Expression of mitogen-activated protein kinase phosphatase-1 in the early phases of human epithelial carcinogenesis.

TitleExpression of mitogen-activated protein kinase phosphatase-1 in the early phases of human epithelial carcinogenesis.
Publication TypeJournal Article
Year of Publication1996
AuthorsLoda M, Capodieci P, Mishra R, Yao H, Corless C, Grigioni W, Wang Y, Magi-Galluzzi C, Stork PJ
JournalAm J Pathol
Date Published1996 Nov
KeywordsBiomarkers, Tumor, Calcium-Calmodulin-Dependent Protein Kinases, Carcinoma, Cell Cycle Proteins, Dual Specificity Phosphatase 1, Epithelium, Humans, Immediate-Early Proteins, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Mitogen-Activated Protein Kinases, Phosphoprotein Phosphatases, Protein Phosphatase 1, Protein Tyrosine Phosphatases, Protein-Tyrosine Kinases

Many mitogens and human oncogenes activate extracellular regulated kinases (ERKs), which in turn convey proliferation signals. ERKs or mitogen-activated protein (MAP) kinases are inactivated in vitro by MAP kinase phosphatases (MKPs). The gene encoding one of these MKPs, MKP-1, is a serum-inducible gene and is transcriptionally activated by mitogenic signals in cultured cells. As MKP-1 has been shown to block DNA synthesis by inhibiting ERKs when expressed at elevated levels in cultured cells, it has been suggested that it may act as a tumor suppressor. MKP-1 mRNA and MAP kinase (ERK-1 and -2) protein expression was assessed in 164 human epithelial tumors of diverse tissue origin by in situ hybridization and immunohistochemistry. MKP-1 was overexpressed in the early phases of prostate, colon, and bladder carcinogenesis, with progressive loss of expression with higher histological grade and in metastases. In contrast, breast carcinomas showed significant MKP-1 expression even when poorly differentiated or in late stages of the disease. MKP-1, ERK-1, and ERK-2 were co-expressed in most tumors examined. In a subset of 15 tumors, ERK-1 enzymatic activity as well as structural alterations that might be responsible for loss of function of MKP-1 during tumor progression, were examined. ERK-1 enzymatic activity was found to be elevated despite MKP-1 overexpression. No loss of 5q35-ter (containing the MKP-1 locus) was detected by polymerase chain reaction in metastases compared with primary tumors. Finally, no mutations were found in the catalytic domain of MKP-1. These data indicate that MKP-1 is an early marker for a wide range of human epithelial tumors and suggest that MKP-1 does not behave as a tumor suppressor in epithelial tumors.

Alternate JournalAm J Pathol
PubMed ID8909245
PubMed Central IDPMC1865259
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