Abstract
The prostate apoptosis response-4 (par-4) gene was isolated in a differential screen for immediate-early genes that are up-regulated during apoptosis of prostate cancer cells. Unlike most other immediate-early genes, par-4 is exclusively induced during apoptosis. The expression or induction of par-4 is not restricted to prostatic cells. The par-4 gene is widely expressed in diverse normal tissues and cell types and conserved during evolution. Par-4 protein contains a leucine zipper domain that is essential for sensitization of cells to apoptosis. Functional studies indicate that par-4 expression is necessary to induce apoptosis. Par-4 protein may induce apoptosis by a p53-independent pathway that involves cytoplasmic inactivation of atypical protein kinase C isoforms resulting in down-regulation of MAP kinase activity and an up-regulation of p38 kinase activity. However, Par-4 is detected in the cytoplasm and in the nucleus, suggesting both cytoplasmic and nuclear roles for the pro-apoptotic protein. Interestingly, Par-4 is predicted to contain a death domain homologous to that of Fas or TRADD, and may therefore trigger a death cascade analogous to that of the death domain proteins. Par-4-dependent apoptosis is abrogated by Bcl-2 and by caspase inhibitors. Identification of the components of the p53-independent apoptosis pathway induced by Par-4 may help to further elucidate the mechanism of Par-4 action. Moreover, in view of the pro-apoptotic function of Par-4, its role in diseases, such as cancer and neurogenerative disorders, whose pathophysiology involves apoptotic cell death needs further investigation.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Williams GT. Programmed cell death: apoptosis and oncogenesis. Cell 1991; 65: 1097–1098.
Wyllie AH. Apoptosis and the regulation of cell numbers in normal and neoplastic tissues: An overview. Cancer Metast Rev 1992; 11: 95–103.
Kerr JFR, Winterford CM, Harmon V. Apoptosis. Its significance in cancer and cancer therapy. Cancer 1994; 73: 2013–2026.
Fraser A, Evan G. A license to kill. Cell 1996; 85: 781–784.
Liu ZG, Smith SW, McLaughlin KA, Schwartz LM, Osborne BA. Apoptotic signals delivered through the T-cell receptor of a T-cell hybrid require the immediate-early gene nur77. Nature 1994; 367: 281–284.
M, Bravo R, Johnson EM. Altered gene expression in neurons during programmed cell death: identification of c.-]un as necessary for neuronal apoptosis. J CellBiol 1994: 127: 1717–1727.
Packham G, Porter CW, Cleveland JL. c-Myc induces apoptosis and cell cycle progression by separable, yet overlapping, pathways. Oncogene 1996; 13: 461–469.
Preston GA, Lyon TT, Yin Y, et al. Induction of apoptosis by c-Fos protein. Mol Cell Biol 1996; 16: 211–218.
Nair P, Sells SF, Muthukkumar S, Sukhatme VP, Rangnekar VM. EGR-1 dependent apoptosis is mediated by p 53. J Biol Chem 1997; 272: 20131–20138.
Sells SF, Wood DP, Joshi-Barve SS, et al. Commonality of the gene programs induced by effectors of apoptosis in androgen-dependent and-independent prostate cells. Cell Growth Differ 1994; 5: 457–466.
Chinnaiyan AM, Dixit VM. The cell-death machine. Curr Biol 1996; 6: 355–562.
Chinnaiyan AM, Dixit VM. Portrait of an executioner: the molecular mechanism of FAS/APO-1-induced apoptosis. Semin lmmunol 1997; 9: 69–76.
Nicholson DW, Thornberry NA. Caspases: killer proteases. Trends Biochem Sci 1997; 22: 299–306.
Kothakota S, Azurna T, Reinhard C, et al. Caspase-3-generated fragment of gelsolin: effector of morphological change in apoptosis. Science 1997; 278: 294–298.
Sells SF, Han S-S, Muthukkumar S, et al. Expression and function of the leucine zipper protein Par-4 in apoptosis. M Cell Biol 1997; 17: 3823–3832.
Baffy G, Miyashita T, Williamson JR, Reed JC. Apoptosis induced by withdrawal of interleukin-3 (IL-3) from an IL-3-dependent hematopoietic cell line is associated with repartitioning of intracellular calcium and is blocked by enforced Bcl-2 oncoprotein production. J Biol Chem 1993; 268: 6511–6519.
Boghaert ER, Sells SF, Walid A-J, et al. Immunohisto-chemical analysis of the proapoptotic protein Par-4 in normal rat tissues. Cell Growth Differ 1997; 8: 881–890.
Diaz-Meco MT, Municio MM, Frutos S, et al. The product of par-4, a gene induced during apoptosis, interacts selectively with the atypical isoforms of protein kinase C. Cell 1996; 86: 777–786.
Cleveland JL, lhle JN. Contenders in FasL/TNF death signaling. Cell 1995; 81: 479–482.
Johnscone RW, See RH, Sells SF, et al. A novel repressor par-4 modulates transcription and growth suppression functions of the Wilms' tumor suppressor, WT1. Mol Cell Biol 1996; 16: 6945–6956.
Berra E, Municio MM, Sanz L, Frutos S, Diaz-Meco MT, Moscot J. Positioning atypical protein kinase C isoforms in the UV-induced apoptotic signaling cascade. Mol Cell Biol 1997; 17: 4346–4354.
Wheeler TM, Rogers E, Aihara M, Scardino PT, Thompson TC. Apoptotic index as a biomarker in prostatic intraepithelial neoplasia (PIN) and prostate cancer. J Cell Biochem 1994; 19: 202–207.