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Molecular and Cellular Biology, February 2005, p. 1146-1161, Vol. 25, No. 3
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.3.1146-1161.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Phosphorylation of Par-4 by Protein Kinase A Is Critical for Apoptosis

Sushma Gurumurthy,1 Anindya Goswami,2 Krishna Murthi Vasudevan,3 and Vivek M. Rangnekar1,2,3,4*

Graduate Center for Toxicology, Departments of,1 Radiation Medicine,2 Microbiology, Immunology, and Molecular Genetics,3 Markey Cancer Center, University of Kentucky, Lexington, Kentucky4

Received 16 September 2004/ Returned for modification 20 October 2004/ Accepted 28 October 2004

Despite distinct dissimilarities, diverse cancers express several common protumorigenic traits. We present here evidence that the proapoptotic protein Par-4 utilizes one such common tumorigenic trait to become selectively activated and induce apoptosis in cancer cells. Elevated protein kinase A (PKA) activity noted in cancer cells activated the apoptotic function of ectopic Par-4 or its SAC (selective for apoptosis induction in cancer cells) domain, which induces apoptosis selectively in cancer cells and not in normal or immortalized cells. PKA preferentially phosphorylated Par-4 at the T155 residue within the SAC domain in cancer cells. Moreover, pharmacological-, peptide-, or small interfering RNA-mediated inhibition of PKA activity in cancer cells resulted in abrogation of both T155 phosphorylation and apoptosis by Par-4. The mechanism of activation of endogenous Par-4 was similar to that of ectopic Par-4, and in response to exogenous stimuli, endogenous Par-4 induced apoptosis by a PKA- and phosphorylated T155-dependent mechanism. Enforced elevation of PKA activity in normal cells resulted in apoptosis by the SAC domain of Par-4 in a T155-dependent manner. Together, these observations suggest that selective apoptosis of cancer cells by the SAC domain of Par-4 involves phosphorylation of T155 by PKA. These findings uncover a novel mechanism engaging PKA, a procancerous activity commonly elevated in most tumor cells, to activate the cancer selective apoptotic action of Par-4.

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

Molecular and Cellular Biology, February 2005, p. 1146-1161, Vol. 25, No. 3
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.3.1146-1161.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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