Bcl-2 Family Proteins as Therapeutic Targets

Czabotar, P.E.; Lessène, Guillaume

doi:10.2174/138161210793292429

Cited by 31 publications

(20 citation statements)

References 154 publications

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“…Bcl-2 prevents mitochondrial membrane disruption, and inhibits Cyto-C activation and that of other pro-apoptotic factors (Czabotar and Lessene, 2010). As shown in Figure 4H, ovariectomy markedly reduced the expression of Bcl-2 in the tibias of the vehicle treated OVX group as compared to that of the sham operated control group ( p < 0.05).…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, mitochondrial dysfunction further facilitates NF-κB activation (Cherry and Piantadosi, 2015). Additionally, Bcl-2 affects the mitochondrial function by regulating Cyto-C release and blocking NF-κB activation (Czabotar and Lessene, 2010). Therefore, the present results may also indicate that FLL treatment regains the mitochondria function by inhibiting Cyto-C activation via resuming Bcl-2 expression, and then preventing NF-κB-p65 activation and phosphorylation via inhibiting Nox4 overexpression in OVX rats.…”

Section: Discussionmentioning

confidence: 99%

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Antioxidant Effect of Fructus Ligustri Lucidi Aqueous Extract in Ovariectomized Rats Is Mediated through Nox4-ROS-NF-κB Pathway

Wang

Guo

et al. 2017

Front. Pharmacol.

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Purpose: This study is designed to explore whether Fructus ligustri lucidi (FLL) exhibits antioxidant effect in ovariectomized (OVX) rats, and to identify the signaling pathway involved in this process.Methods: OVX rats were treated with FLL aqueous extract (3.5 g/kg) for 12 weeks. Serum, uteri, and tibias were harvested from the rats and the levels of total antioxidant capacity (TAC), nitric oxide (NO), malondialdehyde (MDA), 8-hydroxy-desoxyguanosine (8-OHdG), and superoxide dismutase (SOD) were determined. Changes in the levels of NF-κB-p65, phosphorylation of NF-κB-p65 (NF-κB-pp65), NF-κB inhibitor alpha (IκBα), phosphorylation of IκBα (p-IκBα), and NADPH oxidase 4 (Nox4) in uteri and tibias were determined by western blot, immunofluorescent and immunohistochemical analysis, respectively. In addition, the expression of cytochrome C (Cyto-C) and B-cell lymphoma-2 (Bcl-2) were determined in the tibias of rats. Histopathological changes in the bones were evaluated by hematoxylin-eosin staining. Bone mineral density (BMD) was determined in rat femurs by dual X-ray absorptiometry.Results: Treatment of OVX rats with FLL aqueous extract improved redox homeostasis by increasing the levels of TAC and NO as well as decreasing the levels of MDA and 8-OHdG in serum, tibias, and uteri. Further, FLL extract also downregulated the expression of Nox4, NF-κB-p65, NF-κB-pp65, and p-IκBα in the uteri and tibias. Furthermore, administration of FLL–OVX rats increased Bcl-2 expression and prevented cytoplasmic release of mitochondrial Cyto-C in the tibias. In addition, FLL treatment also improved bone microstructure and increased cortical bone thickness as well as increased BMD values in the femurs of OVX rats.Conclusions: FLL treatment may suppress oxidative stress response in OVX rats via regulating the Nox4/ROS/NF-κB signaling pathway. These results suggest the potential of using FLL as a natural antioxidant agent in preventing the development of osteoporosis.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Antioxidant Effect of Fructus Ligustri Lucidi Aqueous Extract in Ovariectomized Rats Is Mediated through Nox4-ROS-NF-κB Pathway

Wang

Guo

et al. 2017

Front. Pharmacol.

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“…Pro-survival Bcl-2 family proteins are currently being pursued in a number of cancer therapeutic discovery projects (46,58). Understanding the primary role of pro-survival proteins in inhibiting apoptosis is important not only for future compound development but also for understanding potential resistance mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Mutation to Bax beyond the BH3 Domain Disrupts Interactions with Pro-survival Proteins and Promotes Apoptosis

Czabotar

Lee

Thompson

et al. 2011

Journal of Biological Chemistry

103

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The Bcl-2 family of proteins plays a central role in the control of apoptosis via the intrinsic pathway (1). The family is composed of two opposing groups, one promoting cell survival (comprising Bcl-2, Bcl-x L , Bcl-w, Mcl-1, and A1, each containing up to four Bcl-2 homology (BH) 3 domains) and another promoting cell death. This latter group includes Bax and Bak, proteins similar in sequence and structure to the pro-survival family members, and the so-called BH3-only proteins. In response to stress or damage signals, BH3-only proteins are up-regulated either transcriptionally or post-translationally, or both. Apoptosis results when the pro-survival proteins are overwhelmed and Bax/Bak undergo a conformational change at the mitochondrial membrane. Apoptogenic factors such as cytochrome c are then released from the mitochondrial intramembrane space into the cytosol, resulting in the activation of caspases.Many biochemical, structural, and cellular studies support an interaction between pro-survival proteins and both subgroups of pro-apoptotic proteins. The helical BH3 domain of pro-apoptotic proteins engages a cognate groove on the prosurvival proteins (2-5). Four hydrophobic amino acids from the BH3 domain insert into pockets in the groove, and a conserved aspartyl residue in the BH3 domain is hydrogen-bonded with a conserved arginyl residue on the pro-survival protein.Although the BH3-only proteins are mostly unstructured in solution (6), Bak and Bax have well characterized globular structures (7,8), remarkably similar to the pro-survival proteins, in which the BH3 domain is located within an amphipathic helix (␣2) with its hydrophobic face buried. Thus Bak and Bax cannot bind to pro-survival proteins without first everting their BH3 domains. The natural trigger for the exposure of the BH3 domain of Bak/Bax is not known, but it could be a chemical stimulus such as H 2 O 2 (9), a physical stimulus such as heat (10), or an interaction between Bak/Bax and a BH3-only protein that is up-regulated in response to cellular stresses. Some evidence supports such interactions, at least between a subset of the BH3-only proteins and Bax/Bak (11-15). The isolation of complexes of this type has proven elusive, but a recent NMR study suggests the BH3 domain of the BH3-only protein Bim binds Bax on the opposite face as compared with where a BH3 peptide binds a pro-survival protein (16). It has been proposed that this interaction triggers a structural rearrangement in Bax or Bak into large homo-oligomeric complexes at the mitochondrial membrane. Other data support a model in

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“…Early studies showed that p53 can bind the Bax gene promoter region and regulate Bax gene transcription [12,13]. The Bcl-2 protein family plays a critical role in the regulation of apoptosis [14]. Because we observed apoptotic changes in CRC cells, we analyzed the levels of P53, Bax and Bcl-2 in cells treated with pEGFP-N1-GADD45B and Si-GADD45B, respectively.…”

Section: Resultsmentioning

confidence: 99%

Abnormal expression of GADD45B in human colorectal carcinoma

Wang

Xiao

et al. 2012

J Transl Med

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BackgroundGADD45B is a member of the growth arrest DNA damage-inducible gene family associated with cell growth control, apoptosis, and DNA damage repair response. The aim of this study is to detect the role of GADD45B in colorectal carcinoma (CRC); the area not studied in depth to date.MethodsThe mRNA and protein levels of GADD45B were examined by Real-Time quantitative PCR (RT-qPCR) and immunohistochemistry (IHC) in CRC tissues and adjacent noncancerous tissues (ANCT). Over-expression plasmids and SiRNA were used to regulate GADD45B expression in CRC cell lines in vitro and flow cytometry and Western blotting were used to detect apoptotic changes.ResultsThe mRNA and protein levels of GADD45B were significantly higher in CRC tissues than those in ANCT (P<0.05). Up-regulation of GADD45B was also correlated with relapse and death of CRC patients (P<0.05). The Kaplan-Meier survival curves indicated that disease-free survival (DFS) was significantly worse in CRC patients who showed GADD45B overexpression. A Cox multivariate analysis revealed that GADD45B overexpression and TNM stage were significant factors affecting patients’ survival. On the other hand, as a tumor suppressor gene, GADD45B amplified from normal colorectal tissues could induce apoptosis in CRC cell lines and may be associated with the p53-mediated apoptotic pathways.ConclusionGADD45B, a tumor suppressor gene potentially through the p53-mediated apoptotic pathways, is paradoxically overexpressed in CRC and as such may play an unappreciated role in tumorigenesis. The exact mechanism of GADD45B inactivation and overexpression requires further investigation. GADD45B could be a potential therapeutic target for CRC treatment in future.

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Bcl-2 Family Proteins as Therapeutic Targets

Cited by 31 publications

References 154 publications

Antioxidant Effect of Fructus Ligustri Lucidi Aqueous Extract in Ovariectomized Rats Is Mediated through Nox4-ROS-NF-κB Pathway

Antioxidant Effect of Fructus Ligustri Lucidi Aqueous Extract in Ovariectomized Rats Is Mediated through Nox4-ROS-NF-κB Pathway

Mutation to Bax beyond the BH3 Domain Disrupts Interactions with Pro-survival Proteins and Promotes Apoptosis

Abnormal expression of GADD45B in human colorectal carcinoma

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