Progress in cell cycle research最新文献

As cell cycle research enters its fourth decade, multiple protein kinases are firmly established as key regulators of the cell cycle, and some of them have emerged as promising drug targets. This review will discuss the serine/threonine-specific protein phosphatases that oppose the actions of protein kinases. Typically, a phosphatase may stimulate one cell cycle transition, and inhibit another; alternatively, two different phosphatase holoenzymes may have opposing effects on the same cell cycle transition. Thus, both activation and inhibition of these enzymes could result in cell cycle arrest and/or apoptosis. Specific findings, the challenges and approaches to exploit this potential will be discussed.

Immunocytochemical detection of cyclins, inhibitors of cyclin-dependent kinases and other cell cycle regulatory proteins, combined with analysis of cell cycle position (DNA content) by multiparameter cytometry offers unique analytical possibilities. This review focuses on applications of the methodology that yield information on the abundance, modification or interactions of these proteins in relation to cell cycle progression that cannot be obtained by other methods. Particular attention is given to the use of multiparameter cytometry in analysis of the mechanism by which antitumor drugs affect cell cycle progression and induce cell cycle phase-specific apoptosis.

Mitotic chromosome condensation is an essential cellular function ensuring proper compaction and segregation of sister chromatids during cell division. Condensin, a five-subunit complex, conserved among eukaryotes, is the key molecular machine of chromosome condensation. Recent advances in the structural biology and functional analysis of condensin demonstrate the unique nature and indispensable biological role of this complex. Condensin functions span chromosome dynamics during mitotic cell division, cell-cycle feedback control mechanisms, as well as formation and maintenance of interphase chromosome structure. Being at the intersection of several cell-cycle regulatory networks condensin is a promising therapeutic target for control over cell proliferation.

Cervical cancer is tightly associated with infection by high-risk human papillomaviruses (HPVs). Many high-risk HPV-positive lesions are genomically unstable and show chromosomal gains and losses already at early stages of carcinogenic progression. These genomic aberrations are caused by the HPV-encoded oncoproteins E6 and E7, which subvert mitotic fidelity of the infected host cell. Whereas E7 drives genomic instability by inducing abnormal centrosome numbers, E6 cooperates with E7 presumably by relaxing critical checkpoint control mechanisms. The ability of E7 to induce centrosome duplication errors (CDEs) may be linked to the re-programming of the host cell cycle machinery, including dysregulation of cyclin/cyclin-dependent kinase (cdk) 2 activity. Given the role of cdk2 as a regulatory node not only for cell cycle progression but also for centrosome duplication, inhibition of cdk2 may not only retard cellular proliferation but also decrease CDEs and centrosome-related mitotic defects. Compared to some conventional cytotoxic agents, which exclusively target DNA replication, modulation of cdk2 activity may hold the promise of diminishing the development of genomically unstable, aneuploid tumor cells that are frequently the source of chemotherapy resistance in malignant tumors.

Deregulation of the tumor suppressor p27kip1 (p27) has been implicated in a variety of human cancers, suggesting it might be a viable therapeutic target. Developing p27-specific intervention strategies requires understanding its role and regulation in normal and pathologic states. Although p27 has been extensively characterized as an inhibitor of cyclin-dependent kinases, disruption of this function is inadequate to explain its role in tumorigenesis. A more comprehensive understanding of p27 biology would facilitate development of therapeutic responses to p27 disruption in human cancers.

Life-threatening fungal infections are becoming more frequent and involve a greater variety of strains, many of which are drug-resistant. Both public research organisations and the pharmaceutical industry are committed to the development of new drugs to satisfy this increasing medical need. The approach described here exemplifies the efforts directed towards the discovery of drugs which are active against novel targets, exemplified by the cell-cycle regulator, Civ1.

The ubiquitin/proteasome-dependent protein degradation pathway plays an essential role in both up-regulation of cell proliferation and down-regulation of cell death in human cancer cells. The idea that proteasome function is required for tumor cell survival has prompted the design, synthesis and evaluation of various pharmacological proteasome inhibitors. Both in vitro and in vivo experimental and clinical results have demonstrated the potential use of proteasome inhibitors as novel anticancer drugs.

Cell division and apoptosis are key aspects of cancer biology. The combination of increased cell proliferation and reduced cell death lies very close to the reason why cancer is a deadly disease. The importance of apoptosis and cell division in tumor biology has made them targets of new anti-cancer therapies. Although the cell division cycle and apoptosis might appear to be quite different from a physiological perspective and thus provide independent targets for therapy, recent evidence suggests that they are intertwined, and that an enzyme in one system might also have an important role in the other system. Protein kinase complexes known as cyclin-dependent kinases (Cdks) are the first example of such enzymes. In this review, we focus on the role of the subunits of different Cdks in both apoptosis and the cell cycle.

Small, cell permeable, and target-specific chemical ligands are highly valuable, not only as therapeutics but also as research tools. The synthesis, identification and characterization of these compounds is often a difficult task. The straightforward genetics of the budding yeast Saccharomyces cerevisiae, and the high degree of conservation of basic cellular processes between yeast and higher organisms makes yeast an excellent tool for drug development studies, particularly in regards to anticancer and anti-fungal drug discovery. Recent advances in yeast functional genomics and proteomics studies are changing the field of yeast research. Many of these new technologies are readily applicable to drug target identification and other aspects of drug discovery. This review will focus on current genetic, genomic, and proteomic methodologies in S. cerevisiae that have the potential to be useful in drug discovery and target validation.

The presence of mutated Ras in more that 30% of human cancers has spurred interest in the identification of molecules that can block its uncontrolled signaling function. A particular focus in recent years has been a key posttranslational modification of Ras that places a farnesyl group on a cysteine residue near the C-terminus of the protein. In this chapter we describe recent progress in the design of inhibitors for the enzyme that catalyzes this step, protein farnesyltransferase, and show their potential for blocking oncogenic cell growth.