Apoptosis regulators and their role in tumorigenesis

The p53–Bcl-2 connection

“…p53-dependent signals, including the induction of Bax, Puma and Noxa and direct inhibition of Bcl-2, synergize with p53-independent signals, like the induction of Bim, to antagonize Bcl-2 function and promote apoptosis human malignancies. 58,59 Second, whereas p53-deficient mice rapidly develop diverse tumor types, 60 Bcl-2 transgenic mice exclusively develop hematopoietic malignancies and then only after a long latency. 61 The broader spectrum of tumor phenotypes produced by p53 mutations can be attributed to the diverse cellular functions of p53.…”

Apoptosis to necrosis switching downstream of apoptosome formation requires inhibition of both glycolysis and oxidative phosphorylation in a BCL-XL- and PKB/AKT-independent fashion

“…The PCD process is defined as apoptosis when these features include the activation of proteases termed caspases, cytoplasmic shrinkage, loss of plasma membrane lipid asymmetry, chromatin condensation and DNA degradation into oligonucleosomal fragments. 1,2 Apoptosis can be initiated by the engagement of the plasma membrane death receptors (extrinsic pathway), or by changes in the mitochondrial integrity following either a broad range of physical and chemical stimuli or growth factor withdrawal (intrinsic pathway 3 ). Pro-and antiapoptotic members of the Bcl-2 family of proteins integrate intrinsic signals, leading either to cell survival by maintaining mitochondrial homeostasis, or to cell death by releasing in the cytosol apoptogenic proteins stored in the mitochondria.…”

“…7 In necrotic cells, the cytosol and the organelles rapidly swell and the nuclear structure and DNA are degraded in a nonspecific fashion. 2 The different forms of PCD comprised between the extremes of apoptosis and necrosis are mostly endowed with a lack of caspase activation and with any degree or combination of other apoptotic-like hallmarks. The choice among these different forms of cell death is determined by complex factors.…”

Transgenic overexpression of a dominant negative mutant of FADD that, although counterselected during tumor progression, cooperates in L‐myc‐induced tumorigenesis

“…1 For a cancer to occur and progress, apoptosis must be inhibited as the tumor cells are constantly exposed to a variety of apoptotic stimuli, e.g., overexpression of apoptosis-inducing oncogenes, hypoxia or lack of survival signals after detachment of metastatic cells from the tumor mass (anoikis). 2 Furthermore, conventional treatment of cancer by chemotherapy and irradiation is based on the selective induction of apoptosis in tumor cells, and tumor resistance to such treatment is a result of the inhibition of drug-or radiation-induced apoptosis.…”

“…Consequently, several mutations have been identified in tumors which lead to impairment of death receptor-induced apoptosis. 1,19 Examples include overexpression of the inhibitory FLIP proteins in melanomas, 20 transcriptional downregulation of caspase-8 mRNA by gene deletion or promoter methylation 21 and CD95 mutations in different cancers. [22][23][24] Direct proof of the tumor-suppressing proapoptotic activity of the CD95 receptor has been obtained by in vivo cooperation experiments.…”