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Human mitogen-activated protein kinase kinase 4 as a candidate tumor suppressor
D H Teng1, W L Perry, J K Hogan
1Myriad Genetics, Inc., Salt Lake City, Utah 84108, USA. tengd@myriad.com
Abstract:
Mitogen-activated protein kinases function in signal transduction pathways that are involved in controlling key cellular processes in many organisms. A mammalian member of this kinase family, MKK4/JNKK1/SEK1, has been reported to link upstream MEKK1 to downstream stress-activated protein kinase/JNK1 and p38 mitogen-activated protein kinase. This mitogen-activated protein kinase pathway has been implicated in the signal transduction of cytokine- and stress-induced apoptosis in a variety of cell types. Here, we report that two human tumor cell lines, derived from pancreatic carcinoma and lung carcinoma, harbor homozygous deletions that eliminate coding portions of the MKK4 locus at 17p, located approximately 10 cM centromeric of p53. In addition, in a set of 88 human cancer cell lines prescreened for loss of heterozygosity, we detected two nonsense and three missense sequence variants of MKK4 in cancer cell lines derived from human pancreatic, breast, colon, and testis cells. In vitro biochemical assays revealed that, when stimulated by MEKK1, four of the five altered MKK4 proteins lacked the ability to phosphorylate stress-activated protein kinase. Thus, the incidence of coding mutations of MKK4 in the set of cell lines is 6 of 213 (approximately 3%). These findings suggest that MKK4 may function as a suppressor of tumorigenesis or metastasis in certain types of cells.
Insights
Mutations in the MKK4 gene, crucial for cell signaling, were found in approximately 3% of human cancer cell lines. These MKK4 alterations may indicate its role in suppressing tumor growth and metastasis.
Area of Science:
- Molecular Biology
- Cell Biology
- Oncology
Background:
- Mitogen-activated protein kinases (MAPK) are key regulators of cellular processes.
- The MKK4 (MAPK kinase 4) pathway is involved in stress- and cytokine-induced apoptosis.
- MKK4 links upstream MEKK1 to downstream stress-activated protein kinase (SAPK)/JNK1 and p38 MAPK.
Purpose of the Study:
- To investigate the role of MKK4 in human cancers.
- To identify mutations and deletions in the MKK4 gene in various cancer cell lines.
Main Methods:
- Analysis of human tumor cell lines for homozygous deletions in the MKK4 locus.
- Screening of cancer cell lines for MKK4 sequence variants (nonsense and missense mutations).
- In vitro biochemical assays to assess the functionality of altered MKK4 proteins.
Main Results:
- Homozygous deletions of MKK4 were identified in pancreatic and lung carcinoma cell lines.
- Five MKK4 sequence variants (2 nonsense, 3 missense) were found in 88 human cancer cell lines.
- Approximately 3% of analyzed cell lines (6 of 213) showed MKK4 coding mutations.
- Four of five altered MKK4 proteins were non-functional in phosphorylating stress-activated protein kinase when stimulated by MEKK1.
Conclusions:
- MKK4 alterations are present in a subset of human cancers.
- Functional MKK4 mutations suggest a potential role as a tumor suppressor.
- MKK4 may inhibit tumorigenesis and metastasis in specific cell types.