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, Philip Stork, M. Loda

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Abstract

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
Volume76
Issue number1
StatePublished - Jan 1997

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Mitogen-Activated Protein Kinase Phosphatases
Dual Specificity Phosphatase 1
Prostatic Neoplasms
Apoptosis
MAP Kinase Kinase 4
Prostate
Mitogen-Activated Protein Kinases
Androgens
MAP Kinase Kinase 1
ras Genes
MAP Kinase Signaling System
Extracellular Signal-Regulated MAP Kinases
Oncogenes

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Magi-Galluzzi, C., Mishra, R., Fiorentino, M., Montironi, R., Yao, H., Capodieci, P., ... Loda, M. (1997). Mitogen-activated protein kinase phosphatase 1 is overexpressed in prostate cancers and is inversely related to apoptosis. Laboratory Investigation, 76(1), 37-51.

Mitogen-activated protein kinase phosphatase 1 is overexpressed in prostate cancers and is inversely related to apoptosis. / Magi-Galluzzi, C.; Mishra, R.; Fiorentino, M.; Montironi, R.; Yao, H.; Capodieci, P.; Wishnow, K.; Kaplan, I.; Stork, Philip; Loda, M.

In: Laboratory Investigation, Vol. 76, No. 1, 01.1997, p. 37-51.

Research output: Contribution to journalArticle

Magi-Galluzzi, C, Mishra, R, Fiorentino, M, Montironi, R, Yao, H, Capodieci, P, Wishnow, K, Kaplan, I, Stork, P & Loda, M 1997, 'Mitogen-activated protein kinase phosphatase 1 is overexpressed in prostate cancers and is inversely related to apoptosis', Laboratory Investigation, vol. 76, no. 1, pp. 37-51.
Magi-Galluzzi C, Mishra R, Fiorentino M, Montironi R, Yao H, Capodieci P et al. Mitogen-activated protein kinase phosphatase 1 is overexpressed in prostate cancers and is inversely related to apoptosis. Laboratory Investigation. 1997 Jan;76(1):37-51.
Magi-Galluzzi, C. ; Mishra, R. ; Fiorentino, M. ; Montironi, R. ; Yao, H. ; Capodieci, P. ; Wishnow, K. ; Kaplan, I. ; Stork, Philip ; Loda, M. / Mitogen-activated protein kinase phosphatase 1 is overexpressed in prostate cancers and is inversely related to apoptosis. In: Laboratory Investigation. 1997 ; Vol. 76, No. 1. pp. 37-51.
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abstract = "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.",
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AU - Mishra, R.

AU - Fiorentino, M.

AU - Montironi, R.

AU - Yao, H.

AU - Capodieci, P.

AU - Wishnow, K.

AU - Kaplan, I.

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