Progress in cell cycle research最新文献

The cyclin B/Cdc2 complex, Cdc2 kinase governs M-phase. Although the intracomplex modification for its activation in vitro has been described extensively, its regulation in vivo is not so well explained so far. In this article, we will focus on the intracellular regulation of the cyclin B/Cdc2 activity, in particular, how it is initially activated in vivo, how its nuclear translocation is executed specifically at the onset of M-phase, and how the activation and the nuclear translocation are coordinated in the cell. These concerted regulations may determine the appropriate timing for the initiation of M-phase.

Normal cell proliferation is under strict regulation governed by checkpoints located at distinct points in the cell cycle. The deregulation of these checkpoint events and the molecules associated with them may transform a normal cell into a cancer cell. One of these checkpoints whose deregulation results in transformation occurs at the Restriction point, near the G1/S boundary. The periodic appearance of one of the recently identified regulatory cyclins, cyclin E, coincides precisely with the timing of the Restriction point. The deregulation in the expression and activity of cyclin E has been associated with a number of cancers and is thought to be involved in the process of oncogenesis. In this chapter, we summarise the current knowledge on the regulation and apparent function of cyclin E in normal proliferating cells and in developing tissue and alterations of these processes in cancer.

Inhibitors of cyclin-dependent kinases (CKIs) play key roles in coordinating cell proliferation and development. They also function to control critical cell cycle transitions and as effectors of checkpoint pathways. The activity of CKIs is tightly controlled through the cell cycle and in response to various signals. Regulation generally affects the levels or availability of the CKIs rather than changing their intrinsic activities. Mechanisms controlling CKI function include the regulation of transcription, translation and proteolysis. In addition some signals appear to induce sequestration of CKIs within the cells, thereby changing their ability to interact with specific targets.

Viruses depend on the host's machineries to replicate and express their genome. Actively replicating cells have large pools of deoxynucleotides and high levels of key enzyme activities that viruses exploit to their own needs. Some viruses have developed strategies for driving quiescent cells into the S phase of the cell cycle, e.g. adenovirus, others, such as parvovirus, wait until the host itself begins to replicate. Viruses may also force the host cell to stay in a favourable phase, e.g. Epstein-Barr virus, or, if necessary, they may inhibit apoptotic cell death, e.g. human cytomegalovirus. In this review, we focus on the different strategies that viruses use to create in infected cells an environment favourable to the accomplishment of the viral life cycle through acting on cell cycle regulators.

HIV-1 possesses six open reading frames in addition to the gag, pol, and env shared by all retroviruses. One of these accessory genes, vpr, is required for maximal viral replication in macrophages. The molecular mechanism underlying this effect may be related to one of the unusual properties of the encoded protein: some believe Vpr promotes nuclear translocation of preintegration complexes in non-dividing cells; also, Vpr arrests the cell cycle in G2 by inhibiting an upstream activator of p34cdc2-cyclin B. Elucidation of Vpr-cell cycle interactions may provide insight into both HIV-1 and basic cell biology.

The cyclin dependent kinase inhibitor, p21, is a multifunctional protein involved in coordinating the cellular response to negative growth signals. Induced by cellular damage under the transcriptional control of the p53 tumour suppressor protein, p21 interfaces with a number of cellular proteins involved in growth control. Although p21 has a diverse range of activities, from assembly factor to transcriptional modulator, its ability to interact with and regulate the activity of the cyclin dependent protein kinases is paramount to many of these functions.

Calcium signals often accompany mitosis. The most obvious example of calcium as a mitotic signal is at fertilization in vertebrate eggs, where the calcium transient induces anaphase onset. New imaging methods have demonstrated smaller calcium signals that control mitosis entry and mitosis exit in sea urchin embryos. Other experiments in mouse and frog embryos indicate that similar signals with similar function may play a part in these embryos, too. The links between these calcium control signals and mitotic kinase activation are adumbrated. It appears that calcium oscillations are a property of the mitotic state. A case is made that calcium may be a universal mitotic signal, with the possible exception of early meiotic events in oocytes.

The assembly of a mitotic spindle requires the interaction of microtubules with chromosomes. As a cell enters mitosis, long microtubules are converted to short ones, as microtubules become unstable. Dynamic microtubules are then stabilised by chromosomes, forming a bipolar spindle. In this review, we discuss the different roles of kinetochores and chromosome arms during spindle assembly. Kinetochores, required for proper chromosomes segregation, capture microtubules and maintain attachment. Chromosome arms greatly enhance microtubule stability, and alone can be sufficient for spindle assembly.

The mos proto-oncogene-encoded serine/threonine protein kinase plays a key cell cycle-regulatory role during meiosis. The Mos protein is required for the activation and stabilisation of M phase-promoting factor MPF. As a component of a large multiprotein complex known as the cytostatic factor (CSF), Mos is involved in causing metaphase II arrest of eggs in vertebrates. Upon expression in somatic cells, Mos causes cell cycle perturbations resulting in cytotoxicity and neoplastic transformation. All the known biological activities of Mos are mediated through activation of the mitogen activated protein (MAP) kinase pathway. Here we discuss the interrelationship between Mos and other cell cycle regulators.

The mammalian cell cycle engine, which is composed of cyclin/CDK holoenzymes, controls the progression throughout the cell cycle by regulating, at least in part, the transcription of two types of genes: genes whose protein products are required for DNA metabolism and genes whose protein products are involved in cell cycle control. Among the targets of cyclin/CDKs, there is a family of negative growth regulators collectively known as pocket proteins. This family of pocket proteins includes the product of the retinoblastoma tumor suppressor gene, pRB and the functionally and structurally related proteins p107 and p130. In this review, the mechanisms by which pocket proteins are thought to regulate cell growth and differentiation are discussed.