| Description | Human Par-4/PAWR is a about 40 kDa protein containing 340 amino acids. Rat Par-4 has 332 amino acids whereas mouse Par-4 has 333 amino acids. Par-4/PAWR has two putative nuclear localization sequences in the N-terminal region and a leucine zipper domain and a nuclear export sequence in the C-terminal portion. There is a SAC domain (147-206 amino acids), selective for apoptosis induction in cancer cells. SAC domain is the effecter domain of Par-4/PAWR. These domains are 100% conserved in human, rat and mouse homologs. |
| Expression | Par-4/PAWR is ubiquitously expressed in normal mammalian tissues. However, Par-4/PAWR is diminished in a majority (>75% specimens) of renal cell carcinoma specimens. Par-4/PAWR expression is also decreased in endometrial tumors, neuroblastoma and in cells of patients with acute lymphatic leukemia and chronic lymphocytic leukemia. |
| Localisation | Immonocytochemical analysis indicates that Par-4/PAWR is predominantly localized in cytoplasm in normal cells and is strongly localized in cytoplasm and nucleus in most cancer cell lines. However, Western blot analysis indicates that Par-4/PAWR is also in the nuclear fraction of normal cells implying it is masked in the nucleus. |
| Function | Par-4/PAWR, a pro-apoptotic protein, was first identified in prostate cancer cells that were induced to undergo apoptosis. Par-4 knockout mice spontaneously develop tumors of the liver, lung, and endometrium; prostatic intraepithelial neoplasia, and an increased frequency of estrogen-inducible tumors in the endometrium and BBN-inducible tumors in the bladder. Endogenous Par-4/PAWR expressed in normal and cancer cells does not, by itself, causes apoptosis, yet is essential for apoptosis via diverse cell death pathways. Par-4/PAWR sensitizes cells to apoptosis by wide variety of pro-apoptotic stimuli, such as growth factor withdrawal, agents that elevate intracellular Ca2+, TNF, TRAIL, UV, X-ray and gamma irradiation, or IFN-gamma. Ectopic Par-4/PAWR over-expression is by itself sufficient to induce apoptosis in most cancer cells, but not in normal or immortalized cells. The cancer selective pro-apoptotic function of Par-4/PAWR is localized in its central core SAC (Selective for Apoptosis-induction in Cancer cells) domain (amino acids 147-206 in human Par-4/PAWR; or 137-195 in rat Par-4) which is 100% conserved in human, mouse and rat. Apoptosis by ectopic Par-4/PAWR requires Par-4/PAWR nuclear translocation and involves both activation of the Fas death receptor signaling pathway and NF-kappaB inhibition. Par-4/PAWR also inhibits the prosurvival protein Bcl-2 and down regulates ERK-2 expression. Neither p53 nor PTEN are directly required for apoptosis by Par-4/PAWR or the SAC domain. Par-4/PAWR has been shown to be i nvolved in suppression of transformation by down-regulation of Ras. Overexpression of Par-4/PAWR results in apoptosis of cells expressing oncogenic Ras.
Several partner proteins of Par-4/PAWR have been identified and partner interaction requires an intact Par-4/PAWR leucine zipper domain. Par-4/PAWR associates with aPKC resulting in inhibition of NF-kappaB activity, interaction with WT1 results in transcriptional repression of Bcl-2, whereas binding to and phosphorylation by Akt1 results in Par-4/PAWR cytoplasm retention by 14-3-3, thus isolating Par-4/PAWR from its nuclear targets. Par-4/PAWR also binds to DLK/ZIP kinase (ZIPK) and induces DAAX/ZIPK-mediated apoptosis. In addition, THAP1 (a novel nuclear pro-apoptotic factor) interacts with Par-4/PAWR and potentiates both serum withdrawal and TNF-induced apoptosis in endothelial cells.
Par-4/PAWR is also involved in sensitization of neurons to apoptosis. Endogenous Par-4/PAWR is reported to be up-regulated in different neurodegenerative diseases including Alzheimer's, Huntington's and Parkinson's diseases and amyotrophic lateral sclerosis.
Post-translational modifications: The apoptosis of Par-4/PAWR requires phosphorylation of the threonine residue (T155 in rat Par-4/PAWR) in the SAC domain by PKA, which is elevated in cancer cells. Amino acid S249 in rat Par-4/PAWR is phosphorylated by AKT for Par-4/PAWR cytoplasm retention and inactivation. |
| Homology | The Par-4/PAWR gene has been identified in various organisms, including mammals (Pan Troglodytes), rodents (mouse, rat), chicken (Gallus gallus), fish(Zebrafish and Pufferfish) and tadpole. The nuclear localization, leucine zipper, nuclear export and SAC domain sequences are highly conserved. |
| Commonality of the gene programs induced by effectors of apoptosis in androgen-dependent and -independent prostate cells. |
| Sells SF, Wood DP Jr, Joshi-Barve SS, Muthukumar S, Jacob RJ, Crist SA, Humphreys S, Rangnekar VM |
| Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research. 1994 ; 5 (4) : 457-466. |
| PMID 8043520 |
| |
| The product of par-4, a gene induced during apoptosis, interacts selectively with the atypical isoforms of protein kinase C. |
| Dˆ‚az-Meco MT, Municio MM, Frutos S, Sanchez P, Lozano J, Sanz L, Moscat J |
| Cell. 1996 ; 86 (5) : 777-786. |
| PMID 8797824 |
| |
| A novel repressor, par-4, modulates transcription and growth suppression functions of the Wilms' tumor suppressor WT1. |
| Johnstone RW, See RH, Sells SF, Wang J, Muthukkumar S, Englert C, Haber DA, Licht JD, Sugrue SP, Roberts T, Rangnekar VM, Shi Y |
| Molecular and cellular biology. 1996 ; 16 (12) : 6945-6956. |
| PMID 8943350 |
| |
| Expression and function of the leucine zipper protein Par-4 in apoptosis. |
| Sells SF, Han SS, Muthukkumar S, Maddiwar N, Johnstone R, Boghaert E, Gillis D, Liu G, Nair P, Monnig S, Collini P, Mattson MP, Sukhatme VP, Zimmer SG, Wood DP Jr, McRoberts JW, Shi Y, Rangnekar VM |
| Molecular and cellular biology. 1997 ; 17 (7) : 3823-3832. |
| PMID 9199316 |
| |
| Par-4 is a mediator of neuronal degeneration associated with the pathogenesis of Alzheimer disease. |
| Guo Q, Fu W, Xie J, Luo H, Sells SF, Geddes JW, Bondada V, Rangnekar VM, Mattson MP |
| Nature medicine. 1998 ; 4 (8) : 957-962. |
| PMID 9701251 |
| |
| Mapping of the human PAWR (par-4) gene to chromosome 12q21. |
| Johnstone RW, Tommerup N, Hansen C, Vissing H, Shi Y |
| Genomics. 1998 ; 53 (2) : 241-243. |
| PMID 9790775 |
| |
| Inactivation of the inhibitory kappaB protein kinase/nuclear factor kappaB pathway by Par-4 expression potentiates tumor necrosis factor alpha-induced apoptosis. |
| Diaz-Meco MT, Lallena MJ, Monjas A, Frutos S, Moscat J |
| The Journal of biological chemistry. 1999 ; 274 (28) : 19606-19612. |
| PMID 10391896 |
| |
| Prostate apoptosis response-4 production in synaptic compartments following apoptotic and excitotoxic insults: evidence for a pivotal role in mitochondrial dysfunction and neuronal degeneration. |
| Duan W, Rangnekar VM, Mattson MP |
| Journal of neurochemistry. 1999 ; 72 (6) : 2312-2322. |
| PMID 10349840 |
| |
| Oncogenic Ras sensitizes cells to apoptosis by Par-4. |
| Nalca A, Qiu SG, El-Guendy N, Krishnan S, Rangnekar VM |
| The Journal of biological chemistry. 1999 ; 274 (42) : 29976-29983. |
| PMID 10514481 |
| |
| Participation of par-4 in the degeneration of striatal neurons induced by metabolic compromise with 3-nitropropionic acid. |
| Duan W, Guo Z, Mattson MP |
| Experimental neurology. 2000 ; 165 (1) : 1-11. |
| PMID 10964480 |
| |
| The prostate apoptosis response-4 protein participates in motor neuron degeneration in amyotrophic lateral sclerosis. |
| Pedersen WA, Luo H, Kruman I, Kasarskis E, Mattson MP |
| The FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2000 ; 14 (7) : 913-924. |
| PMID 10783145 |
| |
| Par-4 drives trafficking and activation of Fas and Fasl to induce prostate cancer cell apoptosis and tumor regression. |
| Chakraborty M, Qiu SG, Vasudevan KM, Rangnekar VM |
| Cancer research. 2001 ; 61 (19) : 7255-7263. |
| PMID 11585763 |
| |
| Regulation of apoptosis in prostate cancer. |
| Gurumurthy S, Vasudevan KM, Rangnekar VM |
| Cancer metastasis reviews. 2001 ; 20 (3-4) : 225-243. |
| PMID 12085964 |
| |
| Apoptosis by Par-4 in cancer and neurodegenerative diseases. |
| El-Guendy N, Rangnekar VM |
| Experimental cell research. 2003 ; 283 (1) : 51-66. |
| PMID 12565819 |
| |
| Identification of a unique core domain of par-4 sufficient for selective apoptosis induction in cancer cells. |
| El-Guendy N, Zhao Y, Gurumurthy S, Burikhanov R, Rangnekar VM |
| Molecular and cellular biology. 2003 ; 23 (16) : 5516-5525. |
| PMID 12897127 |
| |
| ZIP kinase triggers apoptosis from nuclear PML oncogenic domains. |
| Kawai T, Akira S, Reed JC |
| Molecular and cellular biology. 2003 ; 23 (17) : 6174-6186. |
| PMID 12917339 |
| |
| Regulation of mature T lymphocyte proliferation and differentiation by Par-4. |
| Lafuente MJ, Martin P, Garcia-Cao I, Diaz-Meco MT, Serrano M, Moscat J |
| The EMBO journal. 2003 ; 22 (18) : 4689-4698. |
| PMID 12970181 |
| |
| Binding and phosphorylation of par-4 by akt is essential for cancer cell survival. |
| Goswami A, Burikhanov R, de Thonel A, Fujita N, Goswami M, Zhao Y, Eriksson JE, Tsuruo T, Rangnekar VM |
| Molecular cell. 2005 ; 20 (1) : 33-44. |
| PMID 16209943 |
| |
| Phosphorylation of Par-4 by protein kinase A is critical for apoptosis. |
| Gurumurthy S, Goswami A, Vasudevan KM, Rangnekar VM |
| Molecular and cellular biology. 2005 ; 25 (3) : 1146-1161. |
| PMID 15657440 |
| |
| Inactivation of the candidate tumor suppressor par-4 in endometrial cancer. |
| Moreno-Bueno G, Fernandez-Marcos PJ, Collado M, Tendero MJ, Rodriguez-Pinilla SM, Garcia-Cao I, Hardisson D, Diaz-Meco MT, Moscat J, Serrano M, Palacios J |
| Cancer research. 2007 ; 67 (5) : 1927-1934. |
| PMID 17332319 |
| |