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

C. Magi-Galluzzi, R. Mishra, M. Fiorentino, R. Montironi, H. Yao, P. Capodieci, K. Wishnow, I. Kaplan, P. J.S. Stork, M. Loda

Research output: Contribution to journalArticlepeer-review

155 Scopus citations


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 endrogen 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.

Original languageEnglish (US)
Pages (from-to)37-51
Number of pages15
JournalLaboratory Investigation
Issue number1
StatePublished - Jan 1 1997

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Molecular Biology
  • Cell Biology


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