The Role of the Centrosome in Cell Cycle Progression

Andrew M. Fry and Rebecca S. Hames Introduction

The centrosome is a tiny subcellular organelle present in only one or two copies per cell. Yet, through its role as the primary site of microtubule nucleation and organization, it contributes to numerous cellular processes including anteriograde and retrograde transport, positioning of organelles and chromosome segregation. If this was not enough, there is now a growing body of evidence that the centro-some plays additional important roles in orchestrating many of the key transition events that occur during cell cycle progression including mitotic entry, anaphase onset, cytokinesis and S-phase entry. It seems to do this by acting as a solidphase signaling platform providing docking surfaces on which key enzymes can be brought into contact with their substrates and upstream regulators. In this review, we will consider the evidence that has implicated the centrosome in regulating specific cell cycle transitions and discuss the consequences that this new and exciting information has on our understanding of cell cycle control.

Progression through the eukaryotic cell cycle requires the precise coordination and integration of many critical biochemical events. Frequently, these involve protein phosphorylation and dephosphorylation reactions, as well as the activation of targeted proteolysis. However, the cell is not a test-tube and in reality these enzymatic processes are carefully regulated in a spatial as well as temporal fashion [1]. At the simplest level, enzymes and substrates may be physically separated into different subcellular compartments until the appropriate time in the cell cycle. However, on a more sophisticated level, activators or inhibitors may be brought into close physical proximity to their targets through immobilization on particular sub-cellular structures.

The animal cell centrosome is a discrete non-membranous organelle that sits in the cytoplasm close to the nucleus [2, 3]. Its fungal counterpart, the spindle pole body (SPB), may also be found just outside the nuclear envelope or, in some species, within the nuclear envelope [4, 5]. The core structural components of the higher eukaryotic centrosome include two barrel-shaped centrioles, composed pre dominantly of nine highly stable microtubule triplets, and the surrounding peri-centriolar material (PCM). The PCM contains proteins required for microtubule nucleation and anchoring that are held within a fibrous lattice somehow attached to the walls of the centrioles (see Chapters 3, 5, and 15 for a detailed description of centrosome structure and microtubule nucleation). Because the centrosome lacks a surrounding lipid bilayer, its three-dimensional architecture is maintained through specific protein-protein interactions. Not surprisingly, then, most centrosomal proteins contain protein interaction domains, with coiled-coil motifs featuring prominently. These protein interaction domains were originally assumed to contribute solely to the maintenance of the centrosome structure itself and to the recruitment of proteins involved in regulating microtubule nucleation or centriole duplication. However, the growing list of diverse enzymes detected at the centrosome (see [6, 7]) has challenged this assumption and raised the possibility that the centrosome acts as a docking platform for a wide range of regulatory molecules that do not necessarily have a function directly related to centrosome biology itself. In this scenario, the centrosome behaves as a command center integrating signals from different pathways and ensuring the correct output. This activity may be entirely independent of microtubules or it may utilize microtubules to facilitate movement of signaling molecules to and from the centrosome.

Evidence for a centrosomal role in externally-regulated signal transduction pathways remains rather sketchy at the present time. In contrast, there is now abundant and persuasive evidence that the centrosome acts as a scaffold for coordinating intrinsic cell cycle events [8, 9]. How the centrosome plays a key role in regulating mitotic entry, the metaphase-anaphase transition, execution of cytokinesis and S-phase entry will form the central debate of this chapter.

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