Mitogen-activated protein kinase phosphatase 1 is overexpressed in prostate cancers and is inversely related to apoptosis.
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.
Magi-Galluzzi
C
C
Department of Pathology, Deaconess Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA.
Mishra
R
R
Fiorentino
M
M
Montironi
R
R
Yao
H
H
Capodieci
P
P
Wishnow
K
K
Kaplan
I
I
Stork
P J
PJ
Loda
M
M
D017209:Apoptosis; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000096:biosynthesis; D018797:Cell Cycle Proteins; D002455:Cell Division; D054638:Dual Specificity Phosphatase 1; D015870:Gene Expression; D006801:Humans; D017874:Immediate-Early Proteins / Q000032:analysis / Q000096:biosynthesis*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D048031:JNK Mitogen-Activated Protein Kinases; D008297:Male; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D010749:Phosphoprotein Phosphatases; D016133:Polymerase Chain Reaction; D011467:Prostate / Q000166:cytology / Q000201:enzymology* / Q000473:pathology; D011470:Prostatic Hyperplasia / Q000201:enzymology / Q000473:pathology; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000473:pathology*; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000032:analysis / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000096:biosynthesis; D014158:Transcription, Genetic
D018797:Cell Cycle Proteins; D017874:Immediate-Early Proteins; D012333:RNA, Messenger; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1; D017027:Protein Tyrosine Phosphatases