Progress in cell cycle research最新文献

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor responsive to both natural and man-made environmental compounds. AhR-mediated changes in gene expression frequently affect cell growth, and recent evidence reveals a direct role for the AhR in cell cycle control. This review examines the functional interaction between the AhR and the retinoblastoma tumor suppressor protein (pRb), and its impact on the G1 phase of the cell cycle. The discussion emphasizes gaps in our mechanistic understanding, and reveals the AhR signaling pathway as a novel drug target to control cell proliferation.

Members of the HMGA (formerly known as HMGI/Y) family of non-histone chromatin proteins function as important accessory factors in many normal nuclear processes, including the modulation of chromosome structure, chromatin and nucleosome remodeling and the control of gene transcription. The HMGA proteins are also frequently associated with various malignancies. The aberrant expression or over-expression of these proteins is, for example, associated with many different types of tumors. The HMGA proteins also appear to be the host-supplied cofactors necessary for efficient integration of retroviruses, such as HIV, into the genome. The HMGA proteins appear, therefore, to be promising targets for therapeutic drugs aimed at alleviating these and other pathological conditions.

Tuberous sclerosis (TSC) is an autosomal dominant tumor suppressor gene syndrome occurring in about 1 in 6000 live births. Two genes have been shown to be responsible for this disease: TSC1 on chromosome 9q34, encoding hamartin, and TSC2 on chromosome 16p13.3, encoding tuberin. Although several different functions of these proteins have been described, the molecular mechanism for the development of TSC remains elusive. Mammalian and Drosophila TSC genes have been shown to be involved in cell cycle regulation. The Drosophila TSC genes have further been demonstrated to affect cell size control and to be related to the insulin signaling pathway. Very recent data provide evidence that mammalian TSC genes are also involved in cell size regulation.

The mitotic checkpoint is a failsafe mechanism for the cell to ensure accurate chromosome segregation during mitosis. Mutations in genes encoding essential checkpoint proteins lead to chromosome instability and promote carcinogenesis. The BUB and MAD genes are essential components of the mitotic checkpoint pathway. BUB and MAD inhibit the ubiquitin ligase activity of the Anaphase Promoting Complex/Cyclosome (APC/C) during mitosis to ensure cells with unaligned chromosomes do not prematurely enter anaphase. Two models explain how the APC/C is inhibited by the checkpoint. The Sequestration Model postulates that Mad2 and BubR1 bind and sequester Cdc20, an APC/C activator, away from APC/C so substrates whose destruction drives mitotic exit are no longer ubiquitinated. In this model, the unattached kinetochore is postulated to catalytically convert Mad2 to a form that binds Cdc20. In the Direct Inhibition Model, the Mitotic Checkpoint Complex (MCC) consisting of BubR1, Bub3, Mad2 and Cdc20 binds and inhibits the APC/C independently of the kinetochore. However, the "wait anaphase" signal generated by unattached kinetochores sensitizes the APC/C to prolonged inhibition by the MCC. A single unattached kinetochore is proposed to amplify the "wait anaphase" signal through a kinase cascade involving checkpoint kinases such as hBubR1, hBub1 and Mps1.

We are in a new era of drug discovery, in which it is feasible to develop therapeutic agents targeted at a particular protein or biological activity in a living cell. This has been made possible by major advances in our understanding of cell and molecular biology, epitomized by the 2001 Nobel prize award for Physiology or Medicine to Lee Hartwell, Tim Hunt and Paul Nurse, who were recognised for their work on key regulators of the cell cycle. Technological advances have also played a decisive role, leading to the sequencing of the human genome and increased throughput at many stages of the drug discovery and development process. For example, developments in high throughput screening, structural biology and microarray technology are increasing the speed of drug discovery. In this chapter we focus on the long, and often difficult, pathway which leads from identification of a hit in a screen to regulatory approval of a drug for disease treatment. The emphasis in this chapter is on the development of anticancer drugs, as this is our own area of expertise and also because cancer is a disease in which the cell cycle is already a major target for therapeutic intervention. However, many of the concepts, approaches and issues are generally common to other therapeutic areas.

Drugs affecting the cell cycle provide insights into mechanisms underlying cancer and suggest strategies for ablating uncontrolled growth. Essential to an understanding of the activity of such compounds is the identification of the set of proteins affected, either directly or indirectly, by the drug. The combination of novel technologies for stable isotope protein tagging, chromatographic separation, tandem mass spectrometry, and data processing is an extremely powerful means for providing such identifications and, in addition, for establishing a proteome-wide profile of all proteins whose abundance levels or phosphorylation state are affected by the drug.

Cells normally respond to DNA damage by activating checkpoints that delay the transition from G1 to S and from G2 to M while DNA is repaired. The checkpoints thus protect cells by blocking replication of damaged DNA and segregation of damaged chromosomes. Most cancer cells have an inoperative G1 checkpoint due to p53 inactivation, and a functioning but impaired G2 checkpoint. Inhibitors of the G2 checkpoint can selectively sensitize cells with inactive p53 to killing by DNA-damaging drugs or ionizing radiation and might be useful in cancer therapy. Cell-based and target-directed screens for checkpoint inhibitors have been developed and several checkpoint inhibitors have been identified. This review describes their chemical structures, biochemical targets and cellular effects and discusses their therapeutic potential.

The precise duplication of chromosomal DNA during each cell cycle is essential for the maintenance of genetic stability. Failure to correctly regulate chromosomal DNA replication could lead to losses or duplication of chromosome segments. The precise duplication of chromosomes is normally achieved by correct regulation of the replication licensing system. Here we review our current knowledge of the licensing system and how this might be defective in cancer cells. We also review how detection of licensing components can be used for the diagnosis and prognosis of cancer. Finally we discuss the potential of the replication licensing system as a novel anti-cancer target.

Potent and selective small-molecule mediated inhibition of the cell's replication machinery remains a principal aim in the development of novel therapeutics and biological probes. Recent efforts have identified small molecules capable of arresting the cell cycle via specific interaction with a variety of intracellular protein targets. Advances in combinatorial and diversity oriented synthetic methods, coupled with a continued effort to identify sources of bioactive natural products, promise to contribute to the growing library of small-molecule inhibitors of the cell cycle.

The phospho-Ser/Thr-Pro specific prolyl-isomerase Pin1 has been implicated in multiple aspects of cell cycle regulation. It has been suggested that Pin1 function is required for both normal mitotic progression and reentry into the cell cycle from quiescence. In support of this hypothesis, numerous key regulators of G1 and mitosis have been identified as Pin1 interacting proteins. However, the cellular consequence of Pin1 binding to these proteins has rarely been rigorously characterized. In this review we focus on the role of Pin1 and its binding proteins in cell cycle regulation and the potential value of Pin1 as a therapeutic target.