Cell Death & Differentiation

Mehlen, P

doi: 10.1038/sj.cdd.4401708pmid: 16015379

Imyanitov, E; Hanson, K; Zhivotovsky, B

doi: 10.1038/sj.cdd.4401674pmid: 15905874

Ley, R; Ewings, K E; Hadfield, K; Cook, S J

doi: 10.1038/sj.cdd.4401688pmid: 15947788

Ham, J; Towers, E; Gilley, J; Terzano, S; Randall, R

doi: 10.1038/sj.cdd.4401689pmid: 15933736

Stupack, D G

doi: 10.1038/sj.cdd.4401658pmid: 15933741

In the absence of their cognate ligand, dependence receptors trigger programmed cell death. This function is the defining feature of dependence receptors, which include members of several different protein families. The integrins are a family of heterodimeric receptors for extracellular matrix (ECM) proteins, mediating cell anchorage and migration. Integrins share characteristics with dependence receptors, and integrin binding to substrate ECM ligands is essential for cell survival. Although integrins do not conform in all characteristics to the established definitions of dependence receptors, alterations in the expression of integrins and their ligands during physiological and pathological events, such as wound healing, angiogenesis and tumorigenesis, do regulate cell fate in a ligand-dependent manner. This biosensory function of integrins fits well with our current concept of dependence receptor action, and thus integrins may rightly be considered to comprise a distinct subclass of dependence receptor.

Bredesen, D E; Mehlen, P; Rabizadeh, S

doi: 10.1038/sj.cdd.4401680pmid: 16015380

Cells depend for their survival on stimulation by trophic factors and other prosurvival signals, the withdrawal of which induces apoptosis, both via the loss of antiapoptotic signaling and the activation of proapoptotic signaling via specific receptors. These receptors, dubbed dependence receptors, activate apoptotic pathways following the withdrawal of trophic factors and other supportive stimuli. Such receptors may feature in developmental cell death, carcinogenesis (including metastasis), neurodegeneration, and possibly subapoptotic events such as neurite retraction and somal atrophy. Mechanistic studies of dependence receptors suggest that these receptors form ligand-dependent complexes that include specific caspases. Complex formation in the absence of ligand leads to caspase activation by a mechanism that is typically dependent on caspase cleavage of the receptor itself, releasing proapoptotic peptides. Cellular dependence receptors, considered in the aggregate, may thus form a system of molecular integration, analogous to the electrical integration system provided by dendritic arbors in the nervous system.

Chédotal, A; Kerjan, G; Moreau-Fauvarque, C

doi: 10.1038/sj.cdd.4401707pmid: 16015381

Slits, semaphorins and netrins are three families of proteins that can attract or repel growing axons and migrating neurons in the developing nervous system of vertebrates and invertebrates. Recent studies have shown that they are widely expressed outside the nervous system and that they may play important roles in cancers. Several of the genes encoding these proteins are localized on chromosomal region associated with frequent loss-of-heterozygosity in tumors and cancer cell lines and there is also significant hypermethylation of their promoter suggesting that they may act as tumor suppressors. In addition, proteins in all these families and their receptors appear to control the vascularization of the tumors. Last, many axon guidance molecules also regulate cell migration and apoptosis in normal and tumorigenic tissues. Overall, this suggests that molecules that could mimick or block the activity of axon guidance molecules may be used as therapeutic agents for the treatment of malignancy.

Arakawa, H

doi: 10.1038/sj.cdd.4401601pmid: 15818407

The p53 tumor-suppressor gene regulates apoptosis through the transcriptional activation of its target genes. The expression of the axon-guidance molecule UNC5B (also designated p53RDL1), which is a receptor for netrin-1, is directly regulated by p53. In the absence of netrin-1, UNC5B mediates p53-dependent apoptosis. Conversely, in the presence of netrin-1, p53-induced apoptosis is inhibited through the signaling pathway activated by the interaction between netrin-1 and UNC5B. A number of other molecules that are involved in axon guidance are inactivated in human cancers and are also regulated by p53. These findings suggest a close link between axon-guidance molecules and tumorigenesis.

Ekshyyan, O; Aw, T Y

doi: 10.1038/sj.cdd.4401650pmid: 15877105

We previously showed that tert-butyl hydroperoxide (TBH) induced apoptosis in naïve rat pheochromocytoma (nPC12) cells that correlated with cellular redox imbalance and mitochondrial apoptotic signaling. In this study, we tested the hypothesis that differentiation of nPC12 cells results in altered susceptibility to TBH utilizing a model of differentiated PC12 (dPC12) cells induced by nerve growth factor. TBH (100 μM) induced dPC12 apoptosis (12% at 24 h) at levels lower than naïve cells (35%). This resistance was associated with elevated GSH, NADPH (reduced nicotinamide adenine dinucleotide phosphate), TBH metabolism, redox enzyme activities, reduced cellular GSH/GSSG (glutathione disulfide) status and preservation of mitochondrial membrane potential. Altering cellular GSH with ethacrynic acid or N-acetylcysteine, respectively, exacerbated or protected against dPC12 apoptosis. dPC12 apoptosis was mediated by caspase-9 and -3 activation and apoptosis protease activator protein-1 (Apaf-1) expression. These results show that nPC12 transition to dPC12 cells afforded protection against oxidative challenge due to maintenance of reduced GSH/GSSG and decreased Apaf-1 expression.

Kurushima, H; Ohno, M; Miura, T; Nakamura, T Y; Horie, H; Kadoya, T; Ooboshi, H; Kitazono, T; Ibayashi, S; Iida, M; Nakabeppu, Y

doi: 10.1038/sj.cdd.4401648pmid: