| RRC ID |
2032
|
| 著者 |
Furukawa T, Sunamura M, Motoi F, Matsuno S, Horii A.
|
| タイトル |
Potential tumor suppressive pathway involving DUSP6/MKP-3 in pancreatic cancer.
|
| ジャーナル |
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.
|
| 巻・号 |
162(6)
|
| ページ |
1807-15
|
| 公開日 |
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
|
| 引用数 |
163
|
|
WOS 分野
|
PATHOLOGY
|
| リソース情報 |
| 遺伝子材料 |
pAxcw (RDB00917) |
