The c-Jun NH2-terminal kinase (JNK) is activated when cells are exposed to ultraviolet (UV) radiation. However, the functional consequence of JNK activation in UV-irradiated cells has not been established. It is shown here that JNK is required for UV-induced apoptosis in primary murine embryonic fibroblasts. Fibroblasts with simultaneous targeted disruptions of all the functional Jnk genes were protected against UV-stimulated apoptosis. The absence of JNK caused a defect in the mitochondrial death signaling pathway, including the failure to release cytochrome c. These data indicate that mitochondria are influenced by proapoptotic signal transduction through the JNK pathway.

Mitogen-activated protein kinases (MAPKThe mitogen-activated protein kinases (MAPKs) represent an evolutionarily conserved signaling mechanism that is used by cells to respond to changes in their environment (Schaeffer and Weber 1999). The activation of MAPK is mediated by dual phosphorylation on a ThrXaa-Tyr motif located in the kinase activation loop. This phosphorylation is increased in stimulated cells by members of a group of MAPK kinases. These enzymes have dual substrate specificity and can phosphorylate both Thr and Tyr. Studies of a large number of MAPKs demonstrate that this mechanism of activation is conserved in many organisms, including plants, yeast, nematodes, insects, and mammals.Two different MAPK kinases (MKK4 and MKK7) are implicated in the activation of the c-Jun NH 2 -terminal kinase (JNK) group of MAPK (Davis 2000). The presence of two MAPK kinases in a single MAPK signaling module is striking because genetic analysis indicates only a single MAPK kinase in each of the MAPK signaling modules of yeast (Schaeffer and Weber 1999). However, the organization of the JNK signaling pathway is similar to that of other mammalian MAPK modules. Thus, the ERK group of MAPK is activated by MKK1/MKK2 and the p38 group of MAPK is activated by MKK3/MKK6 (Schaeffer and Weber 1999). The presence of two MAPK kinases is therefore a common feature of the organization of mammalian MAPK signaling modules. The functional significance of the dual MAPK kinases found in mammalian MAPK signaling pathways is unclear.Studies of mice demonstrate that both the Mkk4 (Yang et al. 1997;Ganiatsas et al. 1998;Nishina et al. 1999) and Mkk7 genes (Dong et al. 2000) are required for embryonic viability. This observation indicates that the MKK4 and MKK7 protein kinases serve nonredundant functions in vivo. Genetic analysis of the Mkk4 (Han et al. 1998) and Mkk7 (Glise et al. 1995) genes in Drosophila supports this conclusion. However, the molecular basis for the difference in signaling by MKK4 and MKK7 is unclear. Differences in the expression pattern of MKK4 and MKK7 in tissues may be a contributing factor. Alternatively, the distinct biochemical properties of MKK4 and MKK7 may be critical for the nonredundant functions of these protein kinases in vivo.Comparison of the biochemical properties of MKK4 and MKK7 indicates that these protein kinases have different substrate specificities. Thus, in vitro assays demonstrate that MKK4 can activate both JNK and p38 MAPK (Derijard et al. 1995;Lin et al. 1995). In contrast, MKK7 selectively activates only JNK (Holland et al.

SNF5/INI1 is a component of the ATP-dependent chromatin remodeling enzyme family SWI/SNF. Germ line mutations of INI1 have been identified in children with brain and renal rhabdoid tumors, indicating that INI1is a tumor suppressor. Here we report that disruption of Ini1 expression in mice results in early embryonic lethality. Ini1-null embryos die between 3.5 and 5.5 days postcoitum, and Ini1-null blastocysts fail to hatch, form the trophectoderm, or expand the inner cell mass when cultured in vitro. Furthermore, we report that approximately 15% of Ini1-heterozygous mice present with tumors, mostly undifferentiated or poorly differentiated sarcomas. Tumor formation is associated with a loss of heterozygocity at the Ini1 locus, characterizing Ini1 as a tumor suppressor in mice. Thus, Ini1 is essential for embryo viability and for repression of oncogenesis in the adult organism.The compact nature of chromatin structure presents a barrier to cellular processes that require access to DNA. A number of multiprotein complexes have been identified that share the ability to modify chromatin structure. These include the histone acetyltransferases and deacetylases, complexes which chemically modify the amino-terminal tails of histones by the addition or removal of acetyl groups, respectively, as well as a group of enzymes that utilize the energy derived from ATP hydrolysis to alter nucleosome structure (16,20,43,44,50). Included among these ATP-dependent chromatin remodeling enzymes is the SWI/SNF family of chromatin modifiers.SWI/SNF enzymes are large multisubunit enzymes of ϳ1 to 2 MDa. Yeast SWI/SNF genes were originally identified as being required for mating type switching or sucrose fermentation (4,32,42). Later work determined that SWI/SNF genes were required for the induction of a subset of yeast genes and that the SWI2/SNF2 protein possessed a DNA-stimulated ATPase activity (6,22,26,33,34,54). Mutations in SWI/SNF genes could be suppressed by mutations altering histone gene expression, histone structure, or nonhistone chromatin proteins, leading to the suggestion that these gene products facilitated transcriptional activation by altering chromatin structure (15,23,24).Human SWI/SNF (hSWI/SNF) complexes contain either the human BRM (hBRM) (hSNF2␣) or BRG1 (hSNF2␤) homologues of the yeast SWI2/SNF2 ATPase (7,19,30). Both yeast and human SWI/SNF complexes have been shown to possess nucleosome remodeling activity in vitro (8,17,25). Components of mammalian SWI/SNF complexes have been implicated in a variety of cellular processes, including gene activation and repression, development and differentiation, recombination and repair, and cell cycle control. There is evidence supporting a role for SWI/SNF in gene activation events mediated by nuclear hormone receptors, environmental stress, and viral infection (1,7,10,13,30). In contrast, SWI/SNF components also were shown to be involved in repression of c-fos and some E2F-regulated genes (31, 48). Both BRG1 and hBRM can interact with the retinoblastoma oncoprotein and indu...

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