RRC ID 2032
Author Furukawa T, Sunamura M, Motoi F, Matsuno S, Horii A.
Title Potential tumor suppressive pathway involving DUSP6/MKP-3 in pancreatic cancer.
Journal Am J Pathol
Abstract We previously found frequent loss of heterozygosity at 12q21 and 12q22-q23.1 in primary pancreatic cancers, and the DUSP6/MKP-3 gene residing in this region at 12q22 lost its expression in the great majority of pancreatic cancer cell lines. The DUSP6/MKP-3 protein is a dual-specificity phosphatase that dephosphorylates the active form of ERK, making a feedback loop to control ERK activity. Gain-of-function mutations of KRAS2 occur in the great majority of pancreatic cancer cells, and loss of expression of DUSP6/MKP-3 may synergistically promote constitutive activation of ERK and uncontrolled cell growth. To study loss of the feedback pathway and its impact on pancreatic cancer cell growth, we first investigated the expression of DUSP6/MKP-3 in primary pancreatic cancer tissues immunohistochemically; we found up-regulation in mildly as well as severely dysplastic/in situ carcinoma cells and down-regulation in invasive carcinoma, especially in the poorly differentiated type. Adenovirus-mediated reintroduction of DUSP6/MKP-3 into cultured pancreatic cancer cells induced strong expression of recombinant DUSP6/MKP-3 and reduction of phosphorylated ERK in a dose-dependent manner based on the multiplicity of infection and resulted in suppression of cell growth. Moreover, analyses by flow cytometry and immunocytochemistry revealed that the exogenous expression of DUSP6/MKP-3 induced apoptosis. These results show that DUSP6 exerts apparent tumor-suppressive effects in vitro and suggest that DUSP6 is a strong candidate tumor suppressor gene at 12q22 locus.
Volume 162(6)
Pages 1807-15
Published 2003-6-1
DOI 10.1016/S0002-9440(10)64315-5
PII S0002-9440(10)64315-5
PMID 12759238
PMC PMC1868131
MeSH Adenoviridae / genetics Apoptosis / genetics Cell Division / genetics Dual Specificity Phosphatase 6 Flow Cytometry Genes, Tumor Suppressor / physiology Genetic Vectors / genetics Humans Immunohistochemistry Mitogen-Activated Protein Kinases / metabolism Pancreatic Neoplasms / genetics Pancreatic Neoplasms / metabolism Pancreatic Neoplasms / pathology* Phosphorylation Protein Tyrosine Phosphatases / genetics Protein Tyrosine Phosphatases / metabolism* Signal Transduction Transfection Tumor Cells, Cultured
IF 3.491
Times Cited 163
DNA material pAxcw (RDB00917)