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Gene Section Mini Review Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Mini Review PAWR (PRKC apoptosis WT1 regulator protein) Yanming Zhao, Vivek M Rangnekar Department of Radiation Medicine, University of Kentucky, Combs Research Building, Room 309, Lexington, Kentucky 40536, USA Published in Atlas Database: August 2007 Online updated version: http://AtlasGeneticsOncology.org/Genes/PAWRID41641ch12q21.html DOI: 10.4267/2042/38496 This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence. © 2008 Atlas of Genetics and Cytogenetics in Oncology and Haematology Identity Expression Par-4/PAWR is ubiquitously expressed in normal Hugo: PAWR mammalian tissues. However, Par-4/PAWR is Other names: Par-4 (Prostate apoptosis gene 4); PAR4 diminished in a majority (>75% specimens) of renal Location: 12q21.2 cell carcinoma specimens. Par-4/PAWR expression is Local order: Synaptotagmin I 12q21.2 on plus strand also decreased in endometrial tumors, neuroblastoma protein phosphatase 1, regulatory (inhibitor) subunit and in cells of patients with acute lymphatic leukemia 12A 12q21.2 on minus strand PAWR 12q21.2 on and chronic lymphocytic leukemia. minus strand protein tyrosine phosphatase, receptor type, Q 12q21.2 on plus strand. Localisation Immonocytochemical analysis indicates that Par- DNA/RNA 4/PAWR is predominantly localized in cytoplasm in normal cells and is strongly localized in cytoplasm and Description nucleus in most cancer cell lines. However, Western Genomic regions: Par-4/PAWR gene is encoded by the blot analysis indicates that Par-4/PAWR is also in the minus strand of chromosome 12q21.2. The gene nuclear fraction of normal cells implying it is masked encompasses 99.064 kb of DNA; 7 exons and 6 introns. in the nucleus. ATG is located on exon 2. Function Transcription Par-4/PAWR, a pro-apoptotic protein, was first 2.2 kb nucleotides mRNA. 1.02 kb open reading frame. identified in prostate cancer cells that were induced to Pseudogene undergo apoptosis. Par-4 knockout mice spontaneously develop tumors of the liver, lung, and endometrium; Not known. prostatic intraepithelial neoplasia, and an increased frequency of estrogen-inducible tumors in the Protein endometrium and BBN-inducible tumors in the bladder. Endogenous Par-4/PAWR expressed in normal Description and cancer cells does not, by itself, causes apoptosis, Human Par-4/PAWR is a about 40 kDa protein yet is essential for apoptosis via diverse cell death containing 340 amino acids. Rat Par-4 has 332 amino pathways. Par-4/PAWR sensitizes cells to apoptosis by acids whereas mouse Par-4 has 333 amino acids. Par- wide variety of pro-apoptotic stimuli, such as growth 4/PAWR has two putative nuclear localization factor withdrawal, agents that elevate intracellular Ca 2+ , sequences in the N-terminal region and a leucine zipper TNF, TRAIL, UV, X-ray and gamma irradiation, or domain and a nuclear export sequence in the C-terminal IFN-gamma. Ectopic Par-4/PAWR over-expression is portion. There is a SAC domain (147-206 amino acids), by itself sufficient to induce apoptosis in most cancer selective for apoptosis induction in cancer cells. SAC cells, but not in normal or immortalized cells. The domain is the effecter domain of Par-4/PAWR. These cancer selective pro-apoptotic function of Par-4/PAWR domains are 100% conserved in human, rat and mouse is localized in its central core SAC (Selective for homologs. Apoptosis-induction in Cancer cells) domain (amino Atlas Genet Cytogenet Oncol Haematol. 2008;12(2) 122 PAWR (PRKC apoptosis WT1 regulator protein) Zhao Y, Rangnekar V acids 147-206 in human Par-4/PAWR; or 137-195 in rat Par-4) which is 100% conserved in human, mouse Implicated in and rat. Apoptosis by ectopic Par-4/PAWR requires Renal cell carcinoma and endometrial Par-4/PAWR nuclear translocation and involves both tumors activation of the Fas death receptor signaling pathway and NF-kappaB inhibition. Par-4/PAWR also inhibits Note: Par-4/PAWR is down regulated in over 75% of the prosurvival protein Bcl-2 and down regulates ERK- clear cell type of renal cell carcinoma, and in 2 expression. Neither p53 nor PTEN are directly endometrial tumors. It is mutated within its effector required for apoptosis by Par-4/PAWR or the SAC SAC domain in endometrial tumors. domain. Par-4/PAWR has been shown to be involved in suppression of transformation by down-regulation of References Ras. Overexpression of Par-4/PAWR results in Sells SF, Wood DP Jr, Joshi-Barve SS, Muthukumar S, Jacob apoptosis of cells expressing oncogenic Ras. RJ, Crist SA, Humphreys S, Rangnekar VM. Commonality of Several partner proteins of Par-4/PAWR have been the gene programs induced by effectors of apoptosis in identified and partner interaction requires an intact Par- androgen-dependent and -independent prostate cells.. Cell Growth Differ 1994;5:457-466. 4/PAWR leucine zipper domain. Par-4/PAWR associates with aPKC resulting in inhibition of NF- Díaz-Meco MT, Municio MM, Frutos S, Sanchez P, Lozano J, kappaB activity, interaction with WT1 results in Sanz L, Moscat J. The product of Par-4, a gene induced during apoptosis, interacts selectively with the atypical isoforms of transcriptional repression of Bcl-2, whereas binding to protein kinase C. Cell 1996;86:777-786. and phosphorylation by Akt1 results in Par-4/PAWR Johnstone RW, See RH, Sells SF, Wang J, Muthukkumar S, cytoplasm retention by 14-3-3, thus isolating Par- Englert C, Haber DA, Licht JD, Sugrue SP, Roberts T, 4/PAWR from its nuclear targets. Par-4/PAWR also Rangnekar VM, Shi Y. A novel repressor, Par-4, modulates binds to DLK/ZIP kinase (ZIPK) and induces transcription and growth suppression functions of the Wilms' DAAX/ZIPK-mediated apoptosis. In addition, THAP1 tumor suppressor WT1. Mol Cell Biol 1996;16(12):6945-6956. (a novel nuclear pro-apoptotic factor) interacts with Sells SF, Han SS, Muthukkumar S, Maddiwar N, Johnstone R, Par-4/PAWR and potentiates both serum withdrawal Boghaert E, Gillis D, Liu G, Nair P, Monnig S, Collini P, and TNF-induced apoptosis in endothelial cells. Mattson MP, Sukhatme VP, Zimmer SG, Wood DP Jr, McRoberts JW, Shi Y, Rangnekar VM. Expression and function Par-4/PAWR is also involved in sensitization of of the leucine zipper protein Par-4 in apoptosis. Mol Cell Biol neurons to apoptosis. Endogenous Par-4/PAWR is 1997;17:3823-3832. reported to be up-regulated in different Guo Q, Fu W, Xie J, Luo H, Sells SF, Geddes JW, Bondada V, neurodegenerative diseases including Alzheimer's, Rangnekar VM, Mattson MP. Par-4 is a mediator of neuronal Huntington's and Parkinson's diseases and amyotrophic degeneration associated with the pathogenesis of Alzheimer lateral sclerosis. disease. Nat Med 1998;4:957-996. Post-translational modifications: The apoptosis of Par- Johnstone RW, Tommerup N, Hansen C, Vissing H, Shi Y. 4/PAWR requires phosphorylation of the threonine Mapping of the human PAWR (Par-4) gene to chromosome residue (T155 in rat Par-4/PAWR) in the SAC domain 12q21. Genomics 1998;53(2):241-243. by PKA, which is elevated in cancer cells. Amino acid Díaz-Meco MT, Lallena MJ, Monjas A, Frutos S, Moscat J. S249 in rat Par-4/PAWR is phosphorylated by AKT for Inactivation of the inhibitory kappaB protein kinase/nuclear Par-4/PAWR cytoplasm retention and inactivation. factor kappaB pathway by Par-4 expression potentiates tumor necrosis factor alpha-induced apoptosis. Bio l Chem Homology 1999;274(28):19606-19612. The Par-4/PAWR gene has been identified in various Duan W, Rangnekar VM, Mattson MP. Prostate apoptosis organisms, including mammals (Pan troglodytes), response-4 production in synaptic compartments following apoptotic and excitotoxic insults: Evidence for a pivotal role in rodents (mouse, rat), chicken (Gallus gallus), fish mitochondrial dysfunction and neuronal degeneration. J (Zebrafish and Pufferfish) and tadpole. The nuclear Neurochem 1999;72:2312-232. localization, leucine zipper, nuclear export and SAC Nalca A, Qiu SG, El-Guendy N, Krishnan S, Rangnekar VM. domain sequences are highly conserved. Oncogenic Ras sensitizes cells to apoptosis by Par-4. J Biol Chem 1999;274(42):29976-29983. Mutations Duan W, Guo Z, Mattson MP. Participation of Par-4 in the degeneration of striatal neurons induced by metabolic Note: Par-4/PAWR mutations are uncommon although compromise with 3-nitropropionic acid. Exp Neurol 2000;165:1- a single base mutation (Arg (CGA) 189 (TGA) Stop) 11. localized in exon 3 or the SAC domain has been found Pedersen WA, Luo H, Kruman I, Kasarskis E, Mattson MP. in endometrial carcinoma. The prostate apoptosis response-4 protein participates in Atlas Genet Cytogenet Oncol Haematol. 2008;12(2) 123 PAWR (PRKC apoptosis WT1 regulator protein) Zhao Y, Rangnekar V motor neuron degeneration in amyotrophic lateral sclerosis. Lafuente MJ, Martin P, Garcia-Cao I, Diaz-Meco MT, Serrano FASEB J 2000;14:913-924. M, Moscat J. Regulation of mature T lymphocyte proliferation and differentiation by Par-4. EMBO J 2003;22(18):4689-4698. Chakraborty M, Qiu SG, Vasudevan KM, Rangnekar VM. Par-4 drives trafficking and activation of Fas and FasL to induce Goswami A, Burikhanov R, de Thonel A, Fujita N, Goswami M, prostate cancer cell apoptosis and tumor Regression. Cancer Zhao Y, Eriksson JE, Tsuruo T, Rangnekar VM. Binding and Research 2001;61:7255-7263. phosphorylation of Par-4 by Akt is essential for cancer cell survival. Mol. Cell 2005;20(1):33-44. Gurumurthy S, Vasudevan KM, Rangnekar VM. Regulation of apoptosis in prostate cancer. Cancer Metastasis Rev Gurumurthy S, Goswami A, Vasudevan KM, Rangnekar VM. 2001;20(3-4):225-243. Phosphorylation of Par-4 by protein kinase A is critical for apoptosis.
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