Retinoid X Receptor Agonists Increase Bcl2a1 Expression and Decrease Apoptosis of Naive T Lymphocytes

Rasooly, Reuven; Schuster, Gertrud U.; Gregg, Jeffrey P.; Xiao, Jiumei; Chandraratna, Roshantha A.S.; Stephensen, Charles B.

doi:10.4049/jimmunol.175.12.7916

Cited by 48 publications

(41 citation statements)

References 66 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, RXR agonists inhibited apoptosis in human mesangial cells exposed to H 2 O 2 and naive tlymphocytes. [14,15] However, they facilitated apoptosis in tumor cells, such as lung and breast carcinomas, lymphomas, and leukemias. [16][17][18] Thus, there is controversy over pro-or anti-apoptotic effect, which may depend on the type of cells and the nature of the apoptotic stimulus.…”

Section: Discussionmentioning

confidence: 99%

Protective role of retinoid X receptor in H9c2 cardiomyocytes from hypoxia/reoxygenation injury in rats

Shan¹,

Xu²,

Huang³

et al. 2014

World Journal of Emergency Medicine

View full text Add to dashboard Cite

BACKGROUND: Retinoid X receptor (RXR) plays a central role in the regulation of intracellular receptor signaling pathways. The activation of RXR has protective effect on H 2 O 2 -induced apoptosis of H9c2 ventricular cells in rats. But the protective effect and mechanism of activating RXR in cardiomyocytes against hypoxia/reoxygenation (H/R)-induced oxidative iniury are still unclear. METHODS:The model of H/R injury was established through hypoxia for 2 hours and reoxygenation for 4 hours in H9c2 cardiomyocytes of rats. 9-cis-retinoic acid (9-cis RA) was obtained as an RXR agonist, and HX531 as an RXR antagonist. Cultured cardiomyocytes were randomly divided into four groups: sham group, H/R group, H/R+9-cis RA -pretreated group (100 nmol/L 9-cis RA), and H/R+9-cis RA+HX531-pretreated group (2.5 μmol/L HX531). The cell viability was measured by MTT, apoptosis rate of cardiomyocytes by flow cytometry analysis, and mitochondrial membrane potential (ΔΨm) by JC-1 fluorescent probe, and protein expressions of Bcl-2, Bax and cleaved caspase-9 with Western blotting. All measurement data were expressed as mean±standard deviation, and analyzed using one-way ANOVA and the Dunnett test. Differences were considered signifi cant when P was <0.05. RESULTS:Pretreatment with RXR agonist enhanced cell viability, reduced apoptosis ratio, and stabled ΔΨm. Dot blotting experiments showed that under H/R stress conditions, Bcl-2 protein level decreased, while Bax and cleaved caspase-9 were increased. 9-cis RA administration before H/R stress prevented these effects, but the protective effects of activating RXR on cardiomyocytes against H/R induced oxidative injury were abolished when pretreated with RXR pan-antagonist HX531. CONCLUSION:The activation of RXR has protective effects against H/R injury in H9c2 cardiomyocytes of rats through attenuating signaling pathway of mitochondria apoptosis.

show abstract

Section: Discussionmentioning

confidence: 99%

Protective role of retinoid X receptor in H9c2 cardiomyocytes from hypoxia/reoxygenation injury in rats

Shan¹,

Xu²,

Huang³

et al. 2014

World Journal of Emergency Medicine

View full text Add to dashboard Cite

show abstract

“…In addition to NFB, other transcription factors have been implicated in the transcriptional regulation of Bfl-1. These include all-trans retinoic acids in leukemia cells 401 , retinoic X receptor agonists in naïve T lymphocytes 402 , and the transcription factors WT-1 403 and PU.1 404 . On the other hand, Bfl-1 transcription has also been observed to be blocked by the transcription factor Blimp-1 in plasma cells 405 .…”

Section: The Regulation Of Bfl-1mentioning

confidence: 99%

Role of the pro-survival molecule Bfl-1 in melanoma

Hind

Carter

Harris

et al. 2015

The International Journal of Biochemistry & Cell Biology

View full text Add to dashboard Cite

Melanoma, the cancer derived from the melanocytes of the skin, is becoming an ever more common cancer in the ageing population of the developed world and displays an intrinsic resistance to current therapies. This chemo resistance makes metastatic melanoma an extremely difficult cancer to treat leading to a 5 year survival rate of just 20%. As such, it is important to unearth new potential drug targets to increase the prospects for melanoma patients.Bfl-1 is a pro-survival protein of the Bcl-2 family of apoptosis regulating proteins. It has been found to be over-expressed in a small subset of chemo resistant tumours, including melanoma. Accordingly, I characterised the molecule in melanoma cells and determined its role in protecting these cells from chemotherapy-induced apoptosis. I elucidated the expression profile and half-lives of the protein and mRNA across a panel of melanoma cell-lines and healthy melanocytes. I also confirmed, using pathway specific inhibitors, that Bfl-1 was transcriptionally regulated by the NFB pathway and concluded through pulsechase experiments that Bfl-1 protein was degraded, at least in part, by the proteasome. Subcellular fractionation and indirect immunofluorescence techniques elucidated that Bfl-1 was located mostly at the mitochondria in both resting and apoptotic cells, with a diffuse level present throughout the cytoplasm. As well as characterising the protein in both melanoma cells and healthy primary melanocytes, I determined its role in the resistance of these cells to apoptosis. Over-expressed Bfl-1 was found to protect melanoma cells from apoptosis caused by a range of chemotherapeutic agents in A375 melanoma cells, which naturally expressed very low levels of Bfl-1. Further, knock down of Bfl-1 using siRNA technology in melanoma cells revealed the dependence of these cells on Bfl-1 for their resistance to certain chemotherapeutic agents currently used in melanoma treatment, including the MEK inhibitor PD901. All together, this research contributes to our understanding of Bfl-1 and highlights it as a potentially important therapeutic target in metastatic melanoma.

show abstract

“…Besides NF-kB, several other transcription factors have been implicated in BCL2A1 transcriptional regulation, including all-trans retinoic acids 39,40 or retinoic X receptor agonists, 41 the (ÀEX5/ÀKTS) isoform of WT-1 42 and the transcriptional enhancer Spi-1/PU.1. 43 On the other hand, BCL2A1 transcription is repressed by the plasma cell transcription factor PRDI-BF1/Blimp-1 44 ( Figure 4).…”

Section: Regulation Of Bcl2a1mentioning

confidence: 99%