Messengers of cell death: apoptotic signaling in health and disease

BACKGROUND AND OBJECTIVES: Apoptosis is a genetically controlled mechanism of cell death involved in the regulation of tissue homeostasis. Understanding the molecular basis of apoptosis signaling may reveal novel clues for lymphomagenesis. EVIDENCE AND INFORMATION SOURCES: Pro-apoptotic signaling is mediated by specific ligands and surface death receptors (extrinsic pathway of apoptosis regulation), which are capable of delivering a death signal from the microenvironment and can activate the execution of apoptosis in the cell cytoplasm and organelles. Death receptors include tumor necrosis factor-receptor 1, Fas, death receptor (DR) 3, DR4, DR5 and DR6, whereas death ligands include tumor necrosis factor-a, lymphotoxin, Fas-Ligand, Apo3-Ligand and TRAIL (TNF-Related Apoptosis-Inducing Ligand). Once activated, death receptors recruit adaptor proteins, which in turn recruit initiator caspases, giving rise to a pro-apoptotic complex termed the death-inducing signaling complex (DISC). Besides being triggered from microenvironmental signals, apoptosis can also be activated from inside the cell through specific cell sensors residing in the cell nucleus and cytoplasm (intrinsic pathway of apoptosis regulation). The intrinsic pathway of apoptosis leads to the formation of a pro-apoptotic complex termed an apoptosome. Both the extrinsic and the intrinsic pathways of apoptosis signaling converge into a common pathway causing the activation of the effector enzymes caspases. Consistent with the role of apoptosis as a main regulator of B-cell homeostasis in the germinal center, the pathogenesis of several germinal-center-derived lymphomas is characterized by deregulation of one or more steps of the apoptosis signaling pathways. PERSPECTIVES: Tumor-specific alterations in the apoptotic machinery may represent new potential targets for molecular therapy of lymphoma.