Cancer Research Infection and Cancer: Biology, Therapeutics, and Prevention Susan G. Komen for the Cure-AACR Outstanding Investigator Award for Breast Cancer Research
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[Cancer Research 57, 4177-4182, October 1, 1997]
© 1997 American Association for Cancer Research
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Human Mitogen-activated Protein Kinase Kinase 4 as a Candidate Tumor Suppressor

David H-F. Teng1,2,, William L. Perry, III1, James K. Hogan, Michelle Baumgard, Russell Bell, Simin Berry, Thaylon Davis, David Frank, Cheryl Frye, Thomas Hattier, Rong Hu, Srikanth Jammulapati, Teresa Janecki, Amber Leavitt, Jeffrey T. Mitchell, Ralph Pero, David Sexton, Marianne Schroeder, Pi-Hsia Su, Brad Swedlund, John M. Kyriakis, Joseph Avruch, Paul Bartel, Alexander K. C. Wong, Arnold Oliphant, Alun Thomas, Mark H. Skolnick and Sean V. Tavtigian

Myriad Genetics, Inc., Salt Lake City, Utah 84108 [D. H-F. T., W. L. P., M. B., R. B., S. B., T. D., D. F., C. F., T. H., R. H., S. J., T. J., A. L., J. T. M., R. P., D. S., M. S., P-H. S., B. S., P. B., A. K. C. W., A. O., A. T., M. H. S., S. V. T.], and Department of Medicine, Massachusetts General Hospital, Diabetes Unit and Medical Services, and Harvard Medical School, Boston Massachusetts 02129 [J. K. H., J. M. K., J. A.]

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 (~3%). These findings suggest that MKK4 may function as a suppressor of tumorigenesis or metastasis in certain types of cells.

1 These authors are equal contributors.

2 To whom requests for reprints should be addressed, at Myriad Genetic, Inc., 390 Wakara Way, Salt Lake City, UT 84108. Phone: (801) 584-3676; Fax: (801) 584-3650; E-mail: tengd@myriad.com.

Received 7/ 7/97. Accepted 8/13/97.




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Copyright © 1997 by the American Association for Cancer Research.