This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kim, H. L. Articles by Rinker-Schaeffer, C. W. Search for Related Content PubMed PubMed Citation Articles by Kim, H. L. Articles by Rinker-Schaeffer, C. W.

Mitogen-activated Protein Kinase Kinase 4 Metastasis Suppressor Gene Expression Is Inversely Related to Histological Pattern in Advancing Human Prostatic Cancers¹

Section of Urology, Department of Surgery [H. L. K., D. J. V. G., X. Y., D. A. B., Z. D., B. A. Y., M. A. C., M. H. S., A. L., W. M. S., C. W. R-S.], Department of Health Studies [P. Z., T. K.], Department of Pathology [X. Y.], Section of Hematology/Oncology, Department of Medicine [W. M. S., C. W. R.-S.], The Ben May Institute for Cancer Research [A. L.], and The Genitourinary Oncology Research Program, The University of Chicago Comprehensive Cancer Research Center [X. Y., M. H. S., T. K., W. M. S., A. L., C. W. R-S.], The University of Chicago, Chicago, Illinois 60637; Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109 [M. A. R.]; and Department of Urology, Chiba University School of Medicine, Chiba, 263-8522 Japan [Y. I., T. I.]

We have shown recently (B. A. Yoshida et al., Cancer Res., 59: 5483–5487) that mitogen-activated protein kinase kinase 4 (MKK4) can suppress AT6.1 rat prostate cancer metastases in vivo. Evaluation of the expression of components of the MKK4 signaling cascade showed a loss or down-regulation of expression of MKK4 or c-Jun, a downstream mediator of MKK4, in six of eight human prostate cancer cell lines. Given these findings, we next assessed whether MKK4 dysregulation occurs during the development of clinical prostate cancer. Immunohistochemical studies showed high levels of MKK4 expression in the epithelial but not the stromal compartment of normal prostatic tissues. In neoplastic tissues, a statistically significant, direct, inverse relationship between Gleason pattern and MKK4 was established. These results demonstrate that MKK4 protein is consistently down-regulated during prostate cancer progression and support a role for dysregulation of its signaling cascade in clinical disease. To test the possibility that down-regulation of MKK4 protein is the result of allelic loss, metastatic prostate cancer lesions were examined for loss of heterozygosity (LOH) within the MKK4 locus (D17S969). These studies showed a 31% (5 of 16) LOH of MKK4 that is not associated with coding region mutations, which suggests that the nucleotide sequence of the gene in the remaining allele is infrequently mutated.

This article has been cited by other articles:

				V. L. Robinson, O. Shalhav, K. Otto, T. Kawai, M. Gorospe, and C. W. Rinker-Schaeffer 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 Mol. Cancer Res., March 1, 2008; 6(3): 501 - 508. [Abstract] [Full Text] [PDF]

				M. Milstein, C. K. Mooser, H. Hu, M. Fejzo, D. Slamon, L. Goodglick, S. Dry, and J. Colicelli RIN1 Is a Breast Tumor Suppressor Gene Cancer Res., December 15, 2007; 67(24): 11510 - 11516. [Abstract] [Full Text] [PDF]

				G. Sethi, K. S. Ahn, D. Xia, J. M. Kurie, and B. B. Aggarwal Targeted Deletion of MKK4 Gene Potentiates TNF-Induced Apoptosis through the Down-Regulation of NF-{kappa}B Activation and NF-{kappa}B-Regulated Antiapoptotic Gene Products J. Immunol., August 1, 2007; 179(3): 1926 - 1933. [Abstract] [Full Text] [PDF]

				C. Nielsen, J. Thastrup, T. Bottzauw, M. Jaattela, and T. Kallunki c-Jun NH2-Terminal Kinase 2 Is Required for Ras Transformation Independently of Activator Protein 1 Cancer Res., January 1, 2007; 67(1): 178 - 185. [Abstract] [Full Text] [PDF]

				S.-Y. Wang, M. Iordanov, and Q. Zhang c-Jun NH2-terminal Kinase Promotes Apoptosis by Down-regulating the Transcriptional Co-repressor CtBP J. Biol. Chem., November 17, 2006; 281(46): 34810 - 34815. [Abstract] [Full Text] [PDF]

				D. Gioeli, B. E. Black, V. Gordon, A. Spencer, C. T. Kesler, S. T. Eblen, B. M. Paschal, and M. J. Weber Stress Kinase Signaling Regulates Androgen Receptor Phosphorylation, Transcription, and Localization Mol. Endocrinol., March 1, 2006; 20(3): 503 - 515. [Abstract] [Full Text] [PDF]

				J. A. Hickson, D. Huo, D. J. Vander Griend, A. Lin, C. W. Rinker-Schaeffer, and S. D. Yamada The p38 Kinases MKK4 and MKK6 Suppress Metastatic Colonization in Human Ovarian Carcinoma Cancer Res., February 15, 2006; 66(4): 2264 - 2270. [Abstract] [Full Text] [PDF]

				D. J. Vander Griend, M. Kocherginsky, J. A. Hickson, W. M. Stadler, A. Lin, and C. W. Rinker-Schaeffer Suppression of Metastatic Colonization by the Context-Dependent Activation of the c-Jun NH2-Terminal Kinase Kinases JNKK1/MKK4 and MKK7 Cancer Res., December 1, 2005; 65(23): 10984 - 10991. [Abstract] [Full Text] [PDF]

				M. Uhlirova, H. Jasper, and D. Bohmann Non-cell-autonomous induction of tissue overgrowth by JNK/Ras cooperation in a Drosophila tumor model PNAS, September 13, 2005; 102(37): 13123 - 13128. [Abstract] [Full Text] [PDF]

				N Nathoo, A Chahlavi, G H Barnett, and S A Toms Pathobiology of brain metastases J. Clin. Pathol., March 1, 2005; 58(3): 237 - 242. [Abstract] [Full Text] [PDF]

				W. M. Stadler, D. Cao, N. J. Vogelzang, C. W. Ryan, K. Hoving, R. Wright, T. Karrison, and E. E. Vokes A Randomized Phase II Trial of the Antiangiogenic Agent SU5416 in Hormone-Refractory Prostate Cancer Clin. Cancer Res., May 15, 2004; 10(10): 3365 - 3370. [Abstract] [Full Text] [PDF]

				D. J. V. Griend, J. C. Berger, and C. W. Rinker-Schaeffer Suppression of Metastasis--A New Function for Known Proteins J Natl Cancer Inst, March 3, 2004; 96(5): 344 - 345. [Full Text] [PDF]

				D. J. Vander Griend and C. W. Rinker-Schaeffer A New Look at an Old Problem: The Survival and Organ-Specific Growth of Metastases Sci. Signal., January 20, 2004; 2004(216): pe3 - pe3. [Abstract] [Full Text] [PDF]

				S. Bandyopadhyay, S. K. Pai, S. C. Gross, S. Hirota, S. Hosobe, K. Miura, K. Saito, T. Commes, S. Hayashi, M. Watabe, et al. The Drg-1 Gene Suppresses Tumor Metastasis in Prostate Cancer Cancer Res., April 15, 2003; 63(8): 1731 - 1736. [Abstract] [Full Text] [PDF]

				N. J. Kennedy, H. K. Sluss, S. N. Jones, D. Bar-Sagi, R. A. Flavell, and R. J. Davis Suppression of Ras-stimulated transformation by the JNK signal transduction pathway Genes & Dev., March 1, 2003; 17(5): 629 - 637. [Abstract] [Full Text] [PDF]

				S. D. Yamada, J. A. Hickson, Y. Hrobowski, D. J. Vander Griend, D. Benson, A. Montag, T. Karrison, D. Huo, J. Rutgers, S. Adams, et al. Mitogen-activated Protein Kinase Kinase 4 (MKK4) Acts as a Metastasis Suppressor Gene in Human Ovarian Carcinoma Cancer Res., November 15, 2002; 62(22): 6717 - 6723. [Abstract] [Full Text] [PDF]

				Y.-Q. Wu, H. Chen, M. A. Rubin, K. J. Wojno, and K. A. Cooney Loss of Heterozygosity of the Putative Prostate Cancer Susceptibility Gene HPC2/ELAC2 Is Uncommon in Sporadic and Familial Prostate Cancer Cancer Res., December 1, 2001; 61(24): 8651 - 8653. [Abstract] [Full Text] [PDF]