Identification of a unique core domain of Par-4 sufficient for selective apoptosis induction in cancer cells

Nadia El-Guendy, Yanming Zhao, Sushma Gurumurthy, Ravshan Burikhanov, Vivek M. Rangnekar

Research output: Contribution to journalArticlepeer-review

144 Scopus citations

Abstract

Recent studies indicated that the leucine zipper domain protein Par-4 induces apoptosis in certain cancer cells by activation of the Fas prodeath pathway and coparallel inhibition of NF-κB transcriptional activity. However, the intracellular localization or functional domains of Par-4 involved in apoptosis remained unknown. In the present study, structure-function analysis indicated that inhibition of NF-κB activity and apoptosis is dependent on Par-4 translocation to the nucleus via a bipartite nuclear localization sequence, NLS2. Cancer cells that were resistant to Par-4-induced apoptosis retained Par-4 in the cytoplasm. Interestingly, a 59-amino-acid core that included NLS2 but not the C-terminal leucine zipper domain was necessary and sufficient to induce Fas pathway activation, inhibition of NF-κB activity, and apoptosis. Most important, this core domain had an expanded target range for induction of apoptosis, extending to previously resistant cancer cells but not to normal cells. These findings have identified a unique death-inducing domain selective for apoptosis induction in cancer cells (SAC domain) which holds promise for identifying key differences between cancer and normal cells and for molecular therapy of cancer.

Original languageEnglish
Pages (from-to)5516-5525
Number of pages10
JournalMolecular and Cellular Biology
Volume23
Issue number16
DOIs
StatePublished - Aug 2003

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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