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

Tanusree Sen, Nilkantha Sen, Yiping Huang, Debasish Sinha, Zhen Ge Luo, Edward A. Ratovitski, David Sidransky

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

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 NF-κB transcription and protein stability subsequently leading to the cell death phenotype.Wefound that TAp63α induced the expression of the p65 subunit of NF-κB (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 TAp63α-dependent regulation of cell death. We showed that TAp63α and RELA formed protein complexes resulted in their mutual stabilization and inhibition of the RELA ubiquitination. Finally, we showed that TAp63α directly induced RelA transcription by binding to and activating of its promoter and, in turn, leading to activation of the NF-κB-dependent cell death genes. Overall, our data defined the regulatory feedback loop between TAp63α and NF-κB involved in the activation of cell death process of cancer cells.

Original languageEnglish (US)
Pages (from-to)43204-43213
Number of pages10
JournalJournal of Biological Chemistry
Volume286
Issue number50
DOIs
Publication statusPublished - Dec 16 2011

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Sen, T., Sen, N., Huang, Y., Sinha, D., Luo, Z. G., Ratovitski, E. A., & Sidransky, D. (2011). Tumor protein p63/nuclear factor κB feedback loop in regulation of cell death. Journal of Biological Chemistry, 286(50), 43204-43213. https://doi.org/10.1074/jbc.M111.257105