Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cell-cycle transition at G2-M is controlled by MPF (M-phase-promoting factor), a complex consisting of the Cdc2 kinase and a B-type cyclin. We have shown that in mice, targeted disruption of an A-type cyclin gene, cyclin A1, results in a block of spermatogenesis prior to the entry into metaphase I. The meiotic arrest is accompanied by a defect in Cdc2 kinase activation at the G2--M transition, raising the possibility that a cyclin A1-dependent process dictates the activation of MPF. Here we show that like Cdc2, the expression of B-type cyclins is retained in cyclin A1-deficient spermatocytes, while their associated kinases are kept at inactive states. Treatment of arrested germ cells with the protein phosphatase type-1 and -2A inhibitor okadaic acid restores the MPF activity and induces entry into M phase and the formation of normally condensed chromosome bivalents, concomitant with hyperphosphorylation of Cdc25 proteins. Conversely, inhibition of tyrosine phosphatases, including Cdc25s, by vanadate suppresses the okadaic acid-induced metaphase induction. The highest levels of Cdc25A and Cdc25C expression and their subcellular localization during meiotic prophase coincide with that of cyclin A1, and when overexpressed in HeLa cells, cyclin A1 coimmunoprecipitates with Cdc25A. Furthermore, the protein kinase complexes consisting of cyclin A1 and either Cdc2 or Cdk2 phosphorylate both Cdc25A and Cdc25C in vitro. These results suggest that in normal meiotic male germ cells, cyclin A1 participates in the regulation of other protein kinases or phosphatases critical for the G2-M transition. In particular, it may be directly involved in the initial amplification of MPF through the activating phosphorylation on Cdc25 phosphatases.
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PMID:A role for cyclin A1 in the activation of MPF and G2-M transition during meiosis of male germ cells in mice. 1092 75

In vertebrate cells, the nuclear entry of Cdc2-cyclin B1 (MPF) during prophase is thought to be essential for the induction and coordination of M-phase events. Phosphorylation of cyclin B1 is central to its nuclear translocation, but the kinases that are responsible remain unknown. Here we have purified a protein kinase from Xenopus M-phase extracts that phosphorylates a crucial serine residue (S147) in the middle of the nuclear export signal sequence of cyclin B1. We have identified this kinase as Plx1 (ref. 16), a Xenopus homologue of Polo-like kinase (Plk)-1. During cell-cycle progression in HeLa cells, a change in the kinase activity of endogenous Plk1 toward S147 and/or S133 correlates with a kinase activity in the cell extracts. An anti-Plk1 antibody depletes the M-phase extracts of the kinase activity toward S147 and/or S133. An anti-phospho-S147 antibody reacts specifically with cyclin B1 only during G2/M phase. A mutant cyclin B1 in which S133 and S147 are replaced by alanines remains in the cytoplasm, whereas wild-type cyclin B1 accumulates in the nucleus during prophase. Co-expression of constitutively active Plk1 stimulates nuclear entry of cyclin B1. Our results indicate that Plk1 may be involved in targeting MPF to the nucleus during prophase.
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PMID:Polo-like kinase 1 phosphorylates cyclin B1 and targets it to the nucleus during prophase. 1124 82

p53 undergoes phosphorylation on several residues in response to cellular stresses that include UV and ionizing radiation, however the influence of spindle damage on this parameter is relatively unclear. Consequently, the effect of nocodazole on serine 392 phosphorylation was examined in two epithelial cell lines. We show that this process is dependent upon the stepwise activation of p38 mitogen-activated protein kinase (p38 MAPK) and protein kinase casein kinase 2 (CK2). Furthermore, this activation correlated with the biochemical regulation of the maturation-promoting factor (MPF, cdc2/cyclin B), as both DRB and antisense depletion of CK2, as well as SB203580 were associated with an inhibition of its activation in response to nocodazole. Strikingly, when the cell cycle characteristics of nocodazole treated cells were examined, we observed that depletion or inhibition of the catalytic subunit of CK2, in the presence of microtubule inhibitors, resulted in a compromise of the G2 arrest (spindle checkpoint). Furthermore, CK2-depleted, nocodazole treated cells demonstrated a dramatic reduction in the apoptotic cell fraction, confirming that these cells had been endowed with oncogenic properties. These changes were observed in both HeLa cells and HCT116 cells. We also show that this effect is dependent on the presence of functional wild-type p53, as this phenomenon is not apparent in HCT116 p53(-/-) cells. Collectively, our results indicate two novel roles for CK2 in the spindle checkpoint arrest, in concert with p53. Firstly, to maintain increased cyclinB/cdc2 kinase activity, as a component of G2 arrest, and secondly, a role in p53-mediated apoptosis. These findings may have implications for an improved understanding of abnormalities of the spindle checkpoint in human cancers, which is a prerequisite for defining future therapies.
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PMID:Protein kinase CK2 is involved in G2 arrest and apoptosis following spindle damage in epithelial cells. 1170 24

Since almost two decades, it is known that progesterone is responsible of the release of the prophase I arrest of amphibian oocytes and leads to the activation of the universal MPF, through a puzzling transduction pathway. It involves negative regulation of the cAMP-dependent protein kinase (PKA) and synthesis of new proteins, among them the c-Mos protooncogene product. The implication of the Mos/mitogenic activated protein kinase (MAP kinase) pathway in Cdc2 activation has been extensively studied and is now at the centre of a controversial debate. In this paper, we discuss the current progress and our recent results on the molecular mechanisms allowing progesterone to activate MPF and propose a model to partly resolve the long-standing inconsistencies concerning the role of Mos/MAP kinase during this process.
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PMID:From progesterone to active Cdc2 in Xenopus oocytes: a puzzling signalling pathway. 1173 Mar 20

The resumption of meiosis in Xenopus arrested oocytes is triggered by progesterone, which leads to polyadenylation and translation of Mos mRNA, then activation of MAPK pathway. While Mos protein kinase has been reported to be essential for re-entry into meiosis in Xenopus, arrested oocytes can undergo germinal vesicle breakdown (GVBD) independently of MAPK activation, leading us to question what the Mos target might be if Mos is still required. We now demonstrate that Mos is indeed necessary, although is independent of the MAPK cascade, for conversion of inactive pre-MPF into active MPF. We have found that Myt1 is likely to be the Mos target in this process, as Mos interacts with Myt1 in oocyte extracts and Mos triggers Myt1 phosphorylation on some sites in vivo, even in the absence of MAPK activation. We propose that Mos is involved, not only in the MAPK cascade pathway, but also in a mechanism that directly activates MPF in Xenopus oocytes.
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PMID:A new role for Mos in Xenopus oocyte maturation: targeting Myt1 independently of MAPK. 1195 23

The idea that Cdc2 and cyclins play a key role in the control of the G2/M transition of the cell cycle came largely from genetic analysis of fission yeast and physiological studies of clam, frog, sea urchin and starfish eggs and oocytes. However, it took a long time to realise that Cdc2 and cyclins form a stoichiometric complex and that a cyclin subunit is necessary for the Cdc2 subunit to gain its protein kinase activity. Cyclins were first recognized as proteins whose abundance oscillates during the early cell cycles of marine invertebrate eggs and their connection with MPF (maturation-promoting factor), the entity defined in frog and starfish oocytes whose activity controls entry into M phase, was far from clear at first. Indeed, it was a long time before MPF was shown to be a protein kinase, and direct proof that MPF is a heterodimer comprising one molecule of cyclin and one molecule of Cdc2 was finally obtained only when the Cdc2-associated component of purified starfish MPF was sequenced and found to be cyclin B. When this fundamental discovery was confirmed in vertebrates and mammalian members of the Cdc2 family were also shown to bind cyclins, Cdc2 became Cdk1, the first cyclin-dependent protein kinase.
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PMID:From Cdc2 to Cdk1: when did the cell cycle kinase join its cyclin partner? 1204 16

The present study shows that Ca(2+) calmodulin-dependent protein kinase II (CaM kinase II) is physiologically activated in fertilized mouse oocytes and is involved in the Ca(2+) response pathways that link the fertilization Ca(2+) signal to meiosis resumption and cortical granule (CG) exocytosis. After 10 min of insemination, CaM kinase II activity increased transiently, then peaked at 1 h and remained elevated 30 min later when most of the oocytes had completed the emission of the second polar body. In contrast, in ethanol-activated oocytes the early transient activation of CaM kinase II in response to a monotonic Ca(2+) rise was not followed by any subsequent increase. Inhibition of CaM kinase II by 20 micromol/l myristoylated-AIP (autocamtide-2-related inhibitory peptide) negatively affected MPF (maturing promoting factor) inactivation, cell cycle resumption and CG exocytosis in both fertilized and ethanol-activated oocytes. These results indicate that the activation of CaM kinase II in mouse oocytes is differently modulated by a monotonic or repetitive Ca(2+) rise and that it is essential for triggering regular oocyte activation.
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PMID:Possible role for Ca(2+) calmodulin-dependent protein kinase II as an effector of the fertilization Ca(2+) signal in mouse oocyte activation. 1214 7

Starfish oocytes that are extracted from the ovaries are arrested at the prophase of the first meiotic division. At this stage of maturation, they are characterized by a large nucleus called the germinal vesicle. Meiosis resumption (maturation) can be induced in vitro by adding the hormone 1-methyladenine (1-MA) to the seawater in which the oocytes are suspended. Earlier work in our laboratory had detected Ca(2+) increases in both the cytoplasm and the nucleus of the oocytes approx. 2 min after the 1-MA challenge. The nuclear Ca(2+) increase was found to be essential for the continuation of the meiotic cycle, since the injection of bis-(o-aminophenoxy)ethane- N,N,N',N' -tetra-acetic acid (BAPTA) into the nuclear compartment completely blocked the re-initiation of the cell cycle. We have recently confirmed, using confocal microscopy, that the cytoplasmic and nuclear Ca(2+) pools are regulated independently and that the nuclear envelope in starfish oocytes is not freely permeated by the Ca(2+) wave that sweeps across the nuclear region. Studies by others have shown that the sensitivity of the Ins(1,4,5) P (3) (IP(3)) receptors (IP(3)Rs) to IP(3) increases during oocyte maturation, so that they release progressively more calcium in response to the injection of IP(3), as maturation proceeds. We have now shown that the increased sensitivity of the IP(3)Rs may depend on the activation of the cyclin-dependent kinase, MPF (M-phase-promoting factor) that occurs in the nucleus. MPF does not directly phosphorylate IP(3)Rs but phosphorylates instead the actin-binding protein actin depolymerization factor (ADF)/cofilin.
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PMID:Activated M-phase-promoting factor (MPF) is exported from the nucleus of starfish oocytes to increase the sensitivity of the Ins(1,4,5)P3 receptors. 1254 58

Commitment to mitosis is regulated by a protein kinase complex called MPF. MPF is inhibited by Wee1-related kinases and activated by Cdc25 phosphatase. MPF activation further boosts Cdc25 and represses Wee1. This feedback control probably involves polo kinase. A dominant cut12.s11 mutation in the Schizosaccharomyces pombe spindle pole body (SPB) component Cut12 both suppresses the conditional lethal mitotic commitment defect of cdc25.22 and promotes premature association of the S. pombe polo kinase, Plo1, with the SPB. We now show that Cut12 associated with Plo1 in two hybrid and immunoprecipitation assays. Plo1 function was required for recognition of the mitotic SPB by the phospho-specific antibody MPM-2. In vivo MPM-2 staining and in vitro kinase assays established that the loss-of-function mutation, cut12.1, reduced mitotic activation of Plo1, whereas the gain-of-function mutation, cut12.s11, promoted higher levels of Plo1 activity than were normally seen in interphase. cut12.s11 could not promote mitotic commitment of cdc25.22 cells when Plo1 function was compromised. Expression of a constitutively active plo1 allele suppressed the mitotic commitment defect of cdc25.22. These data suggest that cut12.s11 suppresses cdc25.22 by promoting Plo1 activity. Furthermore, the delayed mitotic commitment of plo1.ts2 cells suggests that Plo1 is an integral part of the core controls that modulate MPF activation in S. pombe.
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PMID:Physical and functional interactions between polo kinase and the spindle pole component Cut12 regulate mitotic commitment in S. pombe. 1281 70

The effect of the sulfhydryl reagent, thimerosal (TMS) on meiosis resumption in germinal vesicle (GV)-stage denuded mouse oocytes was studied. It irreversibly inhibits both GV breakdown (GVBD) and the first polar body (pb1) extrusion in concentration- and time-dependent manners, the most striking result being the very early and narrow temporal window during which denuded primary oocytes released from their follicle are susceptible to a pulse of the drug. This inhibition is bypassed by dithiothreitol (DTT) with an efficiency declining with time, while thiosalicylic acid (TA), an analog of TMS devoid of the mercury atom, has no effect on meiosis reinitiation. These results strongly suggest that the inhibitory effect of TMS is a consequence of its sulfhydryl group oxidising activity. The molecular target(s) of this inhibitory oxidation should however be identified. In contrast to DTT, okadaic acid (OA), known to bypass the inhibitory effect of drugs interfering with protein kinase activities, only induces chromatin condensation and GVBD in TMS-pulsed oocytes with a delay of about 8 hr as compared to the control situation. This confirms that a very early thiol oxidation induced by TMS exerts a much more dramatic effect on resumption on meiosis than any pharmacological manipulation of protein kinase activities leading to activation of MPF.
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PMID:The thiol reagent, thimerosal, irreversibly inhibits meiosis reinitiation in mouse oocyte when applied during a very early and narrow temporal window: a pharmacological analysis. 1284 Aug 19


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