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The NEMO (NF-KB Essential Modulator) Binding Domain (NBD) peptide induces apoptosis in several melan

ABSTRACT: The transcription factor NF-kB is an important regulator of genes involved in inflammation and cell proliferation. Several studies previously showed that NF-kB transcription factor was constitutively activated in melanoma cell lines due to the up regulated activity of inhibitor of NF-kB kinases (IKK). In the present study, we tested the activation of NF-kB pathway following TNF stimulation in 9 melanoma cell lines and the subsequent inhibition after the treatment of a small–molecule IKK inhibitor NDB peptide using Secreated Alkaline Phosphate (SEAP) reporter gene assay. The pro-apoptotic effects induced by NBD peptide treatment were determined by flow cytometry as well as by Western Blot testing of PARP’s cleavage. Our findings showed that NBD peptide was able to block IKK-NFKB pathway in all tested cell lines by inducing apoptosis as confirmed by increased levels of active caspase 3 and PARP cleavage after treatment. Moreover, our finding provides the basis for the development of a novel therapeutic approach targeting NF-kB transcription factor to treat melanoma.

ORGANISM(S): Homo sapiens

PROVIDER: GSE27519 | GEO | 2018/01/11

SECONDARY ACCESSION(S): PRJNA137101

REPOSITORIES: GEO

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The Notch/Hes1 pathway sustains NF-M-NM-:B activation through CYLD repression in T cell leukemia

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The Notch/Hes1 pathway sustains NF-κB activation through CYLD repression in T cell leukemia

Project description:The NF-κB pathway is a critical regulator of the immune system and has been implicated in cellular transformation and tumorigenesis. NF-κB response is regulated by the activation state of the IκB kinase (IKK) complex and triggered by a wide spectrum of stimuli. We previously reported that NF-κB is downstream of Notch1 in T cell acute lymphoblastic leukaemia (T-ALL), however both the mechanisms involving Notch1-induced NF-κB activation and the potential importance of NF-κB in the maintenance of the disease are unknown. Here we visualize Notch-induced NF-κB activation using both human T-ALL cell lines and animal models of this type of leukemia. We show that it is not Notch1 itself but Hes1, a canonical Notch target, the responsible for sustaining IKK activation in T-ALL. Hes1 exerts its effects by a direct transcriptional repression of the deubiquitinating enzyme CYLD, a well-characterized IKK inhibitor. Consistently, CYLD expression is significantly reduced in primary T-ALL leukemias. Finally, we demonstrate that IKK complex inhibition is a promising option for the targeted therapy of T-ALL as suppression of IKK function affected both the survival of human T-ALL cells in vitro and the maintenance of the disease in vivo. Transcriptional consequences of NF-kB inactivation in human T-ALL1 cell line

2011-05-07 | GSE20667 | GEO

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2018-10-17 | PXD001873 | Pride

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