PMC:4197335 / 8921-10802 JSONTXT

{"project":"2_test","denotations":[{"id":"25314077-14743220-17318407","span":{"begin":303,"end":307},"obj":"14743220"},{"id":"25314077-17485467-17318407","span":{"begin":303,"end":307},"obj":"17485467"},{"id":"25314077-22260670-17318408","span":{"begin":816,"end":820},"obj":"22260670"},{"id":"25314077-11713530-17318409","span":{"begin":988,"end":992},"obj":"11713530"},{"id":"25314077-11713531-17318409","span":{"begin":988,"end":992},"obj":"11713531"},{"id":"25314077-14743220-17318409","span":{"begin":988,"end":992},"obj":"14743220"},{"id":"25314077-22435567-17318410","span":{"begin":1282,"end":1286},"obj":"22435567"}],"text":"Constitutive NF-κB Activity Promotes the Survival of MM Cells by Inhibiting JNK Signaling\nGADD45β inhibits apoptosis by suppressing JNK signaling. It mediates this function by binding to the JNK kinase MKK7 and blocking its enzymatic activity by engaging the kinase catalytic pocket (Papa et al., 2004, 2007). This activity of GADD45β on the JNK pathway and the elevated GADD45B mRNA levels observed in monoclonal PCs from MM patients (Figure 1A) prompted us to investigate whether GADD45β mediated an antiapoptotic crosstalk between the NF-κB and JNK pathways in MM cells. We reasoned that cell extrinsic stimulation, as well as intrinsic oncogenic signals and NF-κB-pathway mutations, could result in the activation of signaling pathways beyond the IKK/NF-κB cascade, such as the JNK pathway (Davies and Tournier, 2012), which we and others have previously shown can trigger apoptosis in a manner that can be suppressed by NF-κB (De Smaele et al., 2001; Tang et al., 2001; Papa et al., 2004). Indeed, at least in principle, this mechanism could provide a basis for the addiction of MM cells to NF-κB for survival. In line with this hypothesis, in each of five heterogeneous MM cell lines and a B lymphoblastoid cell line, the silencing of the NF-κB subunit RelA (DiDonato et al., 2012) triggered JNK activation and apoptosis (Figures S2A–S2C), and blocking this activation with the JNK inhibitor SP600125 effectively protected NF-κB/RelA-silenced MM cells from cell death (Figures S2D and S2E). Similarly, the small hairpin RNA (shRNA)-mediated silencing of MKK7 rescued MM cells from the cytotoxic effects of each of two pharmacological inhibitors of IKKβ/NF-κB, and the protective effect of this silencing was virtually complete (Figure S2F). Collectively, these data indicate that constitutive NF-κB activity promotes the survival of MM cells by inhibiting MKK7/JNK signaling."}