Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: HUMANGGP:010955 (mda-7)
 464 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Steady-state protein levels are determined by the balance between protein synthesis and degradation. Protein half-lives are determined primarily by degradation, and the major degradation pathways involve either lysosomal destruction or an ATP-dependent process involving ubiquitination to target proteins to the proteosome. Studies have shown that multiple tumor-suppressor proteins are ubiquitinated and degraded by the 26S proteasome. In the present study, we investigated whether the tumor suppressor/cytokine melanoma differentiation-associated gene-7/interleukin-24 gene (MDA-7/IL-24) protein is ubiquitinated and its degradation controlled by the proteasome. Treatment of ovarian (2008) and lung (H1299) tumor cells with adenoviral delivery of mda-7 (Ad-mda7) or Ad-mda7 plus the proteosome inhibitor MG132 showed that MDA-7 protein expression was dependent upon proteosome activity. Western blot and immunoprecipitation analyses verified that the MDA-7 protein was ubiquitinated and that ubiquitinated-MDA-7 levels were increased in MG132-treated cells. These results were confirmed using small interfering RNA (siRNA)-mediated knockdown of ubiquitin. Furthermore, ubiquitinated MDA-7 protein was degraded by the 26S proteasome, as MDA-7 accumulation was observed only when cells were treated with MG132 but not with lysosome or protease inhibitors. Inhibition of the catalytic beta-5 subunit of the 20S proteasome using siRNA resulted in MDA-7 protein accumulation. Finally, treatment of tumor cells with Ad-mda7 plus the proteasome inhibitor bortezomib resulted in increased tumor cell killing. Our results show that MDA-7/IL-24 is ubiquitinated and degraded by the 26S proteasome. Furthermore, inhibition of MDA-7 degradation results in enhanced tumor killing, identifying a novel anticancer strategy.
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PMID:MDA-7/IL-24, a novel tumor suppressor/cytokine is ubiquitinated and regulated by the ubiquitin-proteasome system, and inhibition of MDA-7/IL-24 degradation enhances the antitumor activity. 1782 82

MDA-7/IL-24 was involved in the specific cancer apoptosis through suppression of Bcl-2 expression, which is a key apoptosis regulatory protein of the mitochondrial death pathway. However, the underlying mechanisms of this regulation are unclear. We report here that tumor-selective replicating adenovirus ZD55-IL-24 leads to Bcl-2 S-denitrosylation and concomitant ubiquitination, which take part in the 26S proteasome degradation. IL-24-siRNA completely blocks Bcl-2 ubiquitination via reversion of Bcl-2 S-denitrosylation and protects it from proteasomal degradation which confirmed the significant role of MDA-7/IL-24 in regulating posttranslational modification of Bcl-2 in cancer cells. Nitric oxide (NO) is a key regulator of protein S-nitrosylation and denitrosylation. The NO donor, sodium nitroprusside (SNP), down-regulates Bcl-2 S-denitrosylation, attenuates Bcl-2 ubiquitination and subsequently counteracts MDA-7/IL-24 induced cancer cell apoptosis, whereas NO inhibitor 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxy-3-oxide (PTIO) shows the opposite effect. At the same time, these NO modulators fail to affect Bcl-2 phosphorylation, suggesting that NO regulates Bcl-2 stability in a phosphorylation-independent manner. In addition, Bcl-2 S-nitrosylation reduction induced by ZD55-IL-24 was attributed to both iNOS decrease and TrxR1 increase. iNOS-siRNA facilitates Bcl-2 S-denitrosylation and ubiquitin-degradation, whereas the TrxR1 inhibitor auranofin prevents Bcl-2 from denitrosylation and ubiquitination, thus restrains the caspase signal pathway activation and subsequent cancer cell apoptosis. Taken together, our studies reveal that MDA-7/IL-24 induces Bcl-2 S-denitrosylation via regulation of iNOS and TrxR1. Moreover, denitrosylation of Bcl-2 results in its ubiquitination and subsequent caspase protease family activation, as a consequence, apoptosis susceptibility. These findings provide a novel insight into MDA-7/IL-24 induced growth inhibition and carcinoma apoptosis.
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PMID:MDA-7/IL-24 induces Bcl-2 denitrosylation and ubiquitin-degradation involved in cancer cell apoptosis. 2262 68

Melanoma differentiation-associated gene-7/interleukin-24 (MDA-7/IL-24) uniquely takes on multiple anticancer functions, such as direct tumor cell cytotoxicity, immune stimulation, and antiangiogenic activities. MDA-7/IL-24 protein levels depend on proteasome degradation. Western blotting and coimmunoprecipitation analyses verified that the MDA-7/IL-24 protein was ubiquitinated and degraded by the 26S proteasome in Hela cells, which was confirmed by protein accumulation treated with proteasome inhibitor MG132. MDA-7/IL-24 contains 10 lysine sites: K63, K69, K78, K119, K123, K136, K179, K189, K203, and K206. Site-directed mutagenesis in these sites reveals that lysine 123 is the major internal lysine involvement of MDA-7/IL-24 ubiquitination. Our results further demonstrated that the mutation of lysine 123 to arginine led to the inhibition of ubiquitin-mediated degradation and the recovery of MDA-7/IL-24 protein level. At the same time, the apoptosis-inducing activity of K123R mutant was obviously stronger than wild-type MDA-7/IL-24 detected by 4'-6-diamidino-2-phenylindole (DAPI) assay and annexin V analysis. In addition, K123R mutant tilted the balance between antiapoptotic protein Bcl-2 and proapoptotic protein Bax, which subsequently induced the cleavage of caspase signaling cascade and initiated cell apoptosis. Together, lysine 123 is mainly implicated in the ubiquitination and degradation of MDA-7/IL-24. Inhibition of degradation and ubiquitination of MDA-7/IL-24 through mutation of lysine 123 result in enhanced stability of MDA-7/IL-24 and exhibits persistent tumor suppression activity compared with the wild type.
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PMID:Critical role of lysine 123 in the ubiquitin-mediated degradation of MDA-7/IL-24. 2307 24

Endoplasmic reticulum (ER) stress disrupts among others protein homeostasis in cells leading to the activation of the unfolded protein response (UPR) that is crucial for restoring this balance and cell survival. Hypoxia, reactive oxygen species and nutrient deprivation, conditions commonly present in the tumor microenvironment, are well-known triggers of the UPR. Apart from being an adaptive response, recently the UPR has been implicated in oncogenesis. Here we review the current understanding of the UPR in the most life threatening brain tumor in adults, glioblastoma multiforme (GBM). The UPR is controlled by BiP/GRP78 and three different sensors, PERK, IRE1 and ATF6. In orthotopic GBM mouse models IRE1 was reported to control angiogenesis, invasion and mesenchymal differentiation. Furthermore, PERK also was found to stimulate GBM growth. However, a direct role of the UPR in gliomagenesis remains to be demonstrated. Patient samples display chronic activation of the UPR and in vitro standard chemo- and radiotherapy partially act by aggravating ER stress leading to cell death. The UPR has been linked to enhanced sensitivity for apoptosis-inducing agents such as TRAIL and MDA-7. A number of agents such as proteasome inhibitors and several natural products were reported to exert cytotoxicity by enhancing ER stress in GBM cells, and some demonstrated activity in clinical studies. Finally, ER stress was suggested to be implicated in the maintenance of homeostasis in GBM stem cells. Taken together, the UPR appears to play an important role in GBM tumor progression and is a promising target for developing novel therapeutic interventions.
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PMID:The endoplasmic reticulum stress/unfolded protein response in gliomagenesis, tumor progression and as a therapeutic target in glioblastoma. 2710 78