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Suppression of Metastatic Colonization by the Context-Dependent Activation of the c-Jun NH₂-Terminal Kinase Kinases JNKK1/MKK4 and MKK7

¹ Committee on Cancer Biology; ² Section of Urology, Department of Surgery; Departments of ³ Health Studies and ⁴ Biochemistry and Molecular Biology; ⁵ University of Chicago Cancer Research Center; ⁶ Section of Hematology Oncology, Department of Medicine; and ⁷ Ben May Institute for Cancer Research, The University of Chicago, Chicago, Illinois

Requests for reprints: Carrie Rinker-Schaeffer, Section of Urology, Department of Surgery, The University of Chicago, 5841 South Maryland Avenue, MC6038, Chicago, IL 60637. Phone: 773-702-5882; Fax: 773-702-1001; E-mail: crinker{at}surgery.bsd.uchicago.edu.

Advances in clinical, translational, and basic studies of metastasis have identified molecular changes associated with specific facets of the metastatic process. Studies of metastasis suppressor gene function are providing a critical mechanistic link between signaling cascades and biological outcomes. We have previously identified c-Jun NH₂-terminal kinase (JNK) kinase 1/mitogen-activated protein kinase (MAPK) kinase 4 (JNKK1/MKK4) as a prostate cancer metastasis suppressor gene. The JNKK1/MKK4 protein is a dual-specificity kinase that has been shown to phosphorylate and activate the JNK and p38 MAPKs in response to a variety of extracellular stimuli. In this current study, we show that the kinase activity of JNKK1/MKK4 is required for suppression of overt metastases and is sufficient to prolong animal survival in the AT6.1 model of spontaneous metastasis. Ectopic expression of the JNK-specific kinase MKK7 suppresses the formation of overt metastases, whereas the p38-specific kinase MKK6 has no effect. In vivo studies show that both JNKK1/MKK4 and MKK7 suppress the formation of overt metastases by inhibiting the ability of disseminated cells to colonize the lung (secondary site). Finally, we show that JNKK1/MKK4 and MKK7 from disseminated tumor cells are active in the lung but not in the primary tumor, providing a biochemical explanation for why their expression specifically suppressed metastasis while exerting no effect on the primary tumor. Taken together, these studies contribute to a mechanistic understanding of the context-dependent function of metastasis regulatory proteins.

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