DAP kinase and DAP-3: novel positive mediators of apoptosis.

Programmed cell death is a genetically controlled response for cells to commit suicide. The process, which displays distinctive morphological features, is highly conserved through evolution, and takes place in all nucleated animal cells. It is tightly controlled by environmental stimuli including extracellular diVusible factors, or membrane bound molecules that mediate cell-cell or cell-matrix interactions, and by non-physiological insults to cells such as genotoxic agents. This type of regulation allows the elimination of cells that were either produced in excess during development, have completed their role, are potentially deleterious to the organism, or have become seriously damaged. Programmed cell death is therefore a critical process during embryonic development, tissue remodelling, development of the immune system, and the control of tissue homeostasis. In addition, several disorders associated with the disruption of this fundamental process, have been characterised. While a decrease in the apoptotic rate is linked in some cases to abnormal expansion in cell number (for example, in cancer or autoimmune diseases), an abnormal increase in the apoptotic rate is associated with some cell loss disorders (for example, neurodegenerative diseases). 5 The link to cancer has been extensively studied from diVerent aspects one of which is the apoptotic checkpoint that safeguards cells against hyperproliferative oncogenic signals. Several types of programmed cell death have been characterised according to diVerent morphological characteristics. Altogether, the spectrum of morphological hallmarks that has been attributed to the process is very wide, and includes specific nuclear alterations (for example, chromatin condensation followed by its segmentation, internucleosomal DNA fragmentation), cytoplasmic condensation and/or vacuolisation, disruption of cytoskeletal elements, cell surface blebbing, and in some cases, generation of apoptotic bodies that are rapidly phagocytosed by neighbouring cells. The understanding of molecular mechanisms underlying these diVerent cellular changes has became, in the past few years, an important research goal in the field. The main challenge, in this respect, was to identify the genes that are components of the intracellular pathways that enable cells to receive, process and execute apoptotic signals from their environment. There has been impressive progress in the past few years in understanding the intracellular molecular mechanisms of programmed cell death, emerging from studying both lower invertebrates and mammalian systems (see for example references). Yet, it is clear that enormous gaps still exist in our knowledge, which means that novel approaches and diVerent insights should be introduced into this field. This paper will focus on one of these recently developed approaches, which is based on a powerful genetic screen applied in mammalian cells. The novel molecular information obtained so far by this approach will be detailed, and future prospects will be discussed.