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At least 397 records · Page 22Linked to original sources
PubMed2001

MAD2 haplo-insufficiency causes premature anaphase and chromosome instability in mammalian cells.

The mitotic checkpoint protein hsMad2 is required to arrest cells in mitosis when chromosomes are unattached to the mitotic spindle. The presence of a single, lagging chromosome is sufficient to activate the checkpoint, producing a delay at the metaphase-anaphase transition until the last spindle attachment is made. Complete loss of the mitotic checkpoint results in embryonic lethality owing to chromosome mis-segregation in various organisms. Whether partial loss of checkpoint control leads to more subtle rates of chromosome instability compatible with cell viability remains unknown. Here we report that deletion of one MAD2 allele results in a defective mitotic checkpoint in both human cancer cells and murine primary embryonic fibroblasts. Checkpoint-defective cells show premature sister-chromatid separation in the presence of spindle inhibitors and an elevated rate of chromosome mis-segregation events in the absence of these agents. Furthermore, Mad2+/- mice develop lung tumours at high rates after long latencies, implicating defects in the mitotic checkpoint in tumorigenesis.

Anaphase↗
PubMed2001

Can sequencing shed light on cell cycling?

Every organism must have cells that can replicate indefinitely. Can the draft human genome sequence tell us how the cell cycle works and how it evolved? We studied two protein families--the cyclins and their partners the cyclin-dependent kinases (Cdks)--and a conserved regulatory circuit, the spindle checkpoint. Disappointingly, we discovered a few novel cyclins and no new Cdks or components of the spindle checkpoint, and could shed little light on the organization of the cell cycle.

Amino Acid Sequence↗
PubMed2001

Multiple pathways cooperate in the suppression of genome instability in Saccharomyces cerevisiae.

Gross chromosome rearrangements (GCRs), such as translocations, deletion of a chromosome arm, interstitial deletions and inversions, are often observed in cancer cells. Spontaneous GCRs are rare in Saccharomyces cerevisiae; however, the existence of mutator mutants with increased genome instability suggests that GCRs are actively suppressed. Here we show by genetic analysis that these genome rearrangements probably result from DNA replication errors and are suppressed by at least three interacting pathways or groups of proteins: S-phase checkpoint functions, recombination proteins and proteins that prevent de novo addition of telomeres at double-strand breaks (DSBs). Mutations that inactivate these pathways cause high rates of GCRs and show synergistic interactions, indicating that the pathways that suppress GCRs all compete for the same DNA substrates.

DNA Damage↗
PubMed2001

Forkhead transcription factors contribute to execution of the mitotic programme in mammals.

Cell cycle progression is a process that is tightly controlled by internal and external signals. Environmental cues, such as those provided by growth factors, activate early signals that promote cell cycle entry. Cells that have progressed past the restriction point become independent of growth factors, and cell cycle progression is then controlled endogenously. The phosphatidylinositol 3OH kinase (PI(3)K)/protein kinase B (PKB) pathway must be activated in G1 to inactivate forkhead transcription factors (FKH-TFs) and allow cell cycle entry. Here we show that subsequent attenuation of the PI(3)K/PKB pathway is required to allow transcriptional activation of FKH-TF in G2. FKH-TF activity in G2 controls mammalian cell cycle termination, as interference with FKH transcriptional activation by disrupting PI(3)K/PKB downregulation, or by expressing a transcriptionally inactive FKH mutant, induces cell accumulation in G2/M, defective cytokinesis, and delayed transition from M to G1 of the cell cycle. We demonstrate that FKH-TFs regulate expression of mitotic genes such as cyclin B and polo-like kinase (Plk). Our results support the important role of forkhead in the control of mammalian cell cycle completion, and suggest that efficient execution of the mitotic programme depends on downregulation of PI(3)K/PKB and consequent induction of FKH transcriptional activity.

3T3 Cells↗
PubMed2001

Chromosome segregation and cancer: cutting through the mystery.

Mitosis is the most dramatic--and potentially dangerous--event in the cell cycle, as sister chromatids are irreversibly segregated to daughter cells. Defects in the checkpoints that normally maintain the fidelity of this process can lead to chromosomal instability (CIN) and cancer. However, CIN--a driving force of tumorigenesis--could be the cancer cell's ultimate vulnerability. An important goal is to identify novel anticancer compounds that directly target the mitotic errors at the heart of CIN.

Aneuploidy↗
PubMed2001

To cycle or not to cycle: a critical decision in cancer.

Tumour cells undergo uncontrolled proliferation, yet tumours most often originate from adult tissues, in which most cells are quiescent. So, the proliferative advantage of tumour cells arises from their ability to bypass quiescence. This can be due to increased mitogenic signalling and/or alterations that lower the threshold required for cell-cycle commitment. Understanding the molecular mechanisms that underlie this commitment should provide important insights into how normal cells become tumorigenic and how new anticancer strategies can be devised.

Animals↗
PubMed2003

Phosphorylation of Cdc20 is required for its inhibition by the spindle checkpoint.

The spindle checkpoint delays anaphase until all chromosomes are properly attached to spindle microtubules. When the spindle checkpoint is activated at unattached kinetochores, the checkpoint proteins BubR1, Bub3 and Mad2 bind and inhibit Cdc20, an activator of the anaphase-promoting complex (APC). Here, we show that Xenopus laevis Cdc20 is phosphorylated at Ser 50, Thr 64, Thr 68 and Thr 79 during mitosis and that mitogen-activated protein kinase (MAPK) contributes to the phosphorylation at Thr 64 or Thr 68. Cdc20 mutants that are phosphorylation-deficient are able to activate the APC in X. laevis egg extracts. However, Cdc20 mutants in which any of the four phosphorylation sites were altered to Ala or Val failed to respond to the spindle checkpoint signal, owing to their reduced affinity for the spindle checkpoint proteins. This study demonstrates that the spindle checkpoint stops anaphase by inhibiting fully-phosphorylated Cdc20. Our results also have implications for the spindle checkpoint silencing mechanism.

Animals↗
PubMed2003

S-phase checkpoint controls mitosis via an APC-independent Cdc20p function.

Cells divide with remarkable fidelity, allowing complex organisms to develop and possess longevity. Checkpoint controls contribute by ensuring that genome duplication and segregation occur without error so that genomic instability, associated with developmental abnormalities and a hallmark of most human cancers, is avoided. S-phase checkpoints prevent cell division while DNA is replicating. Budding yeast Mec1p and Rad53p, homologues of human checkpoint kinases ATM/ATR and Chk2, are needed for this control system. How Mec1p and Rad53p prevent mitosis in S phase is not known. Here we provide evidence that budding yeasts avoid mitosis during S phase by regulating the anaphase-promoting complex (APC) specificity factor Cdc20p: Mec1p and Rad53p repress the accumulation of Cdc20p in S phase. Because precocious Cdc20p accumulation causes anaphase onset and aneuploidy, Cdc20p concentrations must be precisely regulated during each and every cell cycle. Catastrophic mitosis induced by Cdc20p in S phase occurs even in the absence of core APC components. Thus, Cdc20p can function independently of the APC.

Anaphase-Promoting Complex-Cyclosome↗
PubMed2004

Intra-nuclear microtubules and a mitotic spindle orientation checkpoint.

Cells of the fission yeast Schizosaccharomyces pombe have a checkpoint mechanism that reportedly monitors the orientation of the mitotic spindle. Astral microtubules in pre-anaphase spindles are thought to contact the contractile actin ring at the plasma membrane in order to rotate the spindle and to sense spindle orientation. Here, we show that these microtubules are actually inside the nuclear envelope.

Actins↗
PubMed2004

The human mitotic checkpoint protein BubR1 regulates chromosome-spindle attachments.

Loss or gain of whole chromosomes, the form of chromosomal instability (CIN) most commonly associated with human cancers, is expected to arise from the failure to accurately segregate chromosomes in mitosis. The mitotic checkpoint is one pathway that prevents segregation errors by blocking the onset of anaphase until all chromosomes make proper attachments to the spindle. Another process that prevents errors is stabilization and destabilization of connections between chromosomes and spindle microtubules. An outstanding question is how these two pathways are coordinated to ensure accurate chromosome segregation. Here we show that in human cells depleted of BubR1 - a critical component of the mitotic checkpoint that can directly regulate the onset of anaphase - chromosomes do not form stable attachments to spindle microtubules. Attachments in these cells are restored by inhibition of Aurora kinase, which is known to stabilize kinetochore-microtubule attachments. Loss of BubR1 function thus perturbs regulation of attachments rather than the ability of kinetochores to bind to microtubules. Consistent with this finding, depletion of BubR1 increases phosphorylation of CENP-A, a kinetochore-specific Aurora kinase substrate. We propose that BubR1 links regulation of chromosome-spindle attachment to mitotic checkpoint signalling.

Aurora Kinases↗
PubMed2006

Regulation of mitotic entry by microcephalin and its overlap with ATR signalling.

Ataxia-telangiectasia mutated and Rad3 related (ATR)-Seckel syndrome and autosomal recessive primary microcephaly (MCPH) syndrome share clinical features. RNA interference (RNAi) of MCPH1 have implicated the protein it encodes as a DNA-damage response protein that regulates the transcription of Chk1 and BRCA1, two genes involved in the response to DNA damage. Here, we report that truncating mutations observed in MCPH-syndrome patients do not impact on Chk1 or BRCA1 expression or early ATR-dependent damage-induced phosphorylation events. However, like ATR-Seckel syndrome cells, MCPH1-mutant cell lines show defective G2-M checkpoint arrest and nuclear fragmentation after DNA damage, and contain supernumerary mitotic centrosomes. MCPH1-mutant and ATR-Seckel cells also show impaired degradation of Cdc25A and fail to inhibit Cdc45 loading onto chromatin after replication arrest. Additionally, microcephalin interacts with Chk1. We conclude that MCPH1 has a function downstream of Chk1 in the ATR-signalling pathway. In contrast with ATR-Seckel syndrome cells, MCPH1-mutant cells have low levels of Tyr 15-phosphorylated Cdk1 (pY15-Cdk1) in S and G2 phases, which correlates with an elevated frequency of G2-like cells displaying premature chromosome condensation (PCC). Thus, MCPH1 also has an ATR-independent role in maintaining inhibitory Cdk1 phosphorylation, which prevents premature entry into mitosis.

Ataxia Telangiectasia Mutated Proteins↗
PubMed2002

Astral microtubules monitor metaphase spindle alignment in fission yeast.

Segregating genetic material along the longest axis of the cell ensures that there is a sufficient distance between daughter chromosomes at the point of cytokinesis. Monitoring the orientation of the mitotic spindle can be subjected to cell cycle controls. In the fission yeast Schizosaccharomyces pombe, the existence of such a cell-cycle checkpoint has been proposed to delay the metaphase to anaphase transition when spindle poles are not properly oriented with respect to the actomyosin ring. Here we show, by using a fission yeast mutant compromised in its assembly of astral microtubules, that in the absence of astral microtubules short metaphase spindles are unable to orient themselves with respect to the long axis of the cell and are delayed in spindle elongation. This astral defect engages a spindle orientation checkpoint because deletion of the transcription factor Atf1, which is involved in maintaining this checkpoint, allows misaligned asterless metaphase spindles to elongate. We propose that astral microtubules are involved directly in monitoring orientation of the metaphase spindle and in controlling the timing of elongation in fission yeast.

Cell Compartmentation↗