Apoptosis: Regulatory Genes and Disease

Abstract Apoptosis is essential for normal development and proceeds by the extrinsic death receptor pathway, or the intrinsic Bcl‐2 blockable pathway. Both pathways activate a class of proteases termed caspases that cleave intracellular substrates resulting in cell death. Excessive apoptosis may excerbate neurological diseases and the damage caused by heart attacks and strokes. Apoptosis is used by metazoans as a defence against pathogens that have, therefore, evolved mechanisms to block the apoptotic machinery. The involvement of apoptosis in disease states has led to the rational design of compounds that target this pathway which are already successfully used in the clinic. Key concepts Apoptosis can occur by the extrinsic death receptor pathway or by the intrinsic Bcl‐2 blockable pathway. Perforin–granzyme‐mediated toxicity is important for NK and T‐cell destruction of pathogen‐infected cells and tumour cell surveillance. p53 is a transcription factor that prevents tumourigensis by initiating the intrinsic cell death pathway. The Bcl‐2 protein family is made up of pro‐ and antiapoptotic proteins that form the core components of the intrinsic cell death pathway and are often dysregulated in cancer. Death receptors regulate immune cell function and development by inducing apoptosis and also by stimulating pro‐survival cellular responses. Rationally designed compounds specifically targeting the intrinsic or extrinsic cell death regulators are hoped to provide new and highly specific cancer therapies.