Reviews & Analysis

The relationship between autophagy and apoptosis is complex; autophagy constitutes an adaptive stress response that avoids cell death and suppresses apoptosis under certain circumstances, whereas in other cellular settings it contributes to the demise of cells through an alternative cell-death pathway.

Mutations in genes that regulate endocrine signalling pathways can increase the lifespans of worms, flies and mammals. Endocrine pathways might therefore serve as targets for the manipulation of the ageing process and prevention of age-related diseases.

According to the free-radical theory, oxidizing species — including hydrogen peroxide (H₂O₂) — are generated during aerobic respiration and cause molecular damage and ageing. However, recent evidence suggests that H₂O₂that is produced as a signalling molecule by a selected genetic programme regulates ageing.

Changes in nuclear architecture are a hallmark of ageing in yeast and mammals. These changes seem to be driven by DNA damage, which results in age-related alterations in gene expression, and may be a conserved cause of ageing.

Convergent mechanisms limit the amount of cellular damage and thereby protect against both cancer and ageing, whereas divergent mechanisms prevent excessive proliferation and, therefore, prevent cancer but promote ageing. The net balance between these mechanisms ensures a healthy, cancer-free lifespan until late adulthood in most individuals.

Various stress signals can induce a state of irreversible cell-cycle arrest that is known as cellular senescence. Understanding the causes of cellular senescence has provided insight into some of its consequences: it is important for suppressing cancer and possibly contributes to ageing.

Evidence from rodent and human experimental studies supports the view that a decline in the regenerative function of stem cells with age contributes to mammalian ageing and, possibly, several age-associated diseases. However, a few crucial questions remain to be resolved.

When quiescent cells re-enter the cell cycle, why do they require several extra hours in the G1 phase before they replicate their DNA? One hypothesis is that the proteins that are required for the formation of pre-replicative complexes are removed from chromatin.

The combination of affinity purification and mass spectrometry (AP–MS) has recently been applied to the detailed characterization of protein complexes and large protein-interaction networks. Emerging AP–MS approaches promise a better understanding of protein-complex stoichiometry, structural organization and the dynamics of protein-complex composition.

Classically, endocytosis involves the formation of clathrin-coated carriers that bud from the plasma membrane by dynamin-dependent mechanisms. Recently, several clathrin-independent endocytic pathways have been identified, which represent the main pathway of entry into cells for a diverse array of cargoes, including receptors, lipids and pathogens.

Many signalling pathways have been shown to control cell shape and cell surface mechanics. Recent insights from diverse disciplines point to adhesion and cortical tension as regulators of cell shape and provide insights into how cell shape controls tissue geometry.

Far from being a static organelle at the end of the endocytic pathway, the lysosome is capable of dynamically fusing with many organelles as well as the plasma membrane. The lysosome provides hydrolytic enzymes for the degradation of macromolecules, has secretory functions and is important for plasma membrane repair.

Intense research has led to the discovery and characterization of a novel signalling network, the Hippo pathway, which is involved in growth control inDrosophila melanogaster. The importance of this pathway is emphasized by its evolutionary conservation and by increasing evidence that its deregulation occurs in human tumours.

Considerable progress has been made in understanding the mechanisms that control cell division in plants. However, little is known about how the cell cycle responds to environmental and developmental stimuli and how the cell cycle is turned on and off.

Although it is now accepted that the infectious agent that causes transmissible spongiform encephalopathies is PrP^Sc, recent insights into the existence of prion strains pose a fascinating challenge to prion research. What is the nature of prion strains? And how can they be discriminated?

Nucleoli are the sites of ribosome-subunit biogenesis, but recent large-scale proteomics analyses and other studies have revealed further cellular functions, including cell-cycle control, stress responses and coordination of the processing and maturation of other classes of ribonucleoprotein in addition to the ribosomal class.

SOS mutagenesis is the 'mutation-prone' cellular replication mechanism that is responsible for UV-induced mutations. More than 50 years of SOS mutagenesis research has exposed the underlying mechanisms of DNA-damage-induced mutagenesis that combine the overlapping functions of replication, repair and recombination.

Protein kinases must recognize their correct substrates in a massive background of other potentially phosphorylatable sites. A multitude of mechanisms have evolved to regulate specificity. Individually they are imperfect, but together they coordinate protein phosphorylation with exquisite precision.

Intermediate filaments (IFs) are thought to function as absorbers of mechanical stress and form cytoskeletal networks that serve to support cell shape. The analysis of disease-causing mutations in IF proteins has revealed that IFs also have important roles in cell-type-specific physiological functions.

Owing to the toxic potential of unfolded proteins, their accumulation in the endoplasmic reticulum activates a cellular stress response. This unfolded protein response remodels the secretory pathway to accommodate the load of unfolded proteins or, if the burden is insurmountable, promotes cell death to protect the organism.