Review
Mutations in apoptosis genes: a pathogenetic factor for human disease

https://doi.org/10.1016/S1383-5742(01)00057-6Get rights and content

Abstract

Cell death by apoptosis is exerted by the coordinated action of many different gene products. Mutations in some of them, acting at different levels in the apoptosis process, have been identified as cause or contributing factor for human diseases. Defects in the transmembrane tumor necrosis factor receptor 1 (TNF-R1) lead to the development of familial periodic fever syndromes. Mutations in the homologous receptor Fas (also named CD95; Apo-1) are observed in malignant lymphomas, solid tumors and the autoimmune lymphoproliferative syndrome type I (ALPS I). A mutation in the ligand for Fas (Fas ligand; CD95 ligand, Apo-1 ligand), which induces apoptosis upon binding to Fas, was described in a patient with systemic lupus erythematodes and lymphadenopathy. Perforin, an other cytotoxic protein employed by T- and NK-cells for target cell killing, is mutated in chromosome 10 linked cases of familial hemophagocytic lymphohistiocytosis. Caspase 10, a representative of the caspase family of proteases, which plays a central role in the execution of apoptosis, is defect in autoimmune lymphoproliferative syndrome type II (ALPS II). The intracellular pro-apoptotic molecule bcl-10 is frequently mutated in mucosa-associated lymphoid tissue (MALT) lymphomas and various non-hematologic malignancies. The p53, an executioner of DNA damage triggered apoptosis, and Bax, a pro-apoptotic molecule with the ability to perturb mitochondrial membrane integrity, are frequently mutated in malignant neoplasms. Anti-apoptotic proteins like bcl-2, cellular-inhibitor of apoptosis protein 2 (c-IAP2) and neuronal apoptosis inhibitory protein 1 (NAIP1) are often altered in follicular lymphomas, MALT lymphomas and spinal muscular atrophy (SMA), respectively. This article reviews the current knowledge on mutations of apoptosis genes involved in the pathogenesis of human diseases and summarises the gradual transformation of discoveries in apoptosis research into benefits for the clinical management of diseases.

Introduction

Apoptosis is a distinct form of cell death that proceeds along a genetically determined execution programme. It exhibits a characteristic morphology [1] and features unique biochemical alterations [2]. An increasing number of genes involved in the execution of the apoptosis programme is identified and concepts of different, although interacting, apoptosis signalling pathways are delineated [3], [4], [5] (Fig. 1).

One major apoptosis pathway involves cell surface ‘death receptors’ (DR) that transmit an apoptosis signal on binding of a specific ‘death ligand’ [3]. The largest known family of DRs is represented by tumor necrosis factor receptors (TNF-Rs) [6]. The best characterised members are TNF-R1 (also called p55, CD120a), TNF-R2 (p75, CD120b), Fas (CD95, Apo-1), death receptor 3 (DR3), death receptor 4 (DR4, TRAIL-R1) and death receptor 5 (DR5, TRAIL-R2) [3] (Fig. 1). The ligands that activate these receptors are structurally related molecules with homologies to tumor necrosis factor α (TNFα) [3], [7], [8], [9], [10]. Upon ligand binding an intracellular ‘death domain’ of the receptor interacts with a homologous domain in an adaptor protein, which recruits specific proteases, the so-called caspases [11], [12], [13] (Fig. 1). Caspases (for ‘cysteine aspartase’) are cysteine dependent proteases that exert a limited proteolyses by cleavage of their substrate after specific aspartate residues. They reside as inactive pro-forms within the cell and become activated by autocleavage when recruited to a DR signaling complex. Activated upstream caspases subsequently initiate a cascade of downstream effector caspases which cleave a plethora of cellular proteins and thereby ultimately cause cell death [11], [12], [13].

A second major apoptosis pathway involves mitochondria [14], [15], [16]. A key molecule in mitochondrial cell death is cytochrome c. When released from mitochondria in response to cell damage it binds to the cytoplasmic adaptor molecule Apaf-1 [14], [15], [16]. The Apaf-1 then recruits pro-caspase 9, which becomes activated by autoprocessing and triggers a cascade of downstream caspase reactions (Fig. 1). Members of the bcl-2 family are involved in the regulation of mitochondrial cell death [17], [18], [19]. Anti-apoptotic members like bcl-2 and bcl-xL inhibit cytochrome c release from mitochondria [20], [21]. Pro-apoptotic members like Bax may act by forming pore complexes in the outer mitochondrial membrane [22].

At least a third major pathway of apoptosis induction seems to exist that does not primarily involve DRs or mitochondria. This pathway is represented by the nuclear protein p53 [23], [24], [25], [26]. The p53 is activated in response to DNA damage. It blocks cells with damaged DNA in the G1 and G2 phase of the cell cycle [27]. If the DNA damage is severe, and dependent on cell type and oncogene composition of a cell, p53 initiates apoptosis by mechanisms that partially rely on the transcription of apoptosis executionary genes like Bax [18] and genes whose products generate reactive oxygen species [28].

A deregulation of apoptosis is implicated in the pathogenesis of various human diseases [29]. In malignant neoplasms, the balance of apoptosis and proliferation is shifted towards proliferation, either by increased mitosis and/or reduced apoptosis [30]. A failure to delete autoreactive lymphocyte clones contributes to the genesis of autoimmune diseases [31]. In neurodegenerative pathologies, such as Parkinson’s disease and spinal muscular atrophy (SMA), neuronal cells are abnormally prone to cell death [32].

For some human diseases defects in apoptosis genes have been identified as causative or contributing pathogenetic factor (Table 1). In various malignant neoplasms pro-apoptotic molecules like Fas [33], [34], [35], [36], [37], [38], [39], [40], Bax [41], [42], p53 [43] and the newly identified bcl-10 [40], [44], [45], [46], [47], [48], as well as anti-apoptotic proteins like bcl-2 [49], [50], [51], [52], [53] and the caspase inhibitor cellular inhibitor of apoptosis 2 (c-IAP2) [54], [55] are mutated. Benign lymphoproliferative diseases, often combined with autoimmune symptoms, are associated with alterations of Fas [56], [57], [58], [59], [60], FasL [61], or caspase 10 [62]. Hereditary fever syndromes [63] and chromosome 10 linked cases of familial hemophagocytic lymphohistiocytosis [64] are caused by defects in TNF-R1 and the cytotoxic molecule perforin, respectively [65], [66]. Deletion of neural apoptosis inhibitory protein 1 (NAIP1), a caspase inhibitory protein, may modify the severity of SMA, which is caused by loss of the survival motor neuron 1 (SMN1) gene [67], [68].

The identification of mutations in the apoptosis genes described, greatly contributes to the understanding of the physiologic significance of the molecules involved, provides useful diagnostic disease markers and offers the chance to design therapies based on the molecular nature of the apoptosis defect.

Section snippets

Tumor necrosis factor receptor (TNF-R)

Tumor necrosis factor (TNF) is a cytokine with pleiotropic biological activities. It stimulates immune cells to secrete cytokines, causes endothelial cells to express adhesion molecules for leucocyte binding and exerts a pyrogenic effect [6], [7]. The TNF induces also apoptosis in some cell types but usually only when new protein synthesı́s is blocked [6], [7]. It is produced predominantly by activated macrophages and in response to infection. The TNF binds two different transmembrane

Fas ligand

Fas ligand (FasL) induces apoptosis on binding to its receptor Fas [8], [9]. It is localised to the cell membrane. A soluble form with less cytotoxic activity than the membrane bound form is generated by metalloproteinase cleavage [8], [9]. The FasL is mainly produced by T- and NK-cells but is also detected in non-lymphoid cells, such as Sertoli cells of the testis, different ocular cell types and various malignant neoplasms [8], [9], [79], [80], [81]. The so-far recognised physiological

Caspase 10 (Mch 4/FLICE 2)

Caspase 10 (also named Mch 4/FLICE 2) takes a proximal position in a cell DR triggered caspase cascade [88] (Fig. 1). It is recruited to the activated receptors Fas and TNF-R1 via the adaptor molecule FADD [88]. Aggregation of pro-caspase 10 within the DR signaling complex promotes activation by auto-cleavage with release of an amino-terminal pro-domain and the formation of heterodimers consisting of two subunits each.

The caspase 10 gene on chromosome locus 2q23 is mutated in human

bcl-2

The bcl-2 is an anti-apoptotic protein that resides on the cytoplasmic face of the mitochondrial outer membrane, endoplasmic reticulum and nuclear envelope. It protects against various cytotoxic insults, e.g. gamma- and ultraviolet-irradiation, cytokine withdrawal, dexamethasone and chemotherapeutic drugs [17], [18]. The bcl-2 is the prototype of a family of related proteins with either anti-apoptotic (bcl-2, bcl-xL) or pro-apoptotic (bax, bcl-xS, bak, bad, bid) functions. Pro- and

Summary and future prospects

Mutations in apoptosis genes contribute to the pathogenesis of human diseases. The spectrum of currently known diseases encompasses mainly non-malignant lymphoproliferative and inflammatory syndromes as well as malignant neoplasms (Table 1). All but one (NAIP1) of the outlined examples of mutated apoptosis genes result in reduced apoptosis and consecutive accumulation of immune or tumor cells. However, mutation is only one mechanism of apoptosis dysregulation. Alterations in the expression of

Acknowledgements

We apologise to those many investigators whose original work was not properly cited because of space limitations. We are grateful to Drs. P. Mazal and J. Pammer for helpful comments on the manuscript. The work in the authors laboratory is supported by the “Bürgermeisterfonds der Bundeshauptstadt Wien” (No. 1688), the “Anton-Dreher Gedächtnisschenkung” (No. 328-99) and the “Jubiläumsfonds der Österreichischen Nationalbank” (No. 8240).

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