ArticleGynecologic oncology2007
Regulation of the metastasis suppressor gene MKK4 in ovarian cancer.
Article in Gynecologic oncology, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers, 1 of them a synthesis that pooled it.
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Who cites it
15 citing papers in PubMed, 1 synthesis or guideline pooled it, 24 citations in OpenAlex.
- Pooled it
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- Metastasis suppressor genes in clinical practice: are they druggable?Cancer metastasis reviews · 2023Review
- Article
- Downregulation of phosphorylated MKK4 is associated with a poor prognosis in colorectal cancer patients.Oncotarget · 2017Article
- MAP3K1: Genomic Alterations in Cancer and Function in Promoting Cell Survival or Apoptosis.Genes & cancer · 2013Article
- Proteomic analysis of energy metabolism and signal transduction in irradiated melanoma cells.International journal of ophthalmology · 2013Article
- Delayed cell cycle progression in selenoprotein W-depleted cells is regulated by a mitogen-activated protein kinase kinase 4-p38/c-Jun NH2-terminal kinase-p53 pathway.The Journal of biological chemistry · 2012Article
- The association between -1304T>G polymorphism in the promoter of mitogen-activated protein kinase kinase 4 gene and the risk of cervical cancer in Chinese population.DNA and cell biology · 2012Article
- Activation of a PAK-MEK signalling pathway in malaria parasite-infected erythrocytes.Cellular microbiology · 2011Article
- Analysis of the mitogen-activated protein kinase kinase 4 (MAP2K4) tumor suppressor gene in ovarian cancer.BMC cancer · 2011Article
- Mapping of genetic abnormalities of primary tumours from metastatic CRC by high-resolution SNP arrays.PloS one · 2010Article
- A conditionally replicative adenovirus, CRAd-S-pK7, can target endometriosis with a cell-killing effect.Human reproduction (Oxford, England) · 2010Article
- Aberrant promoter methylation of SPARC in ovarian cancer.Neoplasia (New York, N.Y.) · 2009Article
- Mitogen-activated protein kinase kinase 4/c-Jun NH2-terminal kinase kinase 1 protein expression is subject to translational regulation in prostate cancer cell lines.Molecular cancer research : MCR · 2008Article
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
objectivesMKK4 is a metastasis suppressor that is downregulated in some ovarian cancers. We sought to investigate whether promoter methylation, loss of heterozygosity, or changes in phosphorylation are involved in MKK4 dysregulation during ovarian carcinogenesis.
methodsBisulfite sequencing was used to determine MKK4 promoter methylation. PCR analysis of tumor/normal DNA was performed to determine LOH at the MKK4 locus. Normal human ovarian surface epithelium (HOSE) and SKOV-3 cells were serum starved and treated with EGF, TGFbeta, or wortmannin. Western blotting was performed using antibodies that detect total and phosphorylated MKK4.
resultsNo MKK4 promoter hypermethylation was detected in 21 ovarian cancers. LOH was detected at the MKK4 intragenic marker D17S969 in 35% of cases and at D17S1303 in 20%. MKK4 protein was detected in 97% of ovarian tumors. The inactivated phosphoserine 80 (ser-80) form comprised 62% of phosphorylated MKK4 protein in ovarian tumors. Treatment of HOSE or SKOV-3 cells with EGF induced a 1.7- to 4.2-fold increase in phosphorylation of ser-80 MKK4 without altering total MKK4 protein. TGFbeta increased MKK4 ser-80 phosphorylation by 5.4-fold above baseline. The PI3K/Akt pathway inhibitor wortmannin decreased the amount of ser-80 MKK4 by 50%, and inhibited EGF stimulation of MKK4 ser-80 phosphorylation by 60%.
conclusionsLOH of MKK4 occurs in some ovarian cancers, but without loss of MKK4 protein. MKK4 expression does not appear to be downregulated by promoter methylation. Peptide growth factors induce MKK4 ser-80 phosphorylation, which downregulates its activity. PI3K/Akt pathway inhibitors can partially block ser-80 phosphorylation and this may have therapeutic implications.
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