Human mitogen-activated protein kinase kinase 4 as a candidate tumor suppressor.
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.
Teng
D H
DH
Myriad Genetics, Inc., Salt Lake City, Utah 84108, USA. tengd@myriad.com
Perry
W L
WL
Hogan
J K
JK
Baumgard
M
M
Bell
R
R
Berry
S
S
Davis
T
T
Frank
D
D
Frye
C
C
Hattier
T
T
Hu
R
R
Jammulapati
S
S
Janecki
T
T
Leavitt
A
A
Mitchell
J T
JT
Pero
R
R
Sexton
D
D
Schroeder
M
M
Su
P H
PH
Swedlund
B
B
Kyriakis
J M
JM
Avruch
J
J
Bartel
P
P
Wong
A K
AK
Tavtigian
S V
SV
D004273:DNA, Neoplasm / Q000235:genetics; D016147:Genes, Tumor Suppressor; D005838:Genotype; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D009363:Neoplasm Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D017384:Sequence Deletion; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D004273:DNA, Neoplasm; D006360:Heat-Shock Proteins; D009363:Neoplasm Proteins; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D048670:MAP Kinase Kinase 4; C482559:MAP2K4 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases