Wiring the cell signaling circuitry by the NF-κB and JNK1 crosstalk and its applications in human diseases

Abstract

Integration of the cell signaling circuitry determines the ultimate response of a cell to extracellular stimuli. The transcription factor nuclear factor-kappa B (NF-jB) and mitogen-activated protein kinase JNK1 are major players in the cell signaling circuitry, regulating numerous cellular events and being implicated in the process of many human diseases and certain types of cancer. The interplay between NF-jB and JNK1 provides a paradigm that shows how the crosstalk between different signaling pathways decides the function of the cell signaling circuitry. Understanding the wiring of the cell signaling circuitry may hold the key for cell signaling-based therapy of human diseases.

Astragali Radix elicits anti-inflammation via activation of MKP-1, concomitant with attenuation of p38 and Erk

“…The key signaling pathway mediating inflammatory responses, from MAP kinases through to the NF B transcription factor, has been well-established in various inflammatory diseases and cancers (Ji et al, 2006;Liu and Lin, 2007). Thus, this signaling pathway is a good target for anti-cancer and anti-inflammatory drug development.…”

“…The MAP kinase family plays a critical role in the control of cellular responses to cytokines and stresses and also regulates cell growth and differentiation (Liu and Lin, 2007). Previous studies with inhibitors of kinases and their upstream kinases, or their hyperactive and dominant negative forms, provide evidence on the role of p38, Erk1/2, and JNK in the transcriptional activation of pro-inflammatory cytokines and their mediators (Wadleigh et al, 2000;Yang et al, 2000).…”

E3 ubiquitin ligase Mule ubiquitinates Miz1 and is required for TNFα-induced JNK activation

“…JNK is essential for TNFα to induce cell death when NF-κB activation is impaired (28)(29)(30)46). To determine whether Mule regulates TNFα-induced cell death, WT MEFs were transfected with control siRNA or siRNA for Mule, followed by the infection with an adenoviral vector encoding the IκBα(AA) mutant, which is the "super-repressor" of NF-κB (47), or LacZ control.…”

“…Thus, Mule regulates TNFα-induced cell death by at least two mechanisms. First, K48-linked polyubiquitination of Miz1 by Mule triggers Miz1 proteasomal degradation, thereby releasing Miz1-mediated inhibition on TNFα-induced JNK activation and apoptosis (28,51). Second, K48-linked polyubiquitination of Mcl-1 by Mule leads to proteasomal degradation of Mcl-1, thereby contributing to TNFα-induced apoptosis (33).…”

“…TRAF2/5 and RIP1 are involved in activation of multiple downstream effectors including JNK, also known as stress-activated protein kinase (SAPK), as well as p38 and the inhibitor of NF-κB kinase (IKK) complex (22)(23)(24)(25)(26)(27). Prolonged JNK activation contributes to TNFα-induced apoptosis when NF-κB activation is impaired (28)(29)(30)(31)(32). Recently, we found that Miz1 selectively suppresses TNFα-induced JNK activation by interfering with TRAF2 K63-linked polyubiquitination (15).…”