Centriole duplication is a vital process for cellular organisation and function, underpinning essential activities such as cell division, microtubule organisation and ciliogenesis. This review summarises the latest research on the mechanisms and regulatory pathways that control this process, focusing on important proteins such as polo-like kinase 4 (PLK4), SCL/TAL1 interrupting locus (STIL) and spindle assembly abnormal protein 6 (SAS-6). This study examines the complex steps involved in semi-conservative duplication, from initiation in the G1–S phase to the maturation of centrioles during the cell cycle. Additionally, we will explore the consequences of dysregulated centriole duplication. Dysregulation of this process can lead to centrosome amplification and subsequent chromosomal instability. These factors are implicated in several cancers and developmental disorders. By integrating recent study findings, this review emphasises the importance of centriole duplication in maintaining cellular homeostasis and its potential as a therapeutic target in disease contexts. The presented findings aim to provide a fundamental understanding that may inform future research directions and clinical interventions related to centriole biology.

Xenopus prophase oocytes reenter meiotic division in response to progesterone. The signaling pathway leading to Cdc2 activation depends on neosynthesized proteins and a decrease in PKA activity. We demonstrate that Eg2 protein, a Xenopus member of the Aurora/Ipl1 family of protein kinases, accumulates in response to progesterone and is degraded after parthenogenetic activation. The polyadenylation and cap ribose methylation of Eg2 mRNA are not needed for the protein accumulation. Eg2 protein accumulation is induced by progesterone through a decrease in PKA activity, upstream of Cdc2 activation. Eg2 kinase activity is undetectable in prophase and is raised in parallel with Cdc2 activation. In contrast to Eg2 protein accumulation, Eg2 kinase activation is under Cdc2 control. Furthermore, by using an anti-sense strategy, we show that Eg2 accumulation is not required in the transduction pathway leading to Cdc2 activation. Altogether, our results strongly suggest that Eg2 is not necessary for Cdc2 activation, though it could participate in the organization of the meiotic spindles, in agreement with the well-conserved roles of the members of the Aurora family, from yeast to man.

EDITORIAL article Front. Oncol., 22 March 2017Sec. Molecular and Cellular Oncology Volume 7 - 2017 | https://doi.org/10.3389/fonc.2017.00048

Protein phosphorylation reactions are carried out in a cell by protein kinases, which predominantly use ATP as a phosphate donor that is transferred and covalently bound to an amino acid on a substrate protein. Protein phosphorylation was discovered in 1954 by Edmond Fischer who shared the Nobel Prize in Medicine or Physiology in 1992 with Edwin Krebs. There are so many kinases that one was called "Just Another Kinase" for JAK kinase. Their counterpart is protein phosphatases that remove phosphates from phosphorylated proteins. Kinases and phosphatases act as switches in the cell that activates or inactivates protein functions. These reactions are reversible; the cell can quickly react to a situation but can then go back to its initial state.

Sister chromatid cohesion, which depends on cohesin, is essential for the faithful segregation of replicated chromosomes. Here, we report that splicing complex Prp19 is essential for cohesion in both G2 and mitosis, and consequently for the proper progression of the cell through mitosis. Inactivation of splicing factors SF3a120 and U2AF65 induces similar cohesion defects to Prp19 complex inactivation. Our data indicate that these splicing factors are all required for the accumulation of cohesion factor Sororin, by facilitating the proper splicing of its pre-mRNA. Finally, we show that ectopic expression of Sororin corrects defective cohesion caused by Prp19 complex inactivation. We propose that the Prp19 complex and the splicing machinery contribute to the establishment of cohesion by promoting Sororin accumulation during S phase, and are, therefore, essential to the maintenance of genome stability.

La progression du cycle cellulaire correspond à une série d’événements qui se succèdent pour aboutir à la division d’une cellule mère pour donner deux cellules filles. Les processus qui permettent à la cellule de se diviser sont très précisément contrôlés par une multitude de réactions enzymatiques parmi lesquelles des réactions de phosphorylation, qui font intervenir des protéines kinases, jouent un rôle clé. Les sérine/thréonine kinases sont des enzymes dont la fonction est de catalyser le transfert d’un groupement phosphate de l’ATP vers une protéine substrat et plus précisément sur un acide aminé, sérine ou thréonine. Trois familles importantes de sérine/thréonine kinases sont impliquées dans la régulation de la progression du cycle cellulaire, les cyclin dependent kinase (CDK) les polo-like kinase (PLK) et celles de la famille Aurora. Le cancer est décrit comme un processus de division cellulaire qui n’est plus contrôlé. Les cellules prolifèrent en effet de manière anarchique et accomplissent des cycles de divisions cellulaires en ignorant les signaux contrôles. Une idée simple est donc apparue très rapidement : stopper ou ralentir la progression du cycle cellulaire reviendrait à inhiber la prolifération cellulaire et donc à lutter contre le cancer. La progression du cycle cellulaire étant contrôlée en particulier par les protéines kinase de la famille CDK, PLK et Aurora, il a été rapidement décidé de rechercher des inhibiteurs de ces protéines kinases. Cet article fera d’abord un rappel général sur la progression du cycle cellulaire et les mécanismes qui le contrôlent. Seront ensuite décrites les fonctions des protéines kinases de la famille CDK, PLK et Aurora en se concentrant sur la phase sensible de la progression du cycle qu’est la mitose. Enfin, cet article abordera les conséquences d’une inhibition des ses protéines kinases dans le cadre de la lutte contre le cancer.

Cell cycle progression corresponds to a series of events, which succeed one another to end in the division of a mother cell to give two daughter cells. The processes that allow the cell to divide are very precisely controlled by a multitude of enzymatic reactions among which protein phosphorylation, carried out by protein kinases, plays a key role. Serine/threonine kinases are enzymes that catalyse the transfer of a phosphate from ATP to a protein substrate, more precisely on a serine or threonine amino acid residue. Three important families of serine/threonine kinases are involved in the regulation of cell cycle progression, the cyclin dependent kinase (CDK) the polo-like kinase (PLK) and those of the Aurora family. The cancer is described as an uncontrolled cell division process. Cancer cells proliferate indeed in an anarchic way, and carry out cycles of cellular division by being unaware of the signals of alarm. A simple idea thus appeared soon: to stop or to slow down cell cycle progression would result in inhibiting cell proliferation and thus fighting against cancer. Cell cycle progression being controlled in particular by protein kinases of the CDK, PLK and Aurora families, it was rapidly decided to look for inhibitors of those protein kinases. We will first make a general recall on cell cycle progression and the mechanisms that control it. The functions of protein kinases of the CDK, PLK and Aurora families will then be described by concentrating on the sensitive phase of the cell cycle progression, i.e. mitosis. Finally, we will approach the consequences of the inhibition of these protein kinases within the framework of the fight against cancer.

In contrast to the well-defined role of Ca2+ signals during mitosis, the contribution of Ca2+ signaling to meiosis progression is controversial, despite several decades of investigating the role of Ca2+ and its effectors in vertebrate oocyte maturation. We have previously shown that during Xenopus oocyte maturation, Ca2+ signals are dispensable for entry into meiosis and for germinal vesicle breakdown. However, normal Ca2+ homeostasis is essential for completion of meiosis I and extrusion of the first polar body. In this study, we test the contribution of several downstream effectors in mediating the Ca2+ effects during oocyte maturation. We show that calmodulin and calcium-calmodulin-dependent protein kinase II (CAMK2) are not critical downstream Ca2+ effectors during meiotic maturation. In contrast, accumulation of Aurora kinase A (AURKA) protein is disrupted in cells deprived of Ca2+ signals. Since AURKA is required for bipolar spindle formation, failure to accumulate AURKA may contribute to the defective spindle phenotype following Ca2+ deprivation. These findings argue that Ca2+ homeostasis is important in establishing the oocyte's competence to undergo maturation in preparation for fertilization and embryonic development.

BACKGROUND:In the quest for novel molecular mediators of glioma progression, we studied the regulation of FBXW7 (hCDC4/hAGO/SEL10), its association with survival of patients with glioblastoma and its potential role as a tumor suppressor gene in glioma cells. The F-box protein Fbxw7 is a component of SCFFbxw7, a Skp1-Cul1-F-box E3 ubiquitin ligase complex that tags specific proteins for proteasome degradation. FBXW7 is mutated in several human cancers and functions as a haploinsufficient tumor suppressor in mice. Any of the identified targets, Cyclin E, c-Myc, c-Jun, Notch1/4 and Aurora-A may have oncogenic properties when accumulated in tumors with FBXW7 loss.RESULTS:We tested the expression of FBXW7 in human glioma biopsies by quantitative PCR and compared the transcript levels of grade IV glioma (glioblastoma, G-IV) with those of grade II tumors (G-II). In more than 80% G-IV, expression of FBXW7 was significantly reduced. In addition, levels of FBXW7 were correlated with survival indicating a possible implication in tumor aggressiveness. Locus 4q31.3 which carries FBXW7 was investigated by in situ hybridization on biopsy touchprints. This excluded allelic loss as the principal cause for low expression of FBXW7 in G-IV tumors. Two targets of Fbxw7, Aurora-A and Notch4 were preferentially immunodetected in G-IV biopsies. Next, we investigated the effects of FBXW7 misregulation in glioma cells. U87 cells overexpressing nuclear isoforms of Fbxw7 lose the expression of the proliferation markers PCNA and Ki-67, and get counterselected in vitro. This observation fits well with the hypothesis that Fbxw7 functions as a tumor suppressor in astroglial cells. Finally, FBXW7 knockdown in U87 cells leads to defects in mitosis that may promote aneuploidy in progressing glioma.CONCLUSION:Our results show that FBXW7 expression is a prognostic marker for patients with glioblastoma. We suggest that loss of FBXW7 plays an important role in glioma malignancy by allowing the accumulation of multiple oncoproteins and that interfering with Fbxw7 or its downstream targets would constitute a new therapeutic advance.

Centrosomes are small cytoplasmic macromolecular assemblies composed from two major components, centrioles and pericentriolar material, each with its own complex architecture. This organelle is of interest because it plays a role in a number of fundamental cellular processes and defects in these processes have recently been correlated with variety of human disease. Increasingly, what is known about the structure of this organelle has been overshadowed by the increasing wealth of information on its biochemistry. In this short review, we highlight some of the common centriole structural errors found in the literature and define a set of rules that define centriole structure.

Centrosomes are small cytoplasmic macromolecular assemblies composed from two major components, centrioles and pericentriolar material, each with its own complex architecture. This organelle is of interest because it plays a role in a number of fundamental cellular processes and defects in these processes have recently been correlated with variety of human disease. Increasingly, what is known about the structure of this organelle has been overshadowed by the increasing wealth of information on its biochemistry. In this short review, we highlight some of the common centriole structural errors found in the literature and define a set of rules that define centriole structure.

Centrosomes are small cytoplasmic macromolecular assemblies composed from two major components, centrioles and pericentriolar material, each with its own complex architecture. This organelle is of interest because it plays a role in a number of fundamental cellular processes and defects in these processes have recently been correlated with variety of human disease. Increasingly, what is known about the structure of this organelle has been overshadowed by the increasing wealth of information on its biochemistry. In this short review, we highlight some of the common centriole structural errors found in the literature and define a set of rules that define centriole structure.

Centrosomes are small cytoplasmic macromolecular assemblies composed from two major components, centrioles and pericentriolar material, each with its own complex architecture. This organelle is of interest because it plays a role in a number of fundamental cellular processes and defects in these processes have recently been correlated with variety of human disease. Increasingly, what is known about the structure of this organelle has been overshadowed by the increasing wealth of information on its biochemistry. In this short review, we highlight some of the common centriole structural errors found in the literature and define a set of rules that define centriole structure.

Summry— Oocyte maturation and early development have been intensively studied for well over 100 years. The earliest theory proposed that after fertilisation and during cell division determinants were unequally distributed to control cell fate; experimental proof came from using frog eggs (Roux, 1888). After understanding the contribution of the nucleus and the chromosomes into cell cycle progression using sea urchin eggs (Boveri, 1902), it was the discovery of the cytoplasm contribution to the G2/M transition that led the cell cycle community in search of the “mitosis‐inducing factor”, MPF. Yoshio Masui was the first to experimentally demonstrate that few nanoliters of cytoplasm taken from a metaphase‐arrested oocyte and microinjected in a G2‐arrested oocyte was able to trigger the G2 to metaphase transition (Masui and Markert 1971). Although the way to identify the mitotic factor seemed obvious, it proved very hard and was not purified until 1988 (Lohka et al, 1988), then work from a variety of organisms including Xenopus, starfish, clams, sea urchins and yeast converged on the identification of MPF as a complex of cdc2 and cyclin B (Dunphy et al., 1988; Gautier et al., 1988; Draetta et al., 1889; Meijer et al., 1989; Labbé et al., 1989; Gautier et al., 1990). Since then, the oocyte and egg extracts developed by Lohka and Masui have often been used to study cell cycle events such as nuclear envelop formation, chromatin condensation, DNA replication, repair, and recombination, Golgi formation, microtubule dynamics, spindle assembly, chromosome segregation as well as cell cycle controls.

We have developed monoclonal antibodies against the human aurora-A serine/threonine kinase. After immunization of a mouse, a fusion was performed to obtain hybridomas that were selected because they produced immunoglobulin positively reacting against the protein used for immunization. We isolated one particular monoclonal that we named 35C1 using a series of selective assays. The first criteria of the screen for monoclonals was an Elisa (Enzyme Linked Immunosorbant Assay) assay performed in 96-well plates against the purified recombinant histidine-tagged aurora-A. The second was a positive Western blot against the same recombinant protein. The third criteria was a positive western blot against an HeLa cell extract, the selected monoclonal should detect only one protein migrating at 46 kDa (kiloDalton) on SDS (Sodium Dodecyl Sulfate)-polyacrylamide gel electrophoresis. Finally, the monoclonal had to bind to duplicated centrosomes and spindle poles in human MCF7 cultured cells by indirect immunofluorescence. At this stage several monoclonals were still positive. We then increased the selectivity by searching for antibodies that were able to cross-react with the mouse aurora-A kinase both by western blot and indirect immunofluorescence. We selected and cloned the 35C1 hybridoma to produce the antibody. Further characterization of the 35C1 antibody revealed that it was able to immunoprecipitate the kinase, that it did not inhibit the aurora-A kinase activity and consequently could be used to measure the aurora-A kinase activity in vivo after immunoprecipitation.

Successful cell division requires that daughter cells inherit not only a complete set of chromosomes, but also only one centrosome, and similar amounts of organelles and cytoplasmic components. The different mitotic processes are driven by cell cycle-regulated protein kinases and phosphatases and their fidelity is closely monitored by a number of checkpoint mechanisms. Histone H3 is phosphorylated during mitosis, but the kinases involved were not known until recently. Recent work has revealed that Aurora kinases are required for mitotic phosphorylation of histone H3 and of its centromeric variant CENP-A. This finding has stimulated functional studies of the role(s) of Aurora kinases and H3 phosphorylation during mitosis, which are reviewed in this chapter.