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PubMed1995

The role of Saccharomyces cerevisiae Cdc40p in DNA replication and mitotic spindle formation and/or maintenance.

Successful progression through the cell cycle requires the coupling of mitotic spindle formation to DNA replication. In this report we present evidence suggesting that, in Saccharomyces cerevisiae, the CDC40 gene product is required to regulate both DNA replication and mitotic spindle formation. The deduced amino acid sequence of CDC40 (455 amino acids) contains four copies of a beta-transducin-like repeat. Cdc40p is essential only at elevated temperatures, as a complete deletion or a truncated protein (deletion of the C-terminal 217 amino acids in the cdc40-1 allele) results in normal vegetative growth at 23 degrees C, and cell cycle arrest at 36 degrees C. In the mitotic cell cycle Cdc40p is apparently required for at least two steps: (1) for entry into S phase (neither DNA synthesis, nor mitotic spindle formation occurs at 36 degrees C and (2) for completion of S-phase (cdc40::LEU2 cells cannot complete the cell cycle when returned to the permissive temperature in the presence of hydroxyurea). The role of Cdc40p as a regulatory protein linking DNA synthesis, spindle assembly/maintenance, and maturation promoting factor (MPF) activity is discussed.

Amino Acid Sequence↗

PubMed1994

Preliminary findings of chromosomal alterations and expression of cell cycle genes in head an neck tumors.

The genesis and progression of malignant tumors may be related to certain somatic mutations and the accumulation of multiple chromosomal alterations. Using four freshly resected malignant tumors, we investigated the relationship between chromosomal alteration and expression of cell cycle regulatory genes. Specimens of thyroid hyperplasia and normal thyroid tissue were also investigated. As cell cycle regulating genes, we chose the cdc2 gene that encodes the p34cdc2 protein kinase, a major kinase of the cell cycle, and the RCC1 gene that is essential for coupling between S and M phases. Three of the malignant tumors contained cells with chromosomal alterations, including one polyploid and two aneuploid. The DNA content of cells in thyroid hyperplasia was the same as in the normal gland. The amount of p34cdc2 protein was very low in cells of both normal thyroid and hyperplastic tissue, and grew very slowly as compared with malignant tumors. There was no significant relationship between the amount of RCC1 and ploidy pattern.

Adaptor Proteins, Signal Transducing↗

PubMed2000

Multiple defects of cell cycle checkpoints in U937-ASPI3K, an U937 cell mutant stably expressing anti-sense ATM gene cDNA.

(Ataxia-telangiectasia mutated gene (ATM) functions in control of cell cycle checkpoints in responding to DNA damage and protects cells from undergoing apoptosis. Knock-out within tumor cells of endogenous ATM will achieve therapeutic benefits and enable a better understanding of the decisive mechanisms of cell death or survival in response to DNA damaging agents.) In present paper, we sought to characterize the cell cycle checkpoint profiles in U937-ASPI3K, a U937 cell mutant that was previously established with endogenous ATM knock-out phenotype. Synchronized U937-ASPI3K was exposed to 137Cs irradiation, G1, S, G2/M cell cycle checkpoint profiles were evaluated by determining cell cycle kinetics, p53/p21 protein, cyclin dependent kinase 2 (CDK2) and p34CDC2 kinase activity in response to irradiation. U937-ASPI3K exhibited multiple defects in cell cycle checkpoints as defined by failing to arrest cells upon irradiation. The accumulation of cellular p53/p21 protein and inhibition of CDK kinase was also abolished in U937-ASPI3K. It was concluded that the stable expression of anti-sense PI3K cDNA fragment completely abolished multiple cell cycle checkpoints in U937-ASPI3K, and hence U937-ASPI3K with an AT-like phenotype could serves as a valuable model system for investigating the signal transduction pathway in responding to DNA damaging-based cancer therapy.

Apoptosis↗

PubMed1999

[ZAP genes: characterizing the protein structure of a new family of proliferation associated genes in the exocrine pancreas].

While interested in proliferation-dependent gene regulation in a pancreatic carcinoma cell line, we cloned a set of proteins (ZAP) characterized by a conserved region consisting of consecutive zinc finger, ankyrin repeat and PH domains. Functional aspects of these domains were obtained by comparison with proteins involved in several signal transduction pathways and cell cycle regulation. The members of the ZAP protein family are individually characterized by different types of supplementary protein domains, their chromosomal localization and their tissue specific gene transcription. All results indicate a wide spectrum of protein-protein interactions. Up to now specific binding partners have not been identified. In summary, the multiplicity of conserved regions and transcriptional data indicate a scaffold function for ZAP proteins in the complex network of proliferation associated intracellular signal transduction pathways.

Amino Acid Sequence↗

PubMed2002

Integrating cytogenetics and gene expression profiling in the molecular analysis of multiple myeloma.

Multiple Myeloma (MM), is a currently incurable malignancy of a terminally differentiated antibody secreting plasma cell (PC) that can be controlled with high dose therapy and stem cell support. Conventional cytogenetic analysis has revealed a genomic instability that sets MM apart from the other blood cell cancers. In spite of this "genomic chaos" recurrent structural rearrangements and ploidy changes have aided the identification of important molecular mechanisms of disease etiology and that have also proved to be useful clinical landmarks. Yet, abnormal cytogenetics, present in only 30% of cases, combined with other clinical parameters, only account for 20% of the variability in clinical outcome, which can range from 2 months to > 10 years. Thus, the genomic chaos may mask a unifying chromosome abnormality, e.g. Philadelphia chromosome in CML, or may indicate that MM is a broad descriptor of constellation of many distinct clinical and molecular entities. The advent of microarray profiling of global gene expression patterns is providing evidence that both of these possibilities may be true. We will discuss how the integration of conventional and molecular cytogenetics with gene expression profiling has confirmed past observations and, yet fundamentally changed the way we view the disease.

Chromosome Aberrations↗

PubMed1998

Regulation of transcription of cell division genes in the Escherichia coli dcw cluster.

The Escherichia coli dcw cluster contains cell division genes, such as the phylogenetically ubiquitous ftsZ, and genes involved in peptidoglycan synthesis. Transcription in the cluster proceeds in the same direction as the progress of the replication fork along the chromosome. Regulation is exerted at the transcriptional and post-transcriptional levels. The absence of transcriptional termination signals may, in principle, allow extension of the transcripts initiated at the up-stream promoter (mraZ1p) even to the furthest down-stream gene (envA). Complementation tests suggest that they extend into ftsW in the central part of the cluster. In addition, the cluster contains other promoters individually regulated by cis- and trans-acting signals. Dissociation of the expression of the ftsZ gene, located after ftsQ and A near the 3' end of the cluster, from its natural regulatory signals leads to an alteration in the physiology of cell division. The complexities observed in the regulation of gene expression in the cluster may then have an important biological role. Among them, LexA-binding SOS boxes have been found at the 5' end of the cluster, preceding promoters which direct the expression of ftsI (coding for PBP3, the penicillin-binding protein involved in septum formation). A gearbox promoter, ftsQ1p, forms part of the signals regulating the transcription of ftsQ, A and Z. It is an inversely growth-dependent mechanism driven by RNA polymerase containing sigma s, the factor involved in the expression of stationary phase-specific genes. Although the dcw cluster is conserved to a different extent in a variety of bacteria, the regulation of gene expression, the presence or absence of individual genes, and even the essentiality of some of them, show variations in the phylogenetic scale which may reflect adaptation to specific life cycles.

Cell Division↗

PubMed2005

[Pathogenesis of the ductal pancreatic adenocarcinoma: implications for future therapies?].

Despite the advances in the knowledge of the molecular pathogenesis, pancreatic cancer remains a devastating disease with an 5-year survival rate below 5%. Current therapeutic approaches are not successful in respect to overall survival. There is a need to transfer the knowledge of basic science to new therapeutic strategies. This review describes the disturbed cell cycle control, anti-apoptotic mechanisms, the process of invasion and metastasis and angioneogenesis of pancreatic cancer cells. This knowledge will allow the development of novel therapeutic strategies for the future.

Apoptosis↗

PubMed2004

Using chemometrics for navigating in the large data sets of genomics, proteomics, and metabonomics (gpm).

This article describes the applicability of multivariate projection techniques, such as principal-component analysis (PCA) and partial least-squares (PLS) projections to latent structures, to the large-volume high-density data structures obtained within genomics, proteomics, and metabonomics. PCA and PLS, and their extensions, derive their usefulness from their ability to analyze data with many, noisy, collinear, and even incomplete variables in both X and Y. Three examples are used as illustrations: the first example is a genomics data set and involves modeling of microarray data of cell cycle-regulated genes in the microorganism Saccharomyces cerevisiae. The second example contains NMR-metabonomics data, measured on urine samples of male rats treated with either of the drugs chloroquine or amiodarone. The third and last data set describes sequence-function classification studies in a set of G-protein-coupled receptors using hierarchical PCA.

Animals↗

PubMed2003

Ionizing irradiation effects on S-phase in checkpoint mutants of the yeast Saccharomyces cerevisiae.

In mammalian cells, gamma-irradiation activates checkpoint controls to delay entry into, or passage through S-phase, while chronic exposure to methyl methanesulfonate or hydroxyurea causes a similar delay in yeast. In yeast, at least five genes are involved: RAD9, RAD17, RAD24, RAD53 and MEC1, a homologue of ATM. Here, using flow cytometry analysis and alkaline sucrose gradient centrifugation of labeled, newly made DNA, we demonstrate, in synchronized RAD wild-type Saccharomyces cerevisiae cells, that: (1) gamma-irradiation at START delays entry into S-phase, (2) irradiation shortly before or during early S-phase delays completion of S-phase and (3) the latter response is largely a consequence of replicon initiation inhibition. The delay produced by irradiation during early S-phase depends on the function of the checkpoint genes RAD9, RAD17, RAD24, RAD53, MEC1 and MEC3. However, at least four, RAD17, RAD53, MEC1, MEC3, are not needed to delay S-phase progression when cells are irradiated shortly before S-phase begins.

DNA↗

PubMed2001

A novel genetic screen identifies checkpoint-defective alleles of Schizosaccharomyces pombe chk1.

The protein kinase Chk1 is required in the fission yeast Schizosaccharomyces pombe for delaying cell cycle progression in response to DNA damage. Chk1 becomes phosphorylated when DNA is damaged by a variety of agents, including the anti-tumor drug camptothecin. To further characterize the behavior of Chk1 in response to DNA damage, we used PCR-based mutagenesis of the chk1 gene coupled with in vivo gap repair to generate mutant alleles. Of 44 chk1 mutants recovered, six encode full-length proteins that confer a DNA damage-sensitive phenotype. All of the alleles render cells checkpoint-defective, but confer subtle differences in sensitivity to camptothecin or UV light. Mutant alleles were sequenced and served to identify regions of the protein that are critical for checkpoint function.

Alleles↗

PubMed2006

The histone chaperone Asf1 at the crossroads of chromatin and DNA checkpoint pathways.

Nucleosome assembly involves deposition of a heterotetramer of histones H3/H4 onto DNA followed by two heterodimers of histones H2A/H2B. Cycles of nucleosome assembly and disassembly are essential to cellular events such as replication, transcription, and DNA repair. After synthesis in the cytoplasm, histones are shuttled into the nucleus where they are associated with chaperone proteins. Chaperones of histones H3/H4 include CAF-I, the Hir proteins, and Asf1. CAF-I and the Hir proteins function as replication-coupled and replication-independent deposition factors for H3/H4, respectively, whereas Asf1 may play a role in both pathways. In addition to acting as assembly factors, histone chaperones assist nucleosome dissociation from DNA and they may recruit other proteins to chromatin. The past few years have witnessed a notable accumulation of genetic, biochemical, and structural data on Asf1, which motivated this review. We discuss the sequence and structural features of Asf1 before considering its roles in nucleosome assembly/disassembly, the cellular response to DNA damage, and the regulation of gene expression. We emphasize the key role of Asf1 as a central node in a network of partners that place it at the crossroads of chromatin and DNA checkpoint pathways.

Cell Cycle↗

PubMed2001

A conserved protein, Nuf2, is implicated in connecting the centromere to the spindle during chromosome segregation: a link between the kinetochore function and the spindle checkpoint.

The centromere is crucial for the proper segregation of chromosomes in all eukaryotic cells. We identified a centromeric protein, Nuf2, which is conserved in fission yeast, human, nematode, and budding yeast. Gene disruption of nuf2+ in the fission yeast Schizosaccharomyces pombe caused defects in chromosome segregation and the spindle checkpoint: the mitotic spindle elongated without segregating the chromosomes, indicating that spindle function was compromised, but that this abnormality did not result in metaphase arrest. Certain nuf2 temperature-sensitive mutations, however, caused metaphase arrest with condensed chromosomes and a short spindle, indicating that, while these mutations caused abnormalities in spindle function, the spindle checkpoint pathway remained intact. Metaphase arrest in these cells was dependent on the spindle checkpoint component Mad2. Interestingly, Nuf2 disappeared from the centromere during meiotic prophase when centromeres lose their connection to the spindle pole body. We propose that Nuf2 acts at the centromere to establish a connection with the spindle for proper chromosome segregation, and that Nuf2 function is also required for the spindle checkpoint.

Amino Acid Sequence↗

PubMed1998

Arabidopsis SKP1, a homologue of a cell cycle regulator gene, is predominantly expressed in meristematic cells.

The yeast SKP1 gene and its human homolog p19skp1 encode a kinetochore protein required for cell cycle progression at both the DNA synthesis and mitosis phases of the cell cycle. In orchids we identified a cDNA (O 108) that is expressed in early stages of ovule development and is homologous to the yeast SKP1. Based on the orchid O 108 cDNA clone, we identified and characterized an Arabidopsis thaliana (L.) Heynh. cDNA designated ATskp1 that also has high sequence similarity to yeast SKP1. The Arabidopsis ATskp1 is a single-copy gene that mapped to chromosome 1. The expression of the ATskp1 gene was highly correlated with meristem activity in that its mRNA accumulated in all of the plant meristems including the vegetative shoot meristem, inflorescence and floral meristems, root meristem, and in the leaf and floral organ primordia. In addition, ATskp1 was also highly expressed in the dividing cells of the developing embryo, and in other cells that become multinucleate or undergo endoreplication events such as the endosperm free nuclei, the tapetum and the endothelium. Based on its spatial pattern of expression, ATskp1 is a marker for cells undergoing division and may be required for meristem activity.

Arabidopsis↗

PubMed2003

Activity of phosphoforms and truncated versions of Ndt80, a checkpoint-regulated sporulation-specific transcription factor of Saccharomyces cerevisiae.

Ndt80 contributes to the highly regulated cascade of sequential gene expression that directs spore formation in Saccharomyces cerevisiae. This DNA-binding transcriptional activator, which is responsible for the expression of a set of middle sporulation-specific genes, is a target of the meiotic recombination checkpoint. Triggering of this checkpoint prevents phosphorylation and accumulation of active Ndt80. In this study we have investigated the requirements for the activation function of Ndt80 by exploring the role of phosphorylation in the regulation of its activity and by examining the effect of C-terminal truncations. Of three phosphoforms of Ndt80 that we resolved, which we refer to as P approximately Ndt80", P approximately Ndt80', and P approximately Ndt80 in order of increasing electrophoretic mobility, the P approximately Ndt80" and P approximately Ndt80' isoforms correlated with active Ndt80. In particular, P approximately Ndt80" was present in lysates from wild-type sporulating cells and in cells that bypassed checkpoint-mediated arrest as a result of mutations in RAD17, SUM1, or SWE1, or overexpression of NDT80. P approximately Ndt80' was the slowest-migrating isoform that accumulated in Delta ime2/Delta ime2 Delta sum1/Delta sum1 cells in sporulation medium and in mitotic cells that ectopically expressed NDT80. Nonphosphorylated Ndt80 and P approximately Ndt80, which had a slightly lower mobility than nonphosphorylated Ndt80 and was the predominant phosphoform present in checkpoint-arrested cells, correlated with inactive Ndt80. These data are consistent with the notion that extensive phosphorylation, but not Ime2-dependent phosphorylation, of Ndt80 is required for its activity. Examination of the effect of increasingly extensive truncation of the C terminal region of Ndt80 revealed that some functions of Ndt80 were more sensitive to a reduction in its activity than others. In particular, we found that a truncated version of Ndt80 that lacked the last 110 residues was able to promote expression of some middle sporulation-specific genes, but could not direct spore formation. Full activity, however, could be restored to this version of Ndt80 by increasing its level of expression.

Cell Cycle Proteins↗

PubMed2001

Hsp90 levels affect telomere length in yeast.

Cdc13 is a Saccharomyces cerevisiae protein that binds to telomeric single-stranded DNA and regulates telomerase activity. Stnl has been shown by two-hybrid analysis to form a physical complex with Cdc13. Temperature-sensitive mutations in CDC13 and STN1, which are both essential genes, activate a DNA damage-dependent checkpoint which is the cause of the arrest seen in the mutant strains. The stn1-13 mutation induces dramatic telomere elongation which is telomerase dependent, as shown here. Additional mutants for STN1, which show a tighter arrest phenotype than stn1-13, were generated in order to perform genetic screens aiming at uncovering new regulators of telomerase. HSC82, which encodes a conserved molecular chaperone of the Hsp90 family, was thus isolated as a high-dosage suppressor of a temperature-sensitive mutation in STN1. Overexpression of HSC82 also partially suppressed the growth defect of cdc13-1 cells. Overexpression of HSC82 was found to correct the telomeric defect associated with stn1 mutations. Shortening of telomeres was also observed in wild-type cells upon overexpression of HSC82, or of its temperature-inducible homologue, HSP82. These results identify Hsc82/Hsp82 as potential regulators of telomerase in yeast cells.

Blotting, Northern↗

PubMed2001

Two alternative cell cycle checkpoint pathways differentially control DNA damage-dependent induction of MAG1 and DDI1 expression in yeast.

Eukaryotic cells respond to DNA damage by activating damage checkpoint pathways, which arrest cell cycle progression and induce gene expression. In order to understand how damage checkpoints control the expression of DNA damage-inducible genes, the transcript level of two closely clustered genes, MAG1 and DDI1, was examined in a number of checkpoint mutants. We previously reported that MAG1 induction was abolished in pol2 and rad53 mutants, but not in the mec1-1 mutant. In this study, we found that mec1Delta and dun1Delta null mutants were defective in MAG1 induction, suggesting that MAG1 shares a common regulatory pathway with the RNR1,2,3,4 genes, which are also regulated by the POL2-MEC1-RAD53-DUN1 checkpoint pathway, and that the mec1-1 mutation probably represents a separation-of-function mutation. However, MAG1 is not activated in precisely the same way as the RNR genes, since mutations in CRT1, TUP1 and SSN6, which encode repressors of RNR genes, did not affect basal or induced expression of MAG1. In contrast, the DDI1 transcript level was not affected by any of the above checkpoint mutations. Interestingly, simultaneous inactivation of RAD53 or DUN1 with PDS1, a newly identified checkpoint gene, resulted in severe down-regulation of DDI1 expression, suggesting that DDI1 is controlled by two damage checkpoint pathways, one mediated by POL2-MEC1-RAD53-DUN1 and the other by CHK1-PDS1. On the other hand, deletion of TEL1, a structural homologue of MEC1, did not affect expression of MAG1, DDI1 or RNR3, suggesting that TEL1 plays no role in induction by DNA damage. Based on these and previous studies, we present a model for the role of checkpoint genes in transcriptional regulation in response to DNA damage.

Blotting, Northern↗

PubMedDate not supplied

Gene expression in Florida red tide dinoflagellate Karenia brevis: analysis of an expressed sequence tag library and development of DNA microarray.

Karenia brevis (Davis) is the dinoflagellate responsible for nearly annual red tides in the Gulf of Mexico. Although the mechanisms regulating the growth and toxicity of this problematic organism are of considerable interest, little information is available on its molecular biology. We therefore constructed a complementary DNA library from which to gain insight into its expressed genome and to develop tools for studying its gene expression. Large-scale sequencing yielded 7001 high-quality expressed sequence tags (ESTs), which clustered into 5280 unique gene groups. The vast majority of genes expressed fell into a low-abundance class, with the highest expressed gene accounting for only 1% of the total ESTs. Approximately 29% of genes were found to have similarity to known sequences in other organisms after BLAST similarity comparisons to the GenBank public protein database using a cutoff of P < 10e(-4). We identified for the first time in a dinoflagellate a suite of conserved eukaryotic genes involved in cell cycle control, intracellular signaling, and the transcription and translation machinery. At least 40% of gene clusters displayed single nucleotide polymorphisms, suggesting the presence of multiple gene copies. The average GC content of ESTs was 51%, with a slight preference for G or C in the third codon position (53.5%). The ESTs were used to develop an oligonucleotide microarray containing 4629 unique features and 3462 replicate probes. Microarray labeling has been optimized, and the microarray has been validated for probe specificity and reproducibility. This is the first information to be developed on the expressed genome of K. brevis and provides the basis from which to begin functional genomic studies on this harmful algal bloom species.

Animals↗

PubMed2000

Constraint structure analysis of gene expression.

A microarray experiment gives a snapshot of the state of an organism in terms of the relative abundances of its mRNA transcripts, locating the organism at a point in a high dimensional state space where each axis represents the relative expression level of a single gene. Multiple experiments generate a cloud of points in this gene expression space. We present a geometric approach to analyzing the covariational properties of such a cloud and use a dataset from Saccharomyces cerevisiae as an illustration. In particular, we use singular value decomposition to identify significant linear sub-structures in the data and analyze the contributions of both individual genes and functional classes of genes to these major directions of variation. Analyzing the publicly available yeast expression data, we show that under all experimental conditions the variation in expression is limited to a small number of linear dimensions. Projections of individual gene axes onto the significant dimensions can order the contribution of individual genes to variation in expression within an experiment. We show that no particular groups of genes characterize particular experimental conditions. Instead, the particular structure of the coordinated expression of the entire genome characterizes a particular experiment.

Gene Expression↗