Dataset Information

Tumor protein p63/nuclear factor ?B feedback loop in regulation of cell death.

ABSTRACT: Tumor protein (TP)-p53 family members often play proapoptotic roles, whereas nuclear factor ?B (NF-?B) functions as a proapoptotic and antiapoptotic regulator depending on the cellular environment. We previously showed that the NF-?B activation leads to the reduction of the TP63 isoform, ?Np63?, thereby rendering the cells susceptible to cell death upon DNA damage. However, the functional relationship between TP63 isotypes and NF-?B is poorly understood. Here, we report that the TAp63 regulates NF-?B transcription and protein stability subsequently leading to the cell death phenotype. We found that TAp63? induced the expression of the p65 subunit of NF-?B (RELA) and target genes involved in cell cycle arrest or apoptosis, thereby triggering cell death pathways in MCF10A cells. RELA was shown to concomitantly modulate specific cell survival pathways, making it indispensable for the TAp63?-dependent regulation of cell death. We showed that TAp63? and RELA formed protein complexes resulted in their mutual stabilization and inhibition of the RELA ubiquitination. Finally, we showed that TAp63? directly induced RelA transcription by binding to and activating of its promoter and, in turn, leading to activation of the NF-?B-dependent cell death genes. Overall, our data defined the regulatory feedback loop between TAp63? and NF-?B involved in the activation of cell death process of cancer cells.

SUBMITTER: Sen T

PROVIDER: S-EPMC3234803 | biostudies-other | 2011 Dec

REPOSITORIES: biostudies-other

ACCESS DATA

Publications

Tumor protein p63/nuclear factor κB feedback loop in regulation of cell death.

Sen Tanusree T Sen Nilkantha N Huang Yiping Y Sinha Debasish D Luo Zhen-Ge ZG Ratovitski Edward A EA Sidransky David D

The Journal of biological chemistry 20111020 50

Tumor protein (TP)-p53 family members often play proapoptotic roles, whereas nuclear factor κB (NF-κB) functions as a proapoptotic and antiapoptotic regulator depending on the cellular environment. We previously showed that the NF-κB activation leads to the reduction of the TP63 isoform, ΔNp63α, thereby rendering the cells susceptible to cell death upon DNA damage. However, the functional relationship between TP63 isotypes and NF-κB is poorly understood. Here, we report that the TAp63 regulates ...[more]

PMID: 22020940

Similar Datasets

Project description:The sensitization of hepatocytes to cell death from tumor necrosis factor ? (TNF?) underlies many forms of hepatic injury, including that from toxins. Critical for hepatocyte resistance to TNF? toxicity is activation of nuclear factor ?B (NF-?B) signaling, which prevents TNF?-induced death by the up-regulation of protective proteins. To further define the mechanisms of hepatocyte sensitization to TNF? killing, immunoblot analysis comparing livers from mice treated with lipopolysaccharide (LPS) alone or LPS together with the hepatotoxin galactosamine (GalN) was performed to identify TNF?-induced protective proteins blocked by GalN. Levels of CCAAT/enhancer-binding protein ? (C/EBP?) were increased after LPS treatment but not GalN/LPS treatment. In a nontransformed rat hepatocyte cell line, TNF?-induced increases in C/EBP? protein levels were dependent on NF-?B-mediated inhibition of proteasomal degradation. Pharmacological inhibition of c-Jun N-terminal kinase (JNK) did not affect C/EBP? degradation, indicating that the process was JNK-independent. C/EBP? functioned to prevent cell death as adenoviral C/EBP? overexpression blocked TNF?-induced apoptosis in cells sensitized to TNF? toxicity by NF-?B inhibition. C/EBP? inhibited TNF?-induced caspase 8 activation and downstream mitochondrial cytochrome c release and caspase 3 and caspase 7 activation. Studies in primary hepatocytes from c/ebp?(-/-) mice confirmed that loss of C/EBP? increased death from TNF?. c/ebp?(-/-) mice were also sensitized to liver injury from a nontoxic dose of LPS or TNF?. The absence of jnk2 failed to reverse the GalN-induced block in C/EBP? induction by LPS, again demonstrating that C/EBP? degradation was JNK-independent.C/EBP? is up-regulated by TNF? and mediates hepatocyte resistance to TNF? toxicity by inhibiting caspase-dependent apoptosis. In the absence of NF-?B signaling, proteasomal degradation of C/EBP? is increased by a JNK-independent mechanism and promotes death from TNF?.

Dataset Information

Tumor protein p63/nuclear factor ?B feedback loop in regulation of cell death.

Publications

Tumor protein p63/nuclear factor κB feedback loop in regulation of cell death.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets