Cell cycle: Mechanisms of control and dysregulation in cancer

Introduction The mitotic cell cycle consists of four discrete phases that comprise the ordered processes required for the accurate division and partition of the genetic material into viable daughter cells (Figure 38.1). These processes are tightly controlled by cellular machinery, which not only orchestrates regulation of the various cell-cycle phases, but also integrates environmental cues to ensure that proliferation occurs only when conditions are favorable. The integrity of these processes is of utmost significance, and deregulation of cell-cycle regulatory mechanisms can contribute to tumorigenesis through a variety of discrete mechanisms, as will be discussed. Mechanisms of G1 control The majority of cells in adult tissues harbor a diploid (2N) DNA content, and have generally exited from the cell cycle. These cells exist outside the conventional active cell cycle in a phase termed G0. This G0 stage encompasses a variety of biological states, including terminal differentiation, quiescence, and senescence. Upon the engagement of appropriate physiological signals, G0 cells can commit to subsequent mitotic cell division. Typically, this entry into the cell cycle is mediated by an increase in mitogenic signaling and/or the removal of intrinsic barriers to proliferation (1). In the case of complex tissues, this stimulation of proliferation could be part of intrinsic tissue homeostasis (e.g. proliferation in the crypt to maintain epithelial integrity), response to injury (e.g. liver regeneration), or response to hormonal stimuli (e.g. expansion of mammary epithelia during pregnancy). Although it is widely accepted that such signaling leads to a transition from G0 into G1, the first gap phase, the factors that specify the G0-phase are poorly understood. In addition to a handful of molecular markers, one clear distinction between the G0- and G1-phases is the relative metabolic activity of cells. As such, analyses of gene expression has been suggested to differentiate G0 cells from their G1 counterparts, which are engaged in biosynthetic processes for cell division (2). In contrast with the G0 to G1 transition, those events that mediate progression through G1 have been extensively studied and the general processes involved are comparatively well defined.