Overexpression of mitogen-activated protein kinase phosphatases MKP1, MKP2 in human breast cancer.
Expression and activity of c-Jun N-terminal and p38 protein kinases were explored in malignant and non-malignant tissue samples from patients with primary breast cancer. Differential expression was observed for p38 and c-Jun N-terminal protein kinases (JNK) in samples from 14 patients in whom there were sufficient malignant and non-malignant tissue to perform the entire assays. As previously noted, Erk1,2 expression and activity were increased sharply in the malignant tissue. The p38 kinase expression and activity were increased 3-fold in breast cancer. The expression of c-Jun N-terminal protein kinase JNK1, but not JNK2, was increased 2.5-fold in malignant as compared to normal breast tissue. Immunohistochemical analysis in situ with antibodies to JNK1 revealed intense staining in samples of cancerous epithelium. In spite of a 3-fold increase in expression, malignant samples displayed a 35% decrease in the activity of this pro-apoptotic protein kinase. The expression of mitogen and extracellularly-activated protein kinase kinase (MEK)2 and MEK3, upstream protein kinases of Erkl,2 and p38, respectively, was elevated 4- to 5-fold. The upstream regulator of JNK (e.g., MEK4), however, displayed normal levels of expression, providing no basis for the reduction in JNK activity observed for breast cancer. Mitogen-activated protein kinase phosphatases (MKP)1 and MKP2 were assayed and the expression was found to be increased 5-fold and 3-fold, respectively, in malignant as compared to non-malignant samples. The reduced activity of JNK1, in spite of its overexpression, appears to reflect increased MKP activity associated with primary breast cancer. Suppression of MKP activity therapeutically may enable the expression of the pro-apoptotic signals from JNK in malignant cells.
Wang
Hsien-yu
HY
Department of Physiology & Biophysics, University Medical Center, SUNY/Stony Brook, Stony Brook, NY 11794-8661, USA. wancih@pharm.sunysb.edu
Cheng
Zhiyong
Z
Malbon
Craig C
CC
D000328:Adult; D017209:Apoptosis; D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology; D018797:Cell Cycle Proteins; D054638:Dual Specificity Phosphatase 1; D054637:Dual-Specificity Phosphatases; D005260:Female; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism*; D015151:Immunoblotting; D048031:JNK Mitogen-Activated Protein Kinases; D020935:MAP Kinase Signaling System; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D054639:Mitogen-Activated Protein Kinase Phosphatases; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010749:Phosphoprotein Phosphatases; D010766:Phosphorylation; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases
D018797:Cell Cycle Proteins; D017874:Immediate-Early Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D054639:Mitogen-Activated Protein Kinase Phosphatases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; C517019:DUSP1 protein, human; C490583:DUSP4 protein, human; D054638:Dual Specificity Phosphatase 1; D054637:Dual-Specificity Phosphatases; D017027:Protein Tyrosine Phosphatases