The Rel/NF-κB Family Directly Activates Expression of the Apoptosis Inhibitor Bcl-x<sub>L</sub>

Chen, Cailin; Edelstein, Leonard C.; Gélinas, Céline

doi:10.1128/mcb.20.8.2687-2695.2000

Cited by 702 publications

(480 citation statements)

References 60 publications

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“…This is consistent with several recent reports that bcl-xl is one of the downstream target genes regulated by RelA/p50. [42][43][44][45][46] We identified the two NF-B binding sites in the bcl-xl promoter that interacts with different homodimers and heterodimers of NF-B (unpublished data). These results suggest that constitutive RelA/NF-B activity confers resistance to apoptosis through regulation of its downstream target genes.…”

Section: Discussionmentioning

confidence: 99%

Role of Rel/NF‐κB transcription factors in apoptosis of human hepatocellular carcinoma cells

Chiao¹,

Ren²,

Niu³

et al. 2002

Cancer

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BACKGROUNDPrimary hepatocellular carcinoma (HCC) is one of the 10 most common human carcinomas in the world. The mechanism by which HCC cells resist apoptosis induced by various treatment modalities is poorly understood.METHODSThe authors sought to determine whether Rel/NF‐κB transcription factors play a key role in controlling apoptosis in human HCCcells. We assessed constitutive and inducible activation of NF‐κB in hepatitis B virus (HBV)‐positive (Hep3B) and in hepatitis virus‐negative (Chang, HepG2) HCC cells, as well as the role of known inhibitors of NF‐κB activity.RESULTSThe current study data demonstrate that 1) RelA/NF‐κB activity is activated constitutively in Hep3B cells, as determined by electrophoretic mobility shift assays; 2) RelA/NF‐κB reporter gene activity is inhibited specifically by dominant‐negative mutants of IκBα, IKK1, IKK2, MEKK1, and MEKK3 and it is activated by overexpression of wild‐type MEKK3, suggesting that upstream kinase cascades induce phosphorylation of IκBα and activate RelA/NF‐κB in Hep3B cells; 3) overexpression of the HBV x gene fails to activate NF‐κB in HepG2 and Chang cell lines; 4) The NF‐κB–inducible gene, bcl‐xl, is overexpressed in Hep3B cells and is inhibited by the proteosome inhibitor PS341, which prevents IκBα degradation and RelA/NF‐κB activation; and 5) inhibition of constitutive RelA/NF‐κB activity by PS341 sensitizes Hep3B cells to doxorubicin‐induced apoptosis.CONCLUSIONSThese results are consistent with the role of RelA/NF‐κB activity in the regulation of apoptosis through activation of its downstream target genes and suggest that signaling pathways that control RelA/NF‐κB activity may be important targets for novel therapeutic approaches in the treatment of human HCC. Cancer 2002;95:1696–705. © 2002 American Cancer Society.DOI 10.1002/cncr.10829

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Section: Discussionmentioning

confidence: 99%

Role of Rel/NF‐κB transcription factors in apoptosis of human hepatocellular carcinoma cells

Chiao¹,

Ren²,

Niu³

et al. 2002

Cancer

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“…For example, Bcl-2 has been seen to be upregulated transcriptionally through NFB and MITF 325 . Activated NFB can also result in the upregulation of Bcl-xL and Bfl-1 326 . External factors such as growth factors (e.g.…”

Section: Regulation Of the Pro-survival Proteinsmentioning

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

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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.

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“…Cyclin D1 and cMyc, two NF-B target genes have an important role in cell growth and proliferation (73,74), and key angiogenesis factors such as vascular endothelial growth factor (VEGF) and interleukin-8 (64), are directly or indirectly enhanced by NF-B activation. Cancer growth inhibition via NF-B inhibition has been shown in colon (75), and the similar results has been shown in other several flavors of human neoplasia such as lung (76) and breast (77).…”

Section: The Role Of Nf-b In Promoting Carcinogenesis Of Colorectal mentioning

confidence: 99%

NF-κB Signaling Pathway, Inflammation and Colorectal Cancer

et al. 2009

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There is growing evidence for a connection between inflammation and tumor development, and the nuclear factor kappa B (NF-B), a proinflammatory transcription factor, is hypothesized to promote tumorigenesis. Although the genetic evidence for the hypothesis has been lacking, recent papers have lent credence to this hypothesis. It has been reported that constitutive NF-B activation in inflammatory bowel diseases (

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The Rel/NF-κB Family Directly Activates Expression of the Apoptosis Inhibitor Bcl-x_L

Cited by 702 publications

References 60 publications

Role of Rel/NF‐κB transcription factors in apoptosis of human hepatocellular carcinoma cells

Role of Rel/NF‐κB transcription factors in apoptosis of human hepatocellular carcinoma cells

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

NF-κB Signaling Pathway, Inflammation and Colorectal Cancer

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The Rel/NF-κB Family Directly Activates Expression of the Apoptosis Inhibitor Bcl-xL

Cited by 702 publications

References 60 publications

Role of Rel/NF‐κB transcription factors in apoptosis of human hepatocellular carcinoma cells

Role of Rel/NF‐κB transcription factors in apoptosis of human hepatocellular carcinoma cells

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

NF-κB Signaling Pathway, Inflammation and Colorectal Cancer

Contact Info

Product

Resources

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The Rel/NF-κB Family Directly Activates Expression of the Apoptosis Inhibitor Bcl-x_L