Progress in cell cycle research最新文献

Cardiovascular diseases are the leading cause of morbidity and mortality in industrialized countries. Most cardiovascular diseases result from complications of atherosclerosis, which is a chronic and progression inflammatory condition characterized by excessive cellular proliferation of vascular smooth muscle cells, endothelial cells and inflammatory cells leading to occlusive vascular disease, myocardial infarction and stroke. Recent studies have revealed the important role of the cyclins, the cyclin-dependent kinases (CDKs), and the cyclin-dependent kinase inhibitors (CKIs) in vascular and cardiac tissue injury, inflammation and wound repair. Tissue remodeling in the cardiovascular system is a regulated balance between pro- and anti-proliferative molecules, and this balance becomes derailed in cardiovascular pathology. Understanding the circuitry of the cyclin-CDK-CKI interactions in normal physiology and disease pathology allows a better understanding of the molecular mechanisms of cardiovascular diseases and permits the rationale design of new classes of therapeutic agents for these diseases.

As essential cell cycle regulators, the CDC25 phosphatases are currently considered as potential targets for the development of novel therapeutic approaches. Here, we review the function and regulation of CDC25 phosphatases, their involvement in cancer and Alzheimer's disease, and the properties of several recently identified inhibitors.

The genomes of small DNA viruses such as papilloma and polyomaviruses code for few or no DNA replication proteins. Consequently, these viruses depend on cellular DNA replication proteins to replicate their genomes and replicate only when the infected cell progresses into S-phase, when these proteins are active. As a consequence of this strict dependence, the relationship between replication of the small DNA viruses and the cell cycle was obvious from the very early studies. The genomes of larger DNA viruses such as adeno- and herpes-viruses, in contrast, encode many of the proteins required for DNA replication. Some of the larger DNA viruses such as adenoviruses, however, also replicate only in S-phase because expression of viral DNA replication proteins is regulated by cellular factors that are activated in S-phase. Other large DNA viruses such as herpes simplex viruses (HSV) can replicate in arrested cells such as neurons, without inducing progression into S-phase. The relationships between cell cycle and replication of these last viruses are, thus, so subtle that their replication was long thought to be independent from cellular proteins whose activities are regulated in a cell cycle dependent manner. In contrast to this hypothesis, recent studies have shown that replication of HSV and other large DNA viruses requires cellular proteins whose activities are normally regulated in a cell cycle dependent manner, such as the cyclin-dependent kinases (cdks). Many excellent reviews on the interactions between cellular proteins involved in cell cycle regulation and smaller DNA viruses (parvo, papilloma, polyoma and adenoviruses) have been published (for example, see (1, 2)). Many reviews on cell cycle regulation also discuss the interactions between the cell cycle and the smaller DNA viruses (for example, see (3-5)). Herein, we will review these relationships only briefly, while focusing on the interactions between cell cycle proteins such as cdks and herpes-, retro, and hepadna-viruses. We will then succinctly discuss the surprising relationships between cdks and replication of some cytoplasmic RNA viruses. Lastly, we will present the possibility of applying the new information on the dependence of viral replication on cyclin-dependent kinases to the development of novel antiviral drugs.

The DNA damage response includes not only checkpoint and apoptosis, but also direct activation of DNA repair networks. Downstream in the DNA damage response pathway are Chk1, an essential checkpoint kinase, and Chk2, which plays a critical role in p53-dependent apoptosis. Chk1 inhibition is expected to lead to chemosensitization of tumors, while Chk2 inhibition could protect normal sensitive tissues from some chemotherapeutic agents. Drugs targeting Chk1 and Chk2 have the potential to significantly improve the therapeutic window of DNA damaging agents available in the clinic.

We propose an integrated application of technologies, computation and statistical methods to design experiments for examination of cellular pathways that are necessary for cell survival and that are candidates for cancer therapy. Our design combines information derived from two very different data sets: tumor screening data from over 36,000 synthetic compounds screened against over 60 tumor cell lines, and replicate microarray gene expression measurements using one cell line and one compound. Data filtering, based on restricted cellular cytotoxicity profiles from chemically similar sets of compounds, has been used to select a class of benzothiazoles for subsequent microarray gene expression measurements in the most chemosensitive tumor cell line. The results confirmed observations that P450 metabolizing isoforms, CYP1A1 and CYP1B1, are overexpressed in MCF-7 tumor cells following treatment with benzothiazole. These results are consistent with the proposed inactivity of the CYP1A1-mediated metabolism of benzothiazole and the antitumor activity of the metabolically resistant halogenated forms.

The mechanism by which neurons die in human neurodegenerative diseases remains an enigma till today. Terminally differentiated neurons of normal brain are incapable of cell division. However, accumulating evidence has suggested that aberrant activation of the cell cycle in certain degenerative diseases leads to their demise. In Alzheimer's disease, regulators spanning every phase of the cell cycle are upregulated in affected neurons, leading to successful DNA replication, but unsuccessful mitosis. The end point of this nonproductive cycle of division is death. Elucidating the details of this cell cycle-mediated degenerative cascade may lead to novel strategies for curbing the onset and progression of degenerative diseases.

The ERK signaling pathway, also known as the p42/p44 MAP kinase pathway, is a major determinant in the control of cell growth, cell differentiation and cell survival. This pathway, which operates downstream of Ras, is often up-regulated in human tumors and as such represents an attractive target for anticancer therapy. In this chapter we review the rationale for targeting the components of the ERK pathway, either alone or in association with cytotoxic anticancer agents. We present the most advanced inhibitors of this pathway and discuss their specificity and mechanism of action.

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.