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Gene Review

PAWR  -  PRKC, apoptosis, WT1, regulator

Homo sapiens

Synonyms: PAR4, PRKC apoptosis WT1 regulator protein, Par-4, Prostate apoptosis response 4 protein, par-4
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Disease relevance of PAWR


Psychiatry related information on PAWR

  • Par-4 (prostate apoptosis response-4) is a leucine zipper protein involved in neuronal degeneration and cholinergic signaling in Alzheimer's disease [6].
  • Our data suggest that Par-4 may be a mediator of neuronal apoptosis in HIV encephalitis and that therapeutic approaches targeting the Par-4 apoptotic cascade may prove beneficial in preventing neuronal degeneration and associated dementia in patients infected with HIV-1 [4].

High impact information on PAWR


Chemical compound and disease context of PAWR


Biological context of PAWR


Anatomical context of PAWR

  • In addition, we found that Par-4 is a component of PML NBs in blood vessels, a major site of PML expression in vivo [16].
  • Intracellular Ca2+ levels were assessed in A549 cells and in mouse fibroblasts expressing the human protease activated receptor (PAR)1, PAR2 or PAR4 [17].
  • Finally, ectopic Par-4 expression significantly reduced Ras-mediated growth in soft agar, but not morphological transformation, highlighting the importance of Par-4 down-regulation in specific aspects of Ras-mediated transformation of epithelial cells [18].
  • Given its pro-apoptotic role in neoplastic lymphocytes and evidence that par-4 antagonizes oncogenic Ras in solid tumors, we hypothesized that par-4 may act as a tumor suppressor impairing transformation induced by p185(BCR-ABL) [19].
  • Par-4 was not detected in the substantia nigra pars compacta [20].

Associations of PAWR with chemical compounds

  • The leucine repeat domain of par-4 was shown to interact with the zinc finger DNA binding domain of WT1 [21].
  • The decrease in the Bcl-2 protein and transcript following all-trans-retinoic acid treatment was accompanied by changes in localization of Par-4 and an induction in the expression of WT1 protein [22].
  • Platelet activation by thrombin, a serine protease, occurs by binding to and cleavage of the extracellular N-terminal domains of protease-activated receptors 1 and 4 (PAR1 and PAR4) [23].
  • Inhibition of PAR4 signaling mediates ethanol-induced attenuation of platelet function in vitro [24].
  • However, our results showed almost identical levels of peak calcium between wild-type or PAR-4 null mice when stimulated with either ADP or U46619 [25].

Enzymatic interactions of PAWR

  • ZIPK also binds and phosphorylates proapoptotic protein Par-4 [26].

Regulatory relationships of PAWR

  • Association of ZIPK with Daxx was enhanced by coexpression of Par-4 [26].
  • We conclude that Par-4 regulates Bcl-2 through a WT1-binding site on the bcl-2 promoter [22].
  • Furthermore, inhibition of caspase activity by the broad spectrum caspase inhibitor BD-fmk significantly attenuated the Par-4-induced increase in Abeta 1-42 production [27].
  • Prostate apoptosis response-4 enhances secretion of amyloid beta peptide 1-42 in human neuroblastoma IMR-32 cells by a caspase-dependent pathway [27].
  • CONCLUSION: We provide the first evidence that par-4 exhibits an antitransforming capacity by antagonizing p185(BCR-ABL)-induced factor-independent proliferation in hematopoietic cells [19].

Other interactions of PAWR


Analytical, diagnostic and therapeutic context of PAWR


  1. Par-4 is a mediator of neuronal degeneration associated with the pathogenesis of Alzheimer disease. Guo, Q., Fu, W., Xie, J., Luo, H., Sells, S.F., Geddes, J.W., Bondada, V., Rangnekar, V.M., Mattson, M.P. Nat. Med. (1998) [Pubmed]
  2. Par4 is a coactivator for a splice isoform-specific transcriptional activation domain in WT1. Richard, D.J., Schumacher, V., Royer-Pokora, B., Roberts, S.G. Genes Dev. (2001) [Pubmed]
  3. Expression and function of the leucine zipper protein Par-4 in apoptosis. Sells, S.F., Han, S.S., Muthukkumar, S., Maddiwar, N., Johnstone, R., Boghaert, E., Gillis, D., Liu, G., Nair, P., Monnig, S., Collini, P., Mattson, M.P., Sukhatme, V.P., Zimmer, S.G., Wood, D.P., McRoberts, J.W., Shi, Y., Rangnekar, V.M. Mol. Cell. Biol. (1997) [Pubmed]
  4. Evidence that Par-4 participates in the pathogenesis of HIV encephalitis. Kruman, I.I., Nath, A., Maragos, W.F., Chan, S.L., Jones, M., Rangnekar, V.M., Jakel, R.J., Mattson, M.P. Am. J. Pathol. (1999) [Pubmed]
  5. Inactivation of the candidate tumor suppressor par-4 in endometrial cancer. Moreno-Bueno, G., Fernandez-Marcos, P.J., Collado, M., Tendero, M.J., Rodriguez-Pinilla, S.M., Garcia-Cao, I., Hardisson, D., Diaz-Meco, M.T., Moscat, J., Serrano, M., Palacios, J. Cancer Res. (2007) [Pubmed]
  6. Par-4 inhibits choline uptake by interacting with CHT1 and reducing its incorporation on the plasma membrane. Xie, J., Guo, Q. J. Biol. Chem. (2004) [Pubmed]
  7. Complete polarization of single intestinal epithelial cells upon activation of LKB1 by STRAD. Baas, A.F., Kuipers, J., van der Wel, N.N., Batlle, E., Koerten, H.K., Peters, P.J., Clevers, H.C. Cell (2004) [Pubmed]
  8. The product of par-4, a gene induced during apoptosis, interacts selectively with the atypical isoforms of protein kinase C. Díaz-Meco, M.T., Municio, M.M., Frutos, S., Sanchez, P., Lozano, J., Sanz, L., Moscat, J. Cell (1996) [Pubmed]
  9. 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, J.E., Tsuruo, T., Rangnekar, V.M. Mol. Cell (2005) [Pubmed]
  10. Apoptosis by Par-4 in cancer and neurodegenerative diseases. El-Guendy, N., Rangnekar, V.M. Exp. Cell Res. (2003) [Pubmed]
  11. Mapping of the human PAWR (par-4) gene to chromosome 12q21. Johnstone, R.W., Tommerup, N., Hansen, C., Vissing, H., Shi, Y. Genomics (1998) [Pubmed]
  12. Differential involvement of thrombin receptors in Ca2+ release from two different intracellular stores in human platelets. Jardin, I., Ben Amor, N., Bartegi, A., Pariente, J.A., Salido, G.M., Rosado, J.A. Biochem. J. (2007) [Pubmed]
  13. Phosphorylation of Par-4 by protein kinase A is critical for apoptosis. Gurumurthy, S., Goswami, A., Vasudevan, K.M., Rangnekar, V.M. Mol. Cell. Biol. (2005) [Pubmed]
  14. Localization of atypical protein kinase C isoforms into lysosome-targeted endosomes through interaction with p62. Sanchez, P., De Carcer, G., Sandoval, I.V., Moscat, J., Diaz-Meco, M.T. Mol. Cell. Biol. (1998) [Pubmed]
  15. 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, V.M. Mol. Cell. Biol. (2003) [Pubmed]
  16. THAP1 is a nuclear proapoptotic factor that links prostate-apoptosis-response-4 (Par-4) to PML nuclear bodies. Roussigne, M., Cayrol, C., Clouaire, T., Amalric, F., Girard, J.P. Oncogene (2003) [Pubmed]
  17. House dust mite major allergens Der p 1 and Der p 5 activate human airway-derived epithelial cells by protease-dependent and protease-independent mechanisms. Kauffman, H.F., Tamm, M., Timmerman, J.A., Borger, P. Clinical and molecular allergy [electronic resource] : CMA. (2006) [Pubmed]
  18. Ras-mediated loss of the pro-apoptotic response protein Par-4 is mediated by DNA hypermethylation through Raf-independent and Raf-dependent signaling cascades in epithelial cells. Pruitt, K., Ulkü, A.S., Frantz, K., Rojas, R.J., Muniz-Medina, V.M., Rangnekar, V.M., Der, C.J., Shields, J.M. J. Biol. Chem. (2005) [Pubmed]
  19. Prostate apoptosis response gene-4 (par-4) abrogates the survival function of p185(BCR-ABL) in hematopoietic cells. Kukoc-Zivojnov, N., Puccetti, E., Chow, K.U., Bergmann, M., Ruthardt, M., Hoelzer, D., Mitrou, P.S., Weidmann, E., Boehrer, S. Exp. Hematol. (2004) [Pubmed]
  20. Absence of prostate apoptosis response-4 protein in substantia nigra of Parkinson's disease autopsies. Moos, T., Jensen, P.H. Acta Neuropathol. (2004) [Pubmed]
  21. A novel repressor, par-4, modulates transcription and growth suppression functions of the Wilms' tumor suppressor WT1. Johnstone, R.W., See, R.H., Sells, S.F., Wang, J., Muthukkumar, S., Englert, C., Haber, D.A., Licht, J.D., Sugrue, S.P., Roberts, T., Rangnekar, V.M., Shi, Y. Mol. Cell. Biol. (1996) [Pubmed]
  22. Par-4 transcriptionally regulates Bcl-2 through a WT1-binding site on the bcl-2 promoter. Cheema, S.K., Mishra, S.K., Rangnekar, V.M., Tari, A.M., Kumar, R., Lopez-Berestein, G. J. Biol. Chem. (2003) [Pubmed]
  23. Synthesis of Novel Peptide Inhibitors of Thrombin-induced Platelet Activation. Burke, F.M., Warnock, M., Schmaier, A.H., Mosberg, H.I. Chemical biology & drug design (2006) [Pubmed]
  24. Inhibition of PAR4 signaling mediates ethanol-induced attenuation of platelet function in vitro. Kasuda, S., Sakurai, Y., Shima, M., Morimura, Y., Kudo, R., Takeda, T., Ishitani, A., Yoshioka, A., Hatake, K. Alcohol. Clin. Exp. Res. (2006) [Pubmed]
  25. Do heterotrimeric G proteins redistribute upon G protein-coupled receptor stimulation in platelets? Kahner, B.N., Quinton, T.M., Langan, S., Kunapuli, S.P. Platelets (2006) [Pubmed]
  26. ZIP kinase triggers apoptosis from nuclear PML oncogenic domains. Kawai, T., Akira, S., Reed, J.C. Mol. Cell. Biol. (2003) [Pubmed]
  27. Prostate apoptosis response-4 enhances secretion of amyloid beta peptide 1-42 in human neuroblastoma IMR-32 cells by a caspase-dependent pathway. Guo, Q., Xie, J., Chang, X., Du, H. J. Biol. Chem. (2001) [Pubmed]
  28. Identification of mechanically induced genes in human monocytic cells by DNA microarrays. Ohki, R., Yamamoto, K., Mano, H., Lee, R.T., Ikeda, U., Shimada, K. J. Hypertens. (2002) [Pubmed]
  29. Thrombin inhibits intercellular calcium wave propagation in corneal endothelial cells by modulation of hemichannels and gap junctions. D'hondt, C., Ponsaerts, R., Srinivas, S.P., Vereecke, J., Himpens, B. Invest. Ophthalmol. Vis. Sci. (2007) [Pubmed]
  30. Mutually exclusive expression patterns of Bcl-2 and Par-4 in human prostate tumors consistent with down-regulation of Bcl-2 by Par-4. Qiu, G., Ahmed, M., Sells, S.F., Mohiuddin, M., Weinstein, M.H., Rangnekar, V.M. Oncogene (1999) [Pubmed]
  31. Par-4: an emerging pivotal player in neuronal apoptosis and neurodegenerative disorders. Mattson, M.P., Duan, W., Chan, S.L., Camandola, S. J. Mol. Neurosci. (1999) [Pubmed]
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