Effects of physiological and synthetic IAP antagonism on c-IAP-dependent signaling

Abstract

Cellular inhibitor of apoptosis proteins 1 and 2 (c-IAP1/2) play central roles in signal transduction mediated by numerous receptors that participate in inflammatory and immune responses. In certain pathways, such as activation of NF-κB, their degradation is a major regulatory event and is physiologically induced by activation of receptors. Additionally, a number of synthetic compounds have been developed that also target the c-IAPs and induce their degradation. However, the extent of a synthetic IAP antagonist's ability to mirror the transcriptional program by a physiological signal remains unclear. Here we take a systems approach to compare the transcriptional programs triggered by activation of CD30, a well-characterized receptor previously shown to induce the degradation of the c-IAPs, to SM-164, a synthetic IAP antagonist that specifically triggers c-IAP degradation. Employing a technique that allows the specific analysis of newly transcribed RNA, we have generated comparative transcriptome profiles for CD30 activation and SM-164 treatment. Analysis of these profiles revealed that the genes regulated by each stimulus were not completely shared, indicating novel functions of IAP antagonists and consequences of c-IAP1/2 degradation. The data identified a role for c-IAP1/2 in the regulation of the ribosome and protein synthesis, which was subsequently confirmed by biological assays. These findings expand our knowledge of the roles of c-IAP1/2 in signaling and provide insight into the mechanism of synthetic IAP antagonists, furthering our understanding of their therapeutic potential.

Paclitaxel enhances tumoricidal potential of TRAIL via inhibition of MAPK in resistant gastric cancer cells

“…Another crucial point for increasing cell susceptibility to TRAIL is inhibition of the anti-apoptotic protein. Previous studies supported that TRAIL-resistant cells were re-sensitized by Bcl-2 or IAP antagonist (17,18). Here we revealed that PTX itself markedly inhibited expression of C-IAP1, C-IAP2, Livin and Mcl-1 in both SGC-7901 and MGC-803 cells, and combined application of PTX and TRAIL exhibited similar effects.…”

“…The most basic cause is dysfunction of death receptors due to hyper-methylation (11), mutation (12) and loss of cell surface expression (13). The defects in caspase protein (14) and overexpression of prosurvival proteins, such as IAP family and anti-apoptotic Bcl-2 family members (15)(16)(17)(18), are also linked to TRAIL sensitivity. In addition, more recent findings suggested that cell survival signals, including mitogen-activated protein kinase (MAPK) pathway, phosphatidylinositol 3-kinase/Akt pathway, and transcription factor NF-κB played pivotal roles in regulation of TRAIL signaling (19)(20)(21)(22).…”

Inhibitor of apoptosis proteins as intracellular signaling intermediates

“…Caspase-8, an important factor in apoptosis, has been implicated in the regulation of inflammation in an apoptosis-independent manner [82][83][84], and has been shown to participate in the differentiation of monocytes into macrophages through regulation of NF-jB via cleavage of RIP1 [85,86]. Additionally, we found that gene expression regulated by c-IAP degradation was dependent on caspases, illustrating another non-apoptosis-related function for these proteins [70]. These data may broaden the functional scope of the IAP/caspase interaction beyond regulation of cell death, with the IAPs acting as general regulators of caspase activity.…”

Mitogen‐activated protein kinase signaling mediates opioid‐induced presynaptic NMDA receptor activation and analgesic tolerance

“…; Kocab et al . ). In lamina II neurons obtained from morphine‐treated rats, pre‐treatment with SP600125 (40 μM for 1 h) significantly reduced the frequency (4.40 ± 0.44 Hz vs. 6.45 ± 0.60 Hz), but not the amplitude, of mEPSCs ( n = 10 neurons, Fig.…”

“…JNK2 is expressed pre-synaptically and plays a role in NMDAR-mediated glutamate release in the cortex (Nistico et al 2015). SP600125 is an anthrapyrazolone capable of inhibiting JNK1, JNK2, and JNK3 with high affinity Kocab et al 2015). In lamina II neurons obtained from morphine-treated rats, pretreatment with SP600125 (40 lM for 1 h) significantly reduced the frequency (4.40 AE 0.44 Hz vs. 6.45 AE 0.60 Hz), but not the amplitude, of mEPSCs (n = 10 neurons, Fig.…”