title: Suppression of metastatic colonization by the context-dependent activation of the c-Jun NH2-terminal kinase kinases JNKK1/MKK4 and MKK7.
abstract: 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.
authors.affiliation: Committee on Cancer Biology, The University of Chicago, Illinois 60637, USA.
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Vander Griend
authors.forename: Masha
authors.initials: M
authors.lastname: Kocherginsky
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Hickson
authors.forename: Walter M
authors.initials: WM
authors.lastname: Stadler
authors.forename: Anning
authors.initials: A
authors.lastname: Lin
authors.forename: Carrie W
authors.initials: CW
authors.lastname: Rinker-Schaeffer
mesh_terms: D000818:Animals; D004789:Enzyme Activation; D008175:Lung Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000556:secondary*; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism*; D048669:MAP Kinase Kinase 6 / Q000235:genetics / Q000378:metabolism; D048688:MAP Kinase Kinase 7 / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D016513:Mice, SCID; D051381:Rats; D014162:Transfection
chemical_list: D048670:MAP Kinase Kinase 4; D048669:MAP Kinase Kinase 6; D048688:MAP Kinase Kinase 7