inhibits apoptosis in human prostate tumors, perhaps through the JNK pathway.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis*
  • Calcium-Calmodulin-Dependent Protein Kinases / biosynthesis
  • Cell Cycle Proteins*
  • Cell Division
  • Dual Specificity Phosphatase 1
  • Gene Expression
  • Humans
  • Immediate-Early Proteins / analysis
  • Immediate-Early Proteins / biosynthesis*
  • Immunohistochemistry
  • In Situ Hybridization
  • JNK Mitogen-Activated Protein Kinases
  • Male
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases*
  • Phosphoprotein Phosphatases*
  • Polymerase Chain Reaction
  • Prostate / cytology
  • Prostate / enzymology*
  • Prostate / pathology
  • Prostatic Hyperplasia / enzymology
  • Prostatic Hyperplasia / pathology
  • Prostatic Neoplasms / enzymology*
  • Prostatic Neoplasms / pathology*
  • Protein Phosphatase 1
  • Protein Tyrosine Phosphatases / analysis
  • Protein Tyrosine Phosphatases / biosynthesis*
  • RNA, Messenger / biosynthesis
  • Transcription, Genetic


  • Cell Cycle Proteins
  • Immediate-Early Proteins
  • RNA, Messenger
  • Calcium-Calmodulin-Dependent Protein Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • Phosphoprotein Phosphatases
  • Protein Phosphatase 1
  • DUSP1 protein, human
  • Dual Specificity Phosphatase 1
  • Protein Tyrosine Phosphatases