Study of the effect of hydroxyurea on the erythropoietin-sensitive cells.

The response of polycythaemic mice to a standard dose of erythropoietin has been measured at various time intervals after single or repeated injections of hydroxyurea. The results exclude S phase of the cell cycle as the period responsive to erythropoietin. They suggest the existence of feedback mechanisms within the cell cycle, operating at the G1--S boundary and within the G1 phase. Hydroxyurea given to polycythaemic mice at various time intervals after erythropoietin induced characteristic changes in the response. These changes can be explained if both gradual transit of differentiated cells into the DNA synthesis (S phase) and changes in amount of the erythropoietin sensitive cells caused by the feedback mechanisms operating in the cell cycle are considered.     

STUDY OF THE EFFECT OF HYDROXYUREA ON THE ERYTHROPOIETIN-SENSITIVE CELLS

The response of polycythaemic mice to a standard dose of erythropoietin has been measured at various, time intervals after single or repeated injections of hydroxyurea. The results exclude S phase of the cell cycle as the period responsive to erythropoietin. They suggest the existence of feedback mechanisms within the cell cycle, operating at the G₁-S boundary and within the G₁ phase. Hydroxyurea given to polycythaemic mice at various time intervals after erythropoietin induced characteristic changes in the response. These changes can be explained if both gradual transit of differentiated cells into the DNA synthesis (S phase) and changes in amount of the erythropoietin sensitive cells caused by the feedback mechanisms operating in the cell cycle are considered.     

Trichinella spiralis: Subversion of differentiated mammalian skeletal muscle cells

Infection by Trichinella spiralis initiates changes in terminally differentiated mammalian skeletal muscle cells that lead to host cell cycle re-entry, cell cycle arrest in apparent G2/M phase, the repression of differentiated skeletal muscle characteristics and the expression of a phenotype unlike other stages in the muscle lineage. Although the parasite must be involved in initiating these changes, its precise role is unclear. Based on regulatory mechanisms which control myogenesis Douglas Jasmer proposes that host cell regulatory products, expressed as a consequence of cell cycle repositioning may determine aspects of the infected host cell phenotype. Distinguishing between host- and parasite-regulated changes should aid in identifying pertinent parasite molecules and uncovering the significance of host cell changes to parasite growth, developments and survival.     

Cell Cycle-Regulated Protein Abundance Changes in Synchronously Proliferating HeLa Cells Include Regulation of Pre-mRNA Splicing Proteins

Cell proliferation involves dramatic changes in DNA metabolism and cell division, and control of DNA replication, mitosis, and cytokinesis have received the greatest attention in the cell cycle field. To catalogue a wider range of cell cycle-regulated processes, we employed quantitative proteomics of synchronized HeLa cells. We quantified changes in protein abundance as cells actively progress from G1 to S phase and from S to G2 phase. We also describe a cohort of proteins whose abundance changes in response to pharmacological inhibition of the proteasome. Our analysis reveals not only the expected changes in proteins required for DNA replication and mitosis but also cell cycle-associated changes in proteins required for biological processes not known to be cell-cycle regulated. For example, many pre-mRNA alternative splicing proteins are down-regulated in S phase. Comparison of this dataset to several other proteomic datasets sheds light on global mechanisms of cell cycle phase transitions and underscores the importance of both phosphorylation and ubiquitination in cell cycle changes.     

Circadian clock,cell cycle,and breast cancer: an updated review

Some key elements are common to two fundamental periodic regulatory processes; the circadian cycle and the cell cycle. Underlying mechanisms of coordination between the two processes are critical for proper cellular functioning and physiology. Disruption in the mechanisms of one process may affect the role of other that may direct critical physiological changes and may cause severe diseases like cancer, etc. More or less persuasive evidences evolve from the breast cancer research. In this mini review, we highlighted the molecular coordination’s of the elements of circadian cycle and the cell cycle and their altered expressions associated with the genesis and progression of breast cancer.     

Re-cycling Paradigms: Cell Cycle Regulation in Adult Hippocampal Neurogenesis and Implications for Depression

Since adult neurogenesis became a widely accepted phenomenon, much effort has been put in trying to understand the mechanisms involved in its regulation. In addition, the pathophysiology of several neuropsychiatric disorders, such as depression, has been associated with imbalances in adult hippocampal neurogenesis. These imbalances may ultimately reflect alterations at the cell cycle level, as a common mechanism through which intrinsic and extrinsic stimuli interact with the neurogenic niche properties. Thus, the comprehension of these regulatory mechanisms has become of major importance to disclose novel therapeutic targets. In this review, we first present a comprehensive view on the cell cycle components and mechanisms that were identified in the context of the homeostatic adult hippocampal neurogenic niche. Then, we focus on recent work regarding the cell cycle changes and signaling pathways that are responsible for the neurogenesis imbalances observed in neuropathological conditions, with a particular emphasis on depression.     

Analysis of vagally induced sinus arrhythmias.

Vagal stimulation at precise times in successive cardiac cycles can elicit sinus arrhythmias. Two mechanisms have been identified that can, but do not necessarily, cause these vagally induced sinus arrhythmias. First, changes in cycle length elicited by a given concentration of acetylcholine (ACh) depend on the phase of the pacemaker cell action potential when the ACh binds to muscarinic receptors. Second, acetylcholinesterase degrades ACh rapidly enough for the mean concentration of ACh per cardiac cycle to vary from cycle to cycle. We used a mathematical model of the underlying cellular physiology, to examine whether these mechanisms are responsible for arrhythmogenesis. Computer simulation showed that both mechanisms contribute to the vagally induced sinus arrhythmias.     

Identification of Genes Controlling Growth Polarity in the Budding Yeast Saccharomyces Cerevisiae: A Possible Role of N-Glycosylation and Involvement of the Exocyst Complex

The regulation of secretion polarity and cell surface growth during the cell cycle is critical for proper morphogenesis and viability of Saccharomyces cerevisiae. A shift from isotropic cell surface growth to polarized growth is necessary for bud emergence and a repolarization of secretion to the bud neck is necessary for cell separation. Although alterations in the actin cytoskeleton have been implicated in these changes in secretion polarity, clearly other cellular systems involved in secretion are likely to be targets of cell cycle regulation. To investigate mechanisms coupling cell cycle progression to changes in secretion polarity in parallel with and downstream of regulation of actin polarization, we implemented a screen for mutants defective specifically in polarized growth but with normal actin cytoskeleton structure. These mutants fell into three classes: those partially defective in N-glycosylation, those linked to specific defects in the exocyst, and a third class neither defective in glycosylation nor linked to the exocyst. These results raise the possibility that changes in N-linked glycosylation may be involved in a signal linking cell cycle progression and secretion polarity and that the exocyst may have regulatory functions in coupling the secretory machinery to the polarized actin cytoskeleton.     

Chromatin changes during the cell cycle.

Considerable progress has recently been made in elucidating the biochemical mechanisms regulating changes in chromatin structure during all stages of the cell cycle. Although anticipated, the apparently ubiquitous role played by phosphorylation/dephosphorylation reactions in modulating these changes is, nonetheless, remarkable.     

Neurogenesis and cell cycle-reactivated neuronal death during pathogenic tau aggregation

The aim of the present study was to investigate the relation between neurogenesis, cell cycle reactivation and neuronal death during tau pathology in a novel tau transgenic mouse line THY-Tau22 with two frontotemporal dementia with parkinsonism linked to chromosome-17 mutations in a human tau isoform. This mouse displays all Alzheimer disease features of neurodegeneration and a broad timely resolution of tau pathology with hyperphosphorylation of tau at younger age (up to 6 months) and abnormal tau phosphorylation and tau aggregation in aged mice (by 10 months). Here, we present a follow-up of cell cycle markers with aging in control and transgenic mice from different ages. We show that there is an increased neurogenesis during tau hyperphosphorylation and cell cycle events during abnormal tau phosphorylation and tau aggregation preceding neuronal death and neurodegeneration. However, besides phosphorylation, other mechanisms including tau mutations and changes in tau expression and/or splicing may be also involved in these mechanisms of cell cycle reactivation. Altogether, these data suggest that cell cycle events in THY-Tau22 are resulting from neurogenesis in young animals and cell death in older ones. It suggests that neuronal cell death in such models is much more complex than believed.     

Chemical inhibitors of cyclin-dependent kinases

Transient activation o f cyclin-dependent kinases (CDKs) is responsible for transition through the successive phases of the cell-division cycle. Major changes in the expression and regulation of CDKs have been described in human tumours. Enzymatic screening is starting to uncover chemical inhibitors o f CDKs that arrest the cell cycle at various steps. This review summarizes our knowledge of the first generation inhibitors, their molecular mechanisms of action and their effects on the cell cycle and apoptosis, and discusses their potential as synchronizing agents, as ligands for affinity chromatography and as therapeutic agents.     

Control of centrosome reproduction: the right number at the right time.

It is of great importance for the cell to precisely coordinate the doubling of the interphase centrosome with nuclear events during the cell cycle and limit the number of centrosomes it contains at the onset of mitosis to two and only two. The penalties for mistakes are abnormal spindle assembly, inappropriate chromosome distribution, and consequently, genomic instability. We review the functional properties of the mechanisms that control when the centrosome duplicates in the cell cycle and the controls for centrosome copy number. We look to limits that are intrinsic to the centrosome itself and controls imposed by cell cycle linked changes in cytoplasmic conditions. Control of centrosome reproduction is exercised at both levels.     

Epigenetics and cell cycle regulation in cystogenesis

The role of genetic mutations in the development of polycystic kidney disease (PKD), such as alterations in PKD1 and PKD2 genes in autosomal dominant PKD (ADPKD), is well understood. However, the significance of epigenetic mechanisms in the progression of PKD remains unclear and is increasingly being investigated. The term of epigenetics describes a range of mechanisms in genome function that do not solely result from the DNA sequence itself. Epigenetic information can be inherited during mammalian cell division to sustain phenotype specifically and physiologically responsive gene expression in the progeny cells. A multitude of functional studies of epigenetic modifiers and systematic genome-wide mapping of epigenetic marks reveal the importance of epigenomic mechanisms, including DNA methylation, histone/chromatin modifications and non-coding RNAs, in PKD pathologies. Deregulated proliferation is a characteristic feature of cystic renal epithelial cells. Moreover, defects in many of the molecules that regulate the cell cycle have been implicated in cyst formation and progression. Recent evidence suggests that alterations of DNA methylation and histone modifications on specific genes and the whole genome involved in cell cycle regulation and contribute to the pathogenesis of PKD. This review summarizes the recent advances of epigenetic mechanisms in PKD, which helps us to define the term of “PKD epigenetics” and group PKD epigenetic changes in three categories. In particularly, this review focuses on the interplay of epigenetic mechanisms with cell cycle regulation during normal cell cycle progression and cystic cell proliferation, and discusses the potential to detect and quantify DNA methylation from body fluids as diagnostic/prognostic biomarkers. Collectively, this review provides concepts and examples of epigenetics in cell cycle regulation to reveal a broad view of different aspects of epigenetics in biology and PKD, which may facilitate to identify possible novel therapeutic intervention points and to explore epigenetic biomarkers in PKD.     

Fluorescein excitation and emission polarization spectra in living cells: changes during the cell cycle.

Changes in the fluorescein fluorescence emission and excitation polarization spectra in synchronized cultured S3 fibroblasts at G1, mid-S, and mitosis, as well as in human lymphocytes before and after stimulation with mitogens, were studied. In contrast to those measured in aqueous solutions the emission and excitation polarization spectra in living cells exhibit a wavelength dependence characteristic for the state of the cell cycle. Changes in the temperature and in the amount of intracellular water result in quantitative wavelength-independent changes in the polarization spectra. Possible mechanisms for the qualitative wavelength-dependent changes in the fluorescein emission and excitation polarization spectra during the cell cycle are discussed.     

Bot1p is required for mitochondrial translation, respiratory function, and normal cell morphology in the fission yeast Schizosaccharomyces pombe

Maintenance of cell morphology is essential for normal cell function. For eukaryotic cells, a growing body of recent evidence highlights a close interdependence between mitochondrial function, the cytoskeleton, and cell cycle control mechanisms; however, the molecular details of this interconnection are still not completely understood. We have identified a novel protein, Bot1p, in the fission yeast Schizosaccharomyces pombe. The bot1 gene is essential for cell viability. bot1Delta mutant cells expressing lower levels of Bot1p display altered cell size and cell morphology and a disrupted actin cytoskeleton. Bot1p localizes to the mitochondria in live cells and cofractionates with purified mitochondrial ribosomes. Reduced levels of Bot1p lead to mitochondrial fragmentation, decreased mitochondrial protein translation, and a corresponding decrease in cell respiration. Overexpression of Bot1p results in cell cycle delay, with increased cell size and cell length and enhanced cell respiration rate. Our results show that Bot1p has a novel function in the control of cell respiration by acting on the mitochondrial protein synthesis machinery. Our observations also indicate that in fission yeast, alterations of mitochondrial function are linked to changes in cell cycle and cell morphology control mechanisms.