Progress in cell cycle research最新文献

Most physiological, biochemical and behavioural processes have been shown to vary in a regular and predictable periodic manner with respect to time. This review focuses on the circadian rhythm in cell proliferation in bone marrow and gut and how this is associated with a circadian expression of cell cycle proteins in human oral mucosa. The control of circadian rhythms by the suprachiasmatic nuclei and the evolving understanding of the genetic and molecular biology of the circadian clock is outlined. Finally, the potential clinical impact of chronobiology in cancer medicine is discussed.

Tissue modelling during embryogenesis and tissue homeostasis during adult life is governed by a dynamic equilibrium between growth and programmed cell death (apoptosis). Growth control and apoptosis are intimately associated, and a disturbance of the balance between these two processes often leads to pathological situations, such as for example cell accumulations in cancer. To date many of the molecular mechanisms controlling growth control on the one hand, and apoptosis on the other hand are known, whereas the switch that controls the decision between both pathways remains elusive. A cell is continuously exposed to multiple opposing "death" and "survival" triggers. A challenging question is how a cell senses these signals and decides to live or die. A decision in favour of survival should automatically result in a shut down of the death pathways. Alternatively, a decision for death should result in inhibition of futile attempts to survive. The molecular events controlling this balance of signals will be discussed with special emphasis on the role of cyclin-dependent kinases and the ubiquitin-dependent and proteasome-mediated protein degradation pathway.

The continuum model of the mammalian division cycle proposes that there are no G1-phase specific controls or events. The G1 phase is simply the time when processes begun in the previous cell cycle are completed. In this review, the continuum model is applied the variability of the G1-phase, the existence of G1-less cells, the ubiquitous G1-phase arrest phenomenon, the effect of over-expressed cyclins on G1-phase length, the statistical variation of the cell cycle, the reports of G1-phase syntheses, the proposed variation in retinoblastoma protein phosphorylation in G1-phase, and the myriad findings put forward to support the G1-control model of the mammalian division cycle. The continuum model is a valid description of the mammalian division cycle.

Research into cell cycle control in protozoan parasites, which are responsible for major public health problems in the developing world, has been hampered by the difficulties in performing classical genetic analysis with these organisms. Nevertheless, in a large part thanks to the data gathered in other eukaryotic systems and to the acquisition of the sequences of parasite genes homologous to cell cycle regulators, many molecular tools required for an in-depth study of the cell cycle in protozoan parasites have been collected over the past few years. Despite the considerable phylogenetic divergence between these organisms and other eukaryotes, and notwithstanding important specificities such as the apparent lack of checkpoints during cell cycle progression, available data indicate that the major families of cell cycle regulators appear to operate in protozoan parasites. Functional studies are now needed to define the precise role of these regulators in the life cycle of the parasites, and to possibly validate cell cycle control elements as potential targets for chemotherapy.

The proliferating cell nuclear antigen (PCNA), the auxiliary protein of DNA polymerase delta and epsilon, is involved in DNA replication and repair. This protein forms a homotrimeric structure which, encircling DNA, loads the polymerase on the DNA template. A role for PCNA in the cell cycle control is recognised on the basis of the interaction with cyclins, cyclin-dependent kinases (cdks) and the cdk-inhibitor p21 waf1/cip1/sdi1 protein. Association with the growth-arrest and DNA-damage inducible proteins gadd45 and MyD118, further demonstrates the role of PCNA as a component of the cell cycle control apparatus.

Recent work has demonstrated that cdc18p plays a crucial role in regulating the onset of S phase in fission yeast. cdc18p is a major product of START specific transcription and associates with ORC and MCM proteins which are required for the initiation of DNA replication. High expression of cdc18p induces continuing DNA synthesis and is thought to drive the assembly of initiation complexes. In addition to its role in bringing about DNA replication, cdc18p participates in the cell cycle checkpoint control linking S phase to START and mitosis. We propose that cdc18p is central to the molecular mechanism co-ordinating S phase and M phase in concert with changes in activity of the master cell cycle regulator, the cdc2 protein kinase.

Microtubule- and actin-based motors play a wide range of vital roles in the organisation and function of cells during both interphase and mitosis, all of which are likely to be under strict control. Here, we describe how one of these roles--the movement of membranes--is regulated through the cell cycle. Organelle movement in many species is greatly reduced in mitosis as compared to interphase, and this change occurs concomitantly with an inhibition of most membrane traffic functions. Data from in vitro studies is shedding light on how microtubule motor regulation may be achieved.

During mitosis in vertebrates the sister kinetochores on each replicated chromosome interact with two separating arrays of astral microtubules to form a bipolar spindle that produces and/or directs the forces for chromosome motion. In order to ensure faithful chromosome segregation cells have evolved mechanisms that delay progress into and out of mitosis until certain events are completed. At least two of these mitotic "checkpoint controls" can be identified in vertebrates. The first prevents nuclear envelope breakdown, and thus spindle formation, when the integrity of some nuclear component(s) is compromised. The second prevents chromosome disjunction and exit from mitosis until all of the kinetochores are attached to the spindle.

The intestinal epithelium is maintained by a balance between proliferation, differentiation and death that occurs as cells migrate up the crypt-villus axis. Cell cycle regulators such as cyclins, cyclin-dependent kinases (Cdks) and Cdk inhibitory proteins are expressed in a distinct pattern along the crypt-villus structure, suggesting their role in controlling intestinal cells. This is supported by observations that these cell cycle proteins are regulated by growth factors, nutrients and cell-cell contact in cultured intestinal epithelial cells. One of the key regulators of intestinal cell proliferation and differentiation is transforming growth factor-beta, which is expressed in the gut epithelium.

Protein kinase CK2 (also termed casein kinase-2 or -II) is a ubiquitous Ser/Thr-specific protein kinase required for viability and for cell cycle progression. CK2 is especially elevated in proliferating tissues, either normal or transformed, and the expression of its catalytic subunit in transgenic mice is causative of lymphomas. CK2 is highly pleiotropic: more than 160 proteins phosphorylated by it at sites specified by multiple acidic residues are known. Despite its heterotetrameric structure generally composed by two catalytic (alpha and/or alpha') and two non catalytic beta-subunits, the regulation of CK2 is still enigmatic. A number of functional features of the beta-subunit which could cooperate to the modulation of CK2 targeting/activity will be discussed.