Mitotic control

doi:10.1016/0955-0674(91)90151-N

Current Opinion in Cell Biology

Volume 3, Issue 2, April 1991, Pages 269-275

https://doi.org/10.1016/0955-0674(91)90151-N Get rights and content

Abstract

1990 has been a year of continued exciting developments in cell cycle control. Progress has occurred in delineating the mechanism of activation of maturation-promoting factor during entry into mitosis and the mechanism of cyclin degradation responsible for exit from mitosis. Notable advances have also occurred in our understanding of the dependence of mitotic entry on completion of DNA synthesis. Both genetic and biochemical data link this crucial checkpoint to the function of the cdc25 gene product and the extent of phosphorylation of Tyr15 in cdc2 kinase.

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Metaphase II (MII) oocytes are almost exclusively used in cloning by the somatic cell nuclear transfer (SCNT) technique [1], because high maturation promoting factor (MPF) levels in MII oocyte cytoplasm leads to somatic cell nuclear envelope breakdown, chromosome condensation, reorganization of the cytoskeleton and changes in cell morphology [2–4].
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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.
Cyclin-dependent kinase inhibitors attenuate protein hyperphosphorylation, cytoskeletal lesion formation, and motor defects in Niemann-Pick Type C mice
2004, American Journal of Pathology
Citation Excerpt :
How NPC-1 mutations cause activation of cdc2 in degenerating neurons is more difficult to explain. In dividing cells, cdc2 activation is orchestrated with successful and fidelous completion of DNA replication.58 Duplicated chromosomes, along with accumulation of mitotic phosphoepitopes, have been detected in degenerating neurons in AD,59 but there have been no reports to date regarding the status of DNA in other neurodegenerative disorders.
Dysregulation of cyclin-dependent kinases (cdks) and cytoskeletal protein hyperphosphorylation characterizes a subset of human neurodegenerative diseases, including Alzheimer's disease, amyotrophic lateral sclerosis, and Niemann-Pick Type C (NPC). It is thought that these cytoskeletal changes lead eventually to development of hallmark cytoskeletal lesions such as neurofibrillary tangles and axonal spheroids. Although many studies support an involvement of cdks in these neurodegenerative cascades, it is not known whether cdk activity is essential. The naturally occurring npc-1 mutant mouse mimics human NPC, in displaying activation of cdk5, mitotic cdc2, and cdk4, with concomitant cytoskeletal pathology and neurodegeneration. We availed of this model and specific pharmacological inhibitors of cdk activity, to determine whether cdks are necessary for NPC neuropathology. The inhibitors were infused intracerebroventricularly for a 2-week period, initiated at a pathologically incipient stage. While an inactive stereoisomer, iso-olomoucine, was ineffective, two potent inhibitors, roscovitine and olomoucine, attenuated significantly the hyperphosphorylation of neurofilament, tau, and mitotic proteins, reduced the number of spheroids, modulated Purkinje neuron death, and ameliorated motor defects in npc mice. These results suggest that cdk activity is required for neuropathology and subsequent motor impairment in NPC. Studies aimed at knocking down individual cdks in these mice will help identify the specific cdk(s) that are essential, and delineate their precise roles in the neurodegenerative process.
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The PITSLRE protein kinases are parts of the large family of p34cdc2-related kinases. During apoptosis induced by some stimuli, specific PITSLRE isoforms are cleaved by caspase to produce a protein that contains the C-terminal kinase domain of the PITSLRE proteins (p110C). The p110C induces apoptosis when it is ectopically expressed in Chinese hamster ovary cells. In our study, similar induction of this p110C was observed during anoikis in NIH3T3 cells. To investigate the molecular mechanism of apoptosis mediated by p110C, we used the yeast two-hybrid system to screen a human fetal liver cDNA library and identified p21-activated kinase 1 (PAK1) as an interacting partner of p110C. The association of p110C with PAK1 was further confirmed by in vitro binding assay, in vivo coimmunoprecipitation, and confocal microscope analysis. The interaction of p110C with PAK1 occurred within the residues 210–332 of PAK1. Neither association between p58^PITSLRE or p110^PITSLRE and PAK1 nor association between p110C and PAK2 or PAK3 was observed. Anoikis was increased and PAK1 activity was inhibited when NIH3T3 cells were transfected with p110C. Furthermore, the binding of p110C with PAK1 and inhibition of PAK1 activity were also observed during anoikis. Taken together, these data suggested that PAK1 might participate in the apoptotic pathway mediated by p110C.
Constitutive cdc25b tyrosine phosphatase activity in adult brain neurons with m phase-type alterations in alzheimer’s disease
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The Cdc2/cyclin B kinase is a critical regulator of mitosis that is normally absent from terminally differentiated neurons of adult brain. However, unscheduled expression and activation of Cdc2/cyclin B has been seen in neurons undergoing degeneration in Alzheimer’s disease. The presence of this mitotic kinase correlates with accumulation of mitotic phosphoepitopes in protein components of the hallmark neurofibrillary tangles. Of importance to the pathogenic mechanism of Alzheimer’s disease is the striking appearance of Cdc2/cyclin B and mitotic phosphoepitopes prior to neurofibrillary tangle formation, which has suggested that a misappropriate mitotic cascade initiates and mediates the neurodegenerative process.
To explain the atypical activation of Cdc2/cyclin B in degenerating neurons we have investigated the enzyme responsible for Cdc2/cyclin B activation in mitotic cells, i.e. the Cdc25B tyrosine phosphatase, in Alzheimer’s disease brain. Although the enzyme appeared abundant in affected neurons, it was also evident in unaffected neurons of Alzheimer’s disease and control brain. Thus, we have found, surprisingly, that Cdc25B is a normal constituent of adult brain neurons, with detectable basal levels of activity. In Alzheimer’s disease the levels and activity of the enzyme are elevated, and the active enzyme predominates in the cytoplasmic compartment of neurons. Consistent with these M phase-type changes, Cdc25B displays increased immunoreactivity towards the MPM-2 mitotic phosphoepitope antibody.
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Mitotic control

Abstract

Curr Opin Cell Biol

Curr Opin Cell Biol

Cell

Cell

Cell

Cell

Science

Cell

Cell

Purification of MaturationPromoting Factor, an Intracellular Regulator of Early Mitotic Events

MPF from Starfish Oocytes at First Meiotic Metaphase is a Heterodimer Con taining One Molecule of cdc2 and One Molecule of Cyclin B

EMBO J

Fission Yeast p13 Blocks Mitotic Activation and Tyrosine Dephosphorylation of cdc2 Kinase

Cell

Dephosphorylation and Activation of Xenopus p34cdc2 Protein Kinase During the Cell Cycle

Nature

Tyrosine Phosphorylation of the Fission Yeast cdc2+ Protein Kinase Regulates Entry into Mitosis

Nature

Cyclilin Synthesis Drives the Early Embryonic Cell Cycle

Nature

The Product of the MOS Proto-Oncogene as Candidate ‘Initiator’ for Oocyte Maturation

Science

The Role of Drosophila Cyclins A and B in Mitotic Control

Cell

Cyclilin B2 and Pre-MPF Activation in Xenopus Oocytes

EMBO J

Cyclilin Promotes the Tyrosine Phosphorylation of p34cdc2 in a weel+-dependent Manner

EMBO J

Negative Regulation of Mitosis by wee-1+, a Gene Encoding a Protein Kinase Homolog

Cell

Dephosphorylation and Activation of Xenopus p34^cdc2 Protein Kinase During the Cell Cycle

Tyrosine Phosphorylation of the Fission Yeast cdc2⁺ Protein Kinase Regulates Entry into Mitosis

Cyclilin Promotes the Tyrosine Phosphorylation of p34^cdc2 in a weel⁺-dependent Manner

Negative Regulation of Mitosis by wee-1⁺, a Gene Encoding a Protein Kinase Homolog