IKKβ programs to turn on the GADD45α–MKK4–JNK apoptotic cascade specifically via p50 NF-κB in arsenite response

Abstract

Cross talk between NF-κB and c-Jun N-terminal kinases (JNKs) has been implicated in the cell life and death decision under various stresses. Functional suppression of JNK activation by NF-κB has recently been proposed as a key cellular survival mechanism and contributes to cancer cells escaping from apoptosis. We provide a novel scenario of the proapoptotic role of IκB kinase β (IKKβ)–NF-κB, which can act as the activator of the JNK pathway through the induction of GADD45α for triggering MKK4/JNK activation, in response to the stimulation of arsenite, a cancer therapeutic reagent. This effect of IKKβ–NF-κB is dependent on p50 but not the p65/relA NF-κB subunit, which can increase the stability of GADD45α protein through suppressing its ubiquitination and proteasome-dependent degradation. IKKβ–NF-κB can therefore either activate or suppress the JNK cascade and consequently mediate pro- or antiapoptotic effects, depending on the manner of its induction. Furthermore, the NF-κB p50 subunit can exert a novel regulatory function on protein modification independent of the classical NF-κB transcriptional activity.

A Novel Post-translational Modification of Nucleolin, SUMOylation at Lys-294, Mediates Arsenite-induced Cell Death by Regulating gadd45α mRNA Stability

“…SUMOylation of Nucleolin Increased gadd45␣ mRNA Stability-Growth arrest and DNA damage-inducible gene 45␣ (GADD45␣) is one of the mediators of arsenite-induced apoptosis, as we found previously (47,48); therefore, GADD45␣ induction was investigated to define its involvement in the biological function of SUMO-nucleolin. Consistent with inhibition of the apoptotic response, overexpression of Mn-SOD (Fig.…”

“…In terms of nucleolin, we did observe a weak presence of nucleolin SUMOylation without any stimulation, which might account for its steady nuclear sequestration. Meanwhile, the protein SUMO level is dynamically regulated under various stress conditions, including osmotic stress, hypoxia, heat shock, and oxidative stress (36,37,48). On one hand, a low or moderate level of oxidative stress inhibits SUMOylation by oxidation of SUMO E1 and E2 enzymes, leading to disulfide bond formation between SAE1 and UBC9 (62).…”

“…Consistently, here we provided experimental evidence supporting the proapoptotic effect of nucleolin through up-regulating gadd45␣ mRNA stability under lethal oxidative stress conditions initiated by arsenite treatment. GADD45␣ is an evolutionarily conserved protein that is implicated in cell cycle arrest (66), DNA repair (67), and cell survival and apoptosis (47,48,68). GADD45␣ is induced in response to multiple environmental and physiological stresses, including UV radia-FIGURE 6.…”

p27 Suppresses Arsenite-induced Hsp27/Hsp70 Expression through Inhibiting JNK2/c-Jun- and HSF-1-dependent Pathways

“…Therefore, inhibiting Ras activation by interacting with Grb2 might be another possible mechanism for AP-1 pathway repression by p27. In addition, our previous study demonstrated that through regulating GADD45/MKK4/JNK activation, the IB kinase/ NFB p50 pathway mediates the cellular apoptotic process upon arsenite exposure (10). The IB kinase/NFB p50/ GADD45/JNK pathway might be another possible linkage for p27 regulation of JNK/c-Jun-dependent Hsp27 and Hsp70 transcription.…”

“…Arsenite occurs naturally in the earth's crust and is widely distributed in the environment. Our previous studies have demonstrated that arsenite exposure is able to initiate both cell apoptosis and cell transformation through different signaling pathways, dependent on dosages of arsenite exposure in various cell lines (7)(8)(9)(10)(11). In this study, we found, for the first time to our knowledge, that p27 mediated the suppression of Hsp27 and Hsp70 induction by arsenite through inhibiting JNK2/c-Jun-and HSF-1 (heat shock factor 1)-dependent transcriptional activation, which may provide novel molecular mechanisms underlying the tumor-suppressive function of p27 in the arsenite response.…”