Prostate apoptosis response-4 (Par-4) is a protein containing both a leucine zipper and a death domain that was isolated by differential screening for genes upregulated in prostate cancer cells undergoing apoptosis. Par-4 is expressed in the nervous system, where its function is unknown. In Alzheimer disease (AD), neurons may die by apoptosis, and amyloid beta-protein (A beta) may play a role in this. We report here that Par-4 expression is increased in vulnerable neurons in AD brain and is induced in cultured neurons undergoing apoptosis. Blockade of Par-4 expression or function prevented neuronal apoptosis induced by Ab and trophic factor withdrawal. Par-4 expression was enhanced, and mitochondrial dysfunction and apoptosis exacerbated, in cells expressing presenilin-1 mutations associated with early-onset inherited AD.

Apoptosis, a genetically controlled process of cell death, plays a central role in metazoan development and homeostasis (61,74). The apoptotic program is highly conserved during evolution, and striking similarities have been observed in the cell death programs of rodents, mammalian cells, Drosophila melanogaster, and Caenorhabditis elegans (28,81,85,91). In normally proliferating cells, the apoptotic program is actively suppressed or inactivated; however, withdrawal or inhibition of the apoptosis suppressor mechanisms triggers apoptotic pathways (16,37,86). One mechanism by which apoptotic gene products may be prevented from executing their effect may involve direct interaction with specific proteins that act to attenuate the function of the apoptotic activators or effectors. The interaction between antiapoptotic protein Bcl-2 and proapoptotic protein Bax illustrates this point: whether a cell undergoes apoptosis or not is dependent upon the relative levels of these two proteins; an excess of Bax will trigger apoptosis, whereas an excess of Bcl-2 will prevent apoptosis (38,66,68,89,90). Identification of other such antiapoptotic and proapoptotic protein pairs that dictate the survival of cells should enhance our understanding of the apoptosis process.Apoptosis is characterized by cell membrane blebbing, chromatin condensation, changes in nuclear architecture, and oligonucleosome-length DNA fragmentation (87, 88). The process of apoptotic cell death is triggered by diverse stimuli such as cytokines, withdrawal of growth factors, DNA damage, expression of oncogenes or immediate-early genes, and fluctuations in the levels of Bcl-2 family members (3,13,16,37,47,48,54,71,78,86,89). Certain apoptotic stimuli can sequentially activate the basal cell death machinery composed of initiator, amplifier, and effector proteases belonging to the interleukin-1-converting enzyme (ICE) subfamily or an ICE-related family (9,17,21,41,46,91). Downstream targets of these proteases include the ICE subfamily proteases themselves; nuclear enzymes poly(ADP-ribose) polymerase and DNA-dependent protein kinase, which are involved in DNA repair; the nuclear protein U1 ribonucleoprotein and nuclear lamins; and cytoplasmic components such as protein kinase C␦ and cytoskeleton components such as actin (cited in reference 21). However, it is unclear whether any of these cellular components are directly linked to the morphological changes associated with apoptosis.Prostate tissue, which is composed of androgen-dependent and -independent cells (8, 58), provides an excellent model system for studying apoptosis. Androgen ablation in animals leads to an elevation of intracellular calcium that subsequently results in apoptosis of the androgen-dependent but not of the androgen-independent prostatic cells (11,(42)(43)(44). However, apoptosis can be induced in androgen-independent cell cultures by artificially upregulating intracellular calcium with calcium ionophores (53, 69) or with thapsigargin (TG) (22), an

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The early growth response-1 (EGR-1) protein is an anti-proliferative signal for certain tumor cells and is required for apoptosis induced by stimuli that elevate intracellular Ca 2؉. We present evidence that EGR-1 transactivates the promoter of the p53 gene and upregulates p53 RNA and protein levels. Inhibition of p53 function with dominant-negative p53 mutants abrogates EGR-1-dependent apoptosis. These findings establish a direct functional link between EGR-1 and the p53-mediated cell death pathway and suggest that mutant forms of p53 in tumor cells may provide resistance to the antiproliferative effects of EGR-1.Apoptosis, or programmed cell death, a genetic process of coordinated deletion of selective cells, is essential for metazoan development and homeostasis (1-4). The primordial forms of apoptosis in Caenorhabditis elegans and Drosophila have been recapitulated in mammalian cells, and striking similarities have been observed in the cell death programs of invertebrates and vertebrates (5-7). Apoptosis is characterized by cell membrane blebbing, chromatin condensation, changes in nuclear architecture, and oligonucleosome-length DNA fragmentation (8, 9). The apoptotic pathways consist of an early component that includes molecular events that are specific for an inducer or a group of inducers and of downstream effector components that are common to diverse apoptotic signals (10). The common components include a basal cell death machinery composed of initiator, amplifier, and effector proteases belonging to the interleukin-1 converting enzyme subfamily or an interleukin-1 converting enzyme-related family (10 -14). Downstream targets of these proteases include the interleukin-1 converting enzyme subfamily proteases themselves; the nuclear enzymes poly(ADP-ribose) polymerase and DNA-dependent protein kinase, which are involved in DNA repair; the nuclear protein U1 ribonucleoprotein and nuclear lamins; and cytoplasmic components such as protein kinase C␦ and cytoskeleton components such as actin (cited in Ref. 12).Intracellular calcium is a key second messenger implicated in the activation of the apoptotic program in diverse cell types and tissues (15-18). Intracellular calcium levels become elevated after the activation of T lymphocytes by anti-CD3 or that of B lymphocytes by anti-IgM antibodies; after withdrawal of survival factors, such as testosterone in the prostate gland; or after exposure to certain exogenous stimuli, such as calcium ionophores or thapsigargin (TG), 1 a potent inhibitor of the Ca 2ϩ