Progress in cell cycle research最新文献

Cancer chemotherapy is the object of many fundamental and clinical researches. The development in molecular techniques and structural studies at the molecular level have led to the discovery of key proteins involved in the regulation of cell proliferation. This opened perspectives to characterize new anticancer drugs in order to reduce the limitations found with conventional drugs such as the lack of selectivity for cancer cells and resistance phenomena. This review presents the anticancer drugs in clinical investigations that target molecules involved in the signal transduction impairment, the cell cycle deregulation and the differentiation with comments on their mechanisms of action.

G2-arrested Xenopus oocytes are induced to enter M-phase of meiosis by progesterone stimulation. This process, known as meiotic maturation, requires the activation of p34cdc2/cyclin B complexes (pre-MPF) which is brought about by the prior translation of specific maternal mRNAs stored in the oocyte. One of these mRNAs encodes for the protein kinase Mos which has an essential role in oocyte maturation, most likely due to its ability to activate MAP kinase (MAPK). Here we review our current knowledge on the Mos/MAPK signalling pathway and a recently found connection between MAPK-activated p90rsk and the p34cdc2 inhibitory kinase Myt1. We also discuss a pathway that involves the protein kinase Plx1 and leads to the activation of the phosphatase Cdc25, as well as other regulators of p34cdc2/cyclin B activity which may have a role in oocyte maturation.

Human T-cell leukemia virus type I (HTLV-I) is the etiological agent for adult T-cell leukemia (ATL) and various human myopathies/neuropathies. HTLV-I encodes a 40 kDa phosphoprotein, Tax, which has been implicated in cellular transformation. In similarity with several other oncoproteins such as Myc, Jun, and Fos, Tax is a transcriptional activator. How Tax mechanistically dysregulates the cell cycle remains unclear. Recent findings from us and others have shown that Tax targets key regulators of G1/S and M progression such as p16INK4a, cyclin D1, cyclin D3-cdk, and the mitotic spindle checkpoint apparatus. Thus, Tax influences the progression of cells in various phases of the cell cycle. In this regard, we will discuss three distinct mechanisms through which Tax affects cell-cycling: a) through direct association Tax can abrogate the inhibitory function of p16INK4a on the G1-cdks, b) Tax can also directly influence cyclin D-cdk activities by a protein-protein interaction, and c) Tax targets the HsMAD1 mitotic spindle-assembly checkpoint protein. Through these varied routes, the HTLV-I oncoprotein dysregulates cellular growth controls and engenders a proclivity of cells toward a loss of DNA-damage surveillance.

Cell division cycles and circadian rhythms are major periodic phenomena in organisms. Circadian oscillators control biochemical, physiological, and behavioral events in a wide range of living systems including almost all eukaryotes that have been tested and some prokaryotes-in particular, the cyanobacteria. Gating of cell division is one of the key processes that has been reported to be regulated by circadian clocks in many organisms. We survey studies of the circadian control of cell division in eukaryotic microorganisms and introduce recent progress on understanding the interaction between circadian rhythms and cell division cycles in cyanobacteria.

The 14-3-3 proteins constitute a family that is highly conserved in a wide range of organisms, including higher eukaryotes, invertebrates and plants. Variants of 14-3-3 proteins assembled in homo- and heterodimers were found to interact with diverse cellular proteins. Until recently, the biological role of 14-3-3 members was still poorly understood. However, the results of an increasing number of studies on their structure and function are converging to define 14-3-3 proteins as a novel type of adaptor that modulates interactions between components involved in signal transduction pathway and in cell cycle control.

Stimulated by maturation-inducing hormone secreted from follicle cells surrounding the oocytes, fully-grown oocytes mature and become fertilisable. During maturation, immature oocytes resume meiosis arrested at the first prophase and proceed to the first or second metaphase at which they are naturally inseminated. Paying special attention to general and species-specific aspects, we summarise the mechanisms regulating the initial phase of oocyte maturation, from the reception of hormonal signals on the oocyte surface to activation of the maturation-promoting factor in the cytoplasm, in amphibians, fishes, mammals and marine invertebrates.

Alzheimer disease, the leading cause of senile dementia, is characterised by the degeneration of select neuronal populations. While the mechanism(s) underlying such cell loss are largely unknown, recent findings indicate inappropriate re-entry into the cell cycle resembling an abortive oncogeny. In postmitotic neurons, such mitotic re-entrance is deleterious and one that involves virtually the entire spectrum of the described pathological events in Alzheimer disease including, ultimately, cell death.

Two distinct products are specified by the CDKN2A locus, the p16INK4a cyclin dependent kinase inhibitor and a protein termed ARF. ARF has been shown to bind to the Mdm2-p53 complex, resulting in stabilisation of both proteins, and a feedback loop exists through which ARF levels are negatively regulated by p53. Significantly, ARF expression is positively regulated by members of the E2F family of transcription factors. This provides a link between the Rb and p53 pathways and a mechanism whereby inactivation of Rb and release of E2F will lead to the stabilisation and functional activation of p53. The alternative exon encoding the functional amino terminal portion of ARF presumably represents an independent gene that has become co-localized with p16INK4a in order to exploit a common regulatory mechanism or purpose.

Pho85 is a multifunctional cyclin-dependent kinase (Cdk) in Saccharomyces cerevisiae that has emerged as an important model for the role of Cdks in both cell cycle control and other processes. Pho85 was originally discovered as a regulator of phosphate metabolism but roles for Pho85 in glycogen biosynthesis, actin regulation and cell cycle progression have since been discovered. Ten genes encoding known or putative Pho85 cyclins (Pcls) have been identified and the Pcls appear to target Pho85 to specific cellular functions and substrates. In this chapter, we review the functions of the various Pcl-Pho85 complexes in budding yeast. We focus on the known biological roles of Pho85 with an emphasis on Pho85 substrates and cyclin-Cdk specificity.

Activation of cyclin-dependent kinases in higher eukaryotic cells can be achieved through dephosphorylation by members of the Cdc25 phosphatase family, Cdc25A, Cdc25B and Cdc25C. Cdc25A plays an important role at the G1/S-phase transition. Cdc25B undergoes activation during S-phase and plays a role in activating the mitotic kinase Cdk1/cyclin B in the cytoplasm. Active Cdk1/cyclin B then phosphorylates and activates Cdc25C leading to a positive feedback mechanism and to entry into mitosis. Cdc25A and B are potential human oncogenes. In addition, Cdc25 is a main player of the G2 arrest caused by DNA damage or in the presence of unreplicated DNA.