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Molecular and Cellular Biology, August 2003, p. 5516-5525, Vol. 23, No. 16
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.16.5516-5525.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Identification of a Unique Core Domain of Par-4 Sufficient for Selective Apoptosis Induction in Cancer Cells

Nadia El-Guendy,1 Yanming Zhao,2 Sushma Gurumurthy,3 Ravshan Burikhanov,2 and Vivek M. Rangnekar1,2,3,4*

Departments of Microbiology, Immunology and Molecular Genetics,1 Radiation Medicine,2 Graduate Center for Toxicology,3 Markey Cancer Center, University of Kentucky, Lexington, Kentucky 405364

Received 31 December 2002/ Returned for modification 7 February 2003/ Accepted 19 May 2003

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-{kappa}B 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-{kappa}B 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-{kappa}B 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.

* Corresponding author. Mailing address: Department of Radiation Medicine, University of Kentucky, Combs Research Building, Rm. 303, 800 Rose Street, Lexington, KY 40536. Phone: (859) 257-2677. Fax: (859) 257-9608. E-mail: vmrang01{at}pop.uky.edu.

Molecular and Cellular Biology, August 2003, p. 5516-5525, Vol. 23, No. 16
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.16.5516-5525.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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