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The 2 major pathways of apoptosis are the extrinsic Fas and other TNFR superfamily members and ligands and the intrinsic mitochondria-associated pathways, both of which are found in the cytoplasm. The extrinsic pathway is triggered by death receptor engagement, which initiates a signaling cascade mediated by caspase-8 activation. Caspase-8 both feeds directly into caspase-3 activation and stimulates the release of cytochrome c by the mitochondria.

Caspase-3 activation leads to the degradation of cellular proteins necessary to maintain cell survival and integrity. The intrinsic pathway occurs when various apoptotic stimuli trigger the release of cytochrome c from the mitochondria independently of caspase-8 activation. Cytochrome c interacts with Apaf-1 and caspase-9 to promote the activation of caspase Recent studies point to the ER as a third subcellular compartment implicated in apoptotic execution.

Differential expression of these genes between tissues, developmental and disease states and, indeed, between organisms, has been studied to establish pathway s of apoptotic regulation. Modified from Hwang and Dempsey et al. Accession numbers listed correspond to the putatively identified gene. ESTs matching significantly only to non-human GenBank database entries were designated as isologs of those genes.

Intensities reflect the frequency of a given EST in a particular library, as a percentage of total ESTs in that library. Each column represents a distinct cDNA library.

KEGG PATHWAY: Apoptosis - Homo sapiens (human)

Total: ESTs. The genes and gene families idenitified in our database are described here, including recent data from those characterized further in our laboratory. Individual genes are classified according to their function as described in the literature. The discovery of death effector genes in C. To date there are at least 14 known human members of this family [19] , and studies have shown that caspases are primary death effectors that can be inhibited to block apoptosis [20]. Consequent to cellular apoptotic inducement, caspase proforms are proteolytically cleaved to generate activated forms of the enzyme.

Recently, caspases have been found to play an important role in regulating apoptosis in the cardiovascular system for a review, see Ref. In vitro, apoptosis induced in cultured rat myocytes was attenuated with ZVAD-fmk, a caspase-specific inhibitor [24] ; caspase-3 was found to be present in staurosporine-induced apoptotic cells, implicating this family member as an effector of apoptosis. Two members of the ICE family may provide further insight into a link between apoptosis regulation and cardiac development. Ich-1L and Ich-1S, also known as caspase-2, has been uncovered through random sequencing of a heart cDNA library [16].

These genes represent two Ich-1 mRNA species that have been reported through alternative splicing: Ich-1L, a gene encoding a amino acid protein that induces programmed cell death; and Ich-1S, a truncated version of Ich-1L whose overexpression suppresses apoptosis [25]. Spawning from previous work in the nematode C. Named Bcl-2, this gene served as a prototype for a large family of related apoptotic regulators, including various isoforms and homologues e.

A striking feature of the Bcl-2 family and one that has helped pave the way for the discovery of novel family members is the ability of the molecules to form homodimers and heterodimers, a trait that appears to play a significant role in controlling apoptosis [28,29]. The involvement of Bcl-2 family members in ischemia and oxidative stress is significant [30,31] , although the exact mechanism by which apoptosis is signalled remains a mystery.

Early work reported that Bcl-2 may play an important role in preventing cell death through the scavenging of free radicals, but a direct involvement in myocardial ischemia may not be as significant as suggested previously, considering that it also functions to attenuate apoptosis under anaerobic conditions [29]. Consequently, alternative mechanisms of apoptosis in this condition have been investigated. Both H 2 O 2 and O 2 — were found to induce apoptosis in isolated cardiac cells but without a concomitant increase in Bcl-2 or Bax protein levels; furthermore, H 2 O 2 induces an upregulation of Bad protein, following which, Bad and Bax form heterodimers with Bcl-2 [32].


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It appears, however, that this pathway is independent from those triggered by free radicals e. Support for this lies in the findings that Bcl-2 and NFkappaB are differentially regulated in response to ischemia and reperfusion. During repeated cyclic episodes of short-term ischemia followed by a short period of reperfusion, cardiomyocyte apoptosis and DNA fragmentation were reduced; associated with increased expression of Bcl-2 mRNA and activation of NFkappaB [33]. Thus, Bcl-2 and its family members appear to have crucial roles in the progression of apoptosis during ischemia, although the involvement of each component remains to be fully elucidated.

Consistent with these data, we have identified several Bcl-2 family members in our heart databases. In addition to Bcl-2 itself and related proteins, other genes that have been found to be expressed in the cardiovascular system Table 1a including Bclbinding component 6, Bak, Bcl-x, and BID identified in a human endothelial cell library; data not shown. Bak and Bcl-x have recently been implicated in cytokine-induced cardiac myocyte apoptosis [34]. BID, a BH3 domain-containing death agonist protein [35] , binds to other family member proteins especially Bax and Bcl-2 to induce apoptosis [36].

Through the course of cDNA library sequencing, we have identified apoptosis-related genes Table 1 previously characterized in other tissues or organisms, but whose role in the cardiovascular system is either newly-emerging or poorly recognized at this time. With further study these genes may provide significant insight into the mechanisms and pathways of apoptosis in cardiac tissue.


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MA-3 is a novel mouse gene whose level was found to be induced in apoptosis-induced mouse cell lines including thymocytes, T cells, B cells and pheochromocytoma [37]. The MA-3 gene appears to be highly conserved during evolution in vertebrates and in Drosophila. The Nip family of proteins were identified using a yeast-two hybrid screen which sought to identify factors interacting with adenovirus E1B 19 kDa protein and its functional substitute, Bcl-2 [38].

Thus, interaction of Nip with these two proteins appears to contribute to cell survival [38]. However, Nip 3 nineteen kDa interacting protein-3 is a homodimerizing Bcl-2 binding protein [39] and a potent mitochondrial membrane-bound pro-apoptotic regulator found to overcome suppressor effects of Bcl-2 [40]. Stannin is a protein involved in the neurotoxicity of trimethylin, a potent chemical that damages neurons in the nervous system [41].

Stannin is highly expressed in apoptotic neuronal cells, implying a role for this protein in neurovascular pathology. Although Northern blot failed to detect any appreciable levels of stannin mRNA in rat heart [42] , the finding of a stannin isolog in a human fetal heart cDNA library reveals the benefits of large-scale sequencing in discovering low-expressed genes, as stannin may be expressed at a level below the detection limit of Northern blot.

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In hamster cell lines, a mutant form of DAD-1 was found to induce apoptosis, suggesting a role for this protein as an apoptotic suppressor [43]. In silico analysis has shown that DAD-1 is more highly expressed in cardiac hypertrophy compared to normal adult heart, and thus may play a role in controlling cell numbers during disease.

In fact, of the apoptotic regulators identified in our database, DAD-1 was the only gene found to be expressed in a hypertrophic heart library Table 1. Neuronal apoptosis inhibitory protein NAIP appears to play a key role in spinal muscular atrophy. In individuals suffering from this disease, a deletion in the NAIP gene — homologous to baculoviral apoptosis inhibitor — has been linked to increased apoptosis in neuronal cells [44].

Whereas effectors and suppressors act intracellularly to modulate apoptosis directly, receptor-associated proteins and signal transducers work in concert to regulate cell death initiated by extracellular agonists. Within the complex of the Fas receptor system, FAF1 associates with the cytoplasmic domain of FAS and has been found to potentiate apoptosis in mice [56]. Further studies will confirm their involvement in cardiovascular apoptosis.

The TNF-alpha receptor system is especially interesting for modulating apoptosis as it appears to serve a dual function: not only does it induce apoptosis through mediators such as FADD, it also can act as an apoptotic suppressor via the activation of NFkappaB. Originally identified in baculoviruses, homologous mammalian inhibitory apoptotic proteins IAPs have been identified and characterized. Members of the p38 family have been shown to play significant roles in regulating apoptosis in cardiovascular disease.

Expression of p38 mitogen-activated protein kinase MAPK was found to be higher in cardiac hypertrophy [60] and during ischemia [61].

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Inhibiting p38 MAPK during ischemia significantly reduces apoptosis and injury following reperfusion [62]. We have identified in our database a clone representing pG4, a mammalian proliferation-associated nuclear protein which is modified during the cell cycle and was previously observed in murine macrophages [63].

Although not a MAPK, this gene represents an interesting novel member of the p38 family with regard to cell regulation. Recent studies have implicated members of the zinc finger protein ZFP family of transcription factors in the positive or negative regulation of apoptosis. Although several ZFPs have been functionally linked to apoptosis, the precise regulatory networks of apoptotic pathways are still not well understood. To understand the pathological mechanisms of heart failure and the involvement of apoptosis, extensive studies of cardiovascular ZFP regulatory networks are required.

As an initial step toward this goal, a recently established profile of ZFPs from heart cDNA libraries could be used as a significant resource of ZFP expression data [70]. Elucidating the function of these and other genes identified in the profile may pave the way in understanding the role of ZFPs in apoptotic regulatory pathways of the heart and will help clarify the pathogenesis of cardiovascular disease. The tumor suppressor DNA-binding protein p53 is widely known as an intermediate effector of apoptosis.

It is involved in mechanisms of growth arrest and apoptosis, and may stimulate cell death in response to DNA damage [71,72] ; conversely, pinduced apoptosis can be inhibited by members of the Bcl-2 family [73]. Exposure of myocytes to H 2 O 2 and O 2 — — and thus stimulating apoptosis — has resulted in increased levels of p53 protein [32].

Our preliminary RT—PCR results have indicated a differential expression of p53 mRNA during human heart development as well as in cardiac hypertrophy unpublished data; results not shown. Finding therapeutic agents that may control the level of pinduced apoptosis may be very important in reducing the consequences of cardiac injury for review see Ref.

In silico Northern analysis has identified a gene, WAF1, which is directly induced by p It contains a pbinding site in its promoter region and was shown to reduce human tumors in culture [76]. The tumor suppressor protein adenomatosis polyposis coli APC was first identified in the cardiovascular system in April, , accession number N; Ref. In an attempt to characterize the role of APC in the cardiovascular system, we have generated preliminary data from a recent study that indicates a possible involvement of APC in the apoptotic process in vitro manuscript submitted for publication.

Inhibition of APC expression by antisense oligonucleotides drastically altered the cellular proliferation rate, reducing the number of cells during the course of the experiment.

In addition, there appeared to be higher cell death in antisense treatment by virtue of a greater number of detached cells. This suggests that APC may also be involved in programmed cell death i. For example, transcription factors such as c-myc are intimately associated with cellular proliferation as its constitutive expression increases the susceptibility of cells to apoptosis [79]. Interestingly, a recent study has shown that APC is involved in the c-myc pathway [80] , providing further evidence for a possible link between APC and apoptotic regulation.

Large-scale EST sequencing of heart cDNA libraries has proven to be a successful means of identifying key regulatory genes involved in cardiovascular development and disease [16,81,82]. As with other well-documented apoptotic regulatory proteins, understanding the involvement of novel cardiac cell modulators is a critical undertaking, considering that in humans, myocytes irreversibly exit the cell cycle just before birth.

Apoptosis gene signature of Survivin and its splice variant expression in breast carcinoma

Cardiomyocytes are especially prone to abnormal imbalances in cell numbers, such as the case in myocardial infarction, in which prolonged deprivation of oxygen leads to local necrosis of cardiomyocytes. This is particularly damaging to the health of the organism because of the inability of cardiomyocytes to re-enter a proliferating mitotic cell cycle thus preventing replacement of lost tissue. Instead, the damage is patched up with non-contractile fibroblasts that form fibrous scar tissue.

In North America, where cardiovascular disease represents the prime cause of death, cardiac research at the molecular level has been focused on elucidating mechanisms underlying cardiomyoctye re-entry into the cell cycle. Since proliferation and apoptosis work in concert to balance cell number, the focus of investigations should also be directed toward understanding mechanisms regulating apoptosis and the manner in which these mechanisms intertwine with those modulating cell cycle re-entry.

This is supported by the observation that the general expression pattern of genes regulating DNA synthesis and replication mirror those that are involved in apoptotic pathways Table 1a and b. How these cells reach a state of apoptotic inducement, and thus upsetting the inherent balance, may provide significant evidence of regulatory effects in cell number homeostasis.

By establishing a profile of cardiovascular gene expression, and identifying those genes involved in modulating this balance, gaining insight into the mechanisms of apoptosis becomes a much simpler task. The use of bioinformatics has provided important preliminary data for studying at the bench level the effects of these candidate genes in a more convenient fashion. One limitation to this approach is the amount of data needed to accurately arrive at conclusions of differential gene expression. Indeed, large-scale sequencing offers the ability to establish a trend of expression patterns between libraries if the number of ESTs generated is significant enough; careful statistical analysis of individual gene expression e.

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Gene expression profiles will no doubt lead to a better understanding and further hypotheses into the regulatory pathways of apoptosis and disease. Further investigation into novel genes may reveal previously unknown apoptotic regulators. In the future, this groundwork will be increasingly beneficial for designing more effective therapeutic interventions in counteracting apoptosis with the hopes of successfully treating cardiovascular disease. We would also like to thank Mr.

Adam Dempsey and Dr. Noel Pabalan for their critical comments and suggestions in the preparation of this manuscript. Reutelingsperger C. Molecular biology of apoptosis. Impact of apoptosis programmed cell death for clinical laboratory sciences. Dai K. Chromosomal, in silico and in vitro expression analysis of cardiovascular-based genes encoding zinc finger proteins.