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.
We conducted a joint (pooled) analysis of three genome-wide association studies (GWAS) 1-3 of esophageal squamous cell carcinoma (ESCC) in ethnic Chinese (5,337 ESCC cases and 5,787 controls) with 9,654 ESCC cases and 10,058 controls for follow-up. In a logistic regression model adjusted for age, sex, study, and two eigenvectors, two new loci achieved genome-wide significance, marked by rs7447927 at 5q31.2 (per-allele odds ratio (OR) = 0.85, 95% CI 0.82-0.88; P=7.72x10−20) and rs1642764 at 17p13.1 (per-allele OR= 0.88, 95% CI 0.85-0.91; P=3.10x10−13). rs7447927 is a synonymous single nucleotide polymorphism (SNP) in TMEM173 and rs1642764 is an intronic SNP in ATP1B2, near TP53. Furthermore, a locus in the HLA class II region at 6p21.32 (rs35597309) achieved genome-wide significance in the two populations at highest risk for ESSC (OR=1.33, 95% CI 1.22-1.46; P=1.99x10−10). Our joint analysis identified new ESCC susceptibility loci overall as well as a new locus unique to the ESCC high risk Taihang Mountain region.
X-linked inhibitor of apoptosis protein (XIAP) overexpression has been found to be associated with malignant cancer progression and aggression in individuals with many types of cancers. However, the molecular basis of XIAP in the regulation of cancer cell biological behavior remains largely unknown. In this study, we found that a deficiency of XIAP expression in human cancer cells by either knock-out or knockdown leads to a marked reduction in -actin polymerization and cytoskeleton formation. Consistently, cell migration and invasion were also decreased in XIAP-deficient cells compared with parental wildtype cells. Subsequent studies demonstrated that the regulation of cell motility by XIAP depends on its interaction with the Rho GDP dissociation inhibitor (RhoGDI) via the XIAP RING domain. Furthermore, XIAP was found to negatively regulate RhoGDI SUMOylation, which might affect its activity in controlling cell motility. Collectively, our studies provide novel insights into the molecular mechanisms by which XIAP regulates cancer invasion and offer a further theoretical basis for setting XIAP as a potential prognostic marker and specific target for treatment of cancers with metastatic properties.The X-linked inhibitor of apoptosis protein (XIAP) 3 is a member of the IAP family that has received substantial attention during the last few years. Biochemical and structural studies have indicated that XIAP has three zinc-binding baculovirus IAP repeat (BIR) domains (BIR1-3), a loop region, and a RING finger (1). The BIR3 domain of XIAP is able to bind and inhibit caspase-9, whereas the BIR2 region binds and inhibits active caspase-3 and caspase-7. The RING domain of XIAP has E3 ligase activity and is able to degrade proteins by linking them to ubiquitin molecules (2-4). More recently, XIAP has been found to be a regulator of the cell cycle through binding the cell cycle regulators MAGED1 and NRAGE and to play an important role in the control of intracellular copper levels through ubiquitin ligase-dependent regulation of the copper-regulating gene MURR1 (5, 6). The ability of XIAP to regulate these pathways, uncoupled with its caspase inhibitory activities, indicates its distinct properties and functions. Based on the finding that XIAP-deficient mice do not display obvious apoptotic phenotypes (7), it was hypothesized that there might be new functions and signaling pathways affected by XIAP, which are probably distinct from those involved in apoptotic caspase cascades.There is growing evidence showing the correlation between high XIAP overexpression and malignant cancer aggression (8, 9). Comparison of XIAP expression between adjacent malignant tissue and normal tissue invariably demonstrates that XIAP is much more highly expressed in the malignant cancer tissue (10 -20). Poorly differentiated carcinomas also display significantly higher levels of XIAP expression than do well differentiated carcinomas (13,(17)(18)(19)(20). Moreover, XIAP expression in metastatic specimens is much higher than that in primary cancers ...
Environmental and occupational exposure to arsenite is associated with an increased risk of human cancers, including skin, urinary bladder, and respiratory tract cancers. Although much evidence suggests that alterations in cell cycle machinery are implicated in the carcinogenic effect of arsenite, the molecular mechanisms underlying the cell cycle alterations are largely unknown. In the present study, we observed that exposure of human keratinocyte HaCat cells to arsenite resulted in the promotion of cell cycle progression, especially G 1 -S transition. Further studies found that arsenite exposure was able to induce cyclin D1 expression. The induction of cyclin D1 by arsenite required nuclear factor-KB (NF-KB) activation, because the inhibition of IKB phosphorylation by overexpression of the dominant-negative mutant, IKKB-KM, impaired arsenite-induced cyclin D1 expression and G 1 -S transition. The requirement of IKB kinase B (IKKB) for cyclin D1 induction was further confirmed by the findings that arsenite-induced cyclin D1 expression was totally blocked in IKKB knockout (IKKB À/À ) mouse embryo fibroblasts. In addition, knockdown of cyclin D1 expression using cyclin D1-specific small interference RNA significantly blocked arsenite-induced cell cycle progression in HaCat cells. Taken together, our results show that arsenite-induced cell cycle from G 1 to S phase transition is through IKKB/NF-KB/cyclin D1-dependent pathway. (Cancer Res 2005; 65(20): 9287-93)
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