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Protein kinases mediate the intracellular signal transduction pathways controlling synaptic plasticity in the central nervous system. While the majority of protein kinases achieve this function via the phosphorylation of synaptic substrates, some kinases may contribute through alternative mechanisms in addition to enzymatic activity. There is growing evidence that protein kinases may often play structural roles in plasticity as well. Cyclin-dependent kinase 5 (Cdk5) has been implicated in learning and synaptic plasticity. Initial scrutiny focused on its enzymatic activity using pharmacological inhibitors and genetic modifications of Cdk5 cofactors. Quite recently Cdk5 has been shown to govern learning and plasticity via regulation of glutamate receptor degradation, a function that may not dependent on phosphorylation of downstream effectors. From these new studies, two roles emerge for Cdk5 in plasticity: one in which it controls structural plasticity via phosphorylation of synaptic substrates, and a second where it regulates functional plasticity via protein-protein interactions. 相似文献
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Expression of Leishmania donovani cyclin 1 (LdCyc1) mRNA during the cell cycle of promastigotes is S-phase specific. Here, we show that the LdCyc1 protein is periodically expressed and the activity of its associated kinase varies during the cell cycle in line with its expression pattern. In addition, we have shown that LdCRK3, homologous to CRK3 from L. mexicana, is the cognate Cdk partner of LdCyc1 and that the activity of the complex is inhibited specifically by heat stable factor(s) from the parasite. 相似文献
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Balog ER Saetern OC Finch W Hoeft CO Thai V Harvey SL Kellogg DR Rubin SM 《Journal of molecular biology》2011,411(3):520-528
Cks (cyclin-dependent kinase subunit) proteins are essential eukaryotic cell cycle regulatory proteins that physically associate with cyclin-dependent kinases (Cdks) to modulate their activity. Cks proteins have also been studied for their ability to form domain-swapped dimers by exchanging β-strands. Domain swapping is mediated by a conserved β-hinge region containing two proline residues. Previous structural studies indicate that Cks in its dimer form is unable to bind Cdk, suggesting that the monomer-dimer equilibrium of Cks may have an effect on Cks-mediated Cdk regulation. We present the crystal structure of a proline-to-alanine mutant Saccharomyces cerevisiae Cks protein (Cks1 P93A) that preferentially adopts the monomer conformation but surprisingly fails to bind Cdk. Comparison of the Cks1 P93A structure to that of other Cks proteins reveals that Pro93 is critical for stabilizing a multiple β-turn structure in the hinge region that properly positions an essential Cdk-binding residue. Additionally, we find that these β-turn formations, conserved in Cks homologs, have implications for the mechanism and preferentiality of strand exchange. Together, our observations suggest that the conservation of Cks hinge-region prolines reflects their functions in forming a Cdk binding interface and that the ability of these prolines to control partitioning between monomer and dimer is a consequence of the β-turn networks within the hinge. 相似文献
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Polo-like kinase 1 (Plk1) plays key roles in many aspects of mitosis. We have previously shown that induction of p21Waf1 by p53 is responsible for protection of cells against adriamycin-induced polyploidy formation and mitotic catastrophe. Here we show that adriamycin treatment suppressed Plk1 expression in a p53- and p21Waf1-dependent manner. Ablation of p21Waf1 inhibited the adriamycin-induced p53 activation, and this inhibition was alleviated by knockdown of Plk1, suggesting that p21Waf1-dependent suppression of Plk1 expression is responsible for maintaining p53 activation during stress response. Plk1 associated with p53 and disrupted its interaction with target gene promoters in cells treated with adriamycin. Overexpression of Plk1 inhibited the p53-mediated prevention of caspase-independent mitotic death, but not polyploidy formation, in adriamycin-treated cells. Together our results indicate that suppression of Plk1 by p21Waf1 is responsible for p53-dependent protection against adriamycin-induced caspase-independent mitotic death. 相似文献
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The Hsp90 chaperone system interacts with a wide spectrum of client proteins, forming variable and dynamic multiprotein complexes that involve the intervention of cochaperone partners. Recent results suggest that the role of Hsp90 complexes is to establish interactions that suppress unwanted client activities, allow clients to be protected from degradation and respond to biochemical signals. Cryo-electron microscopy (cryoEM) provided the first key molecular picture of Hsp90 in complex with a kinase, Cdk4, and a cochaperone, Cdc37. Here, we use a combination of molecular dynamics (MD) simulations and advanced comparative analysis methods to elucidate key aspects of the functional dynamics of the complex, with different nucleotides bound at the N-terminal Domain of Hsp90. The results reveal that nucleotide-dependent structural modulations reverberate in a striking asymmetry of the dynamics of Hsp90 and identify specific patterns of long-range coordination between the nucleotide binding site, the client binding pocket, the cochaperone and the client. Our model establishes a direct atomic-resolution cross-talk between the ATP-binding site, the client region that is to be remodeled and the surfaces of the Cdc37-cochaperone. 相似文献
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Shuhei Kotoshiba Lakshmi Gopinathan Elisabeth Pfeiffenberger Anisa Rahim Leah A. Vardy Keiko Nakayama Keiichi I. Nakayama Philipp Kaldis 《Biochimica et Biophysica Acta (BBA)/Molecular Cell Research》2014
Cyclin-dependent kinase 2 (Cdk2) is dispensable for mitotic cell cycle progression and Cdk2 knockout mice are viable due to the compensatory functions of other Cdks. In order to assess the role of Cdk2 under limiting conditions, we used Skp2 knockout mice that exhibit increased levels of Cdk inhibitor, p27Kip1, which is able to inhibit Cdk2 and Cdk1. Knockdown of Cdk2 abrogated proliferation of Skp2−/− mouse embryonic fibroblasts, encouraging us to generate Cdk2−/−Skp2−/− double knockout mice. Cdk2−/−Skp2−/− double knockout mice are viable and display similar phenotypes as Cdk2−/− and Skp2−/− mice. Unexpectedly, fibroblasts generated from Cdk2−/−Skp2−/− double knockout mice proliferated at normal rates. The increased stability of p27 observed in Skp2−/− MEFs was not observed in Cdk2−/−Skp2−/− double knockout fibroblasts indicating that in the absence of Cdk2, p27 is regulated by Skp2-independent mechanisms. Ablation of other ubiquitin ligases for p27 such as KPC1, DDB1, and Pirh2 did not restore stability of p27 in Cdk2−/−Skp2−/− MEFs. Our findings point towards novel and alternate pathways for p27 regulation. 相似文献
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Laura Owens Scott Simanski Christopher Squire Anthony Smith Jeff Cartzendafner Valerie Cavett Jennifer Caldwell Busby Trey Sato Nagi G. Ayad 《The Journal of biological chemistry》2010,285(9):6761-6769
Cell cycle progression is dependent upon coordinate regulation of kinase and proteolytic pathways. Inhibitors of cell cycle transitions are degraded to allow progression into the subsequent cell cycle phase. For example, the tyrosine kinase and Cdk1 inhibitor Wee1 is degraded during G2 and mitosis to allow mitotic progression. Previous studies suggested that the N terminus of Wee1 directs Wee1 destruction. Using a chemical mutagenesis strategy, we report that multiple regions of Wee1 control its destruction. Most notably, we find that the activation domain of the Wee1 kinase is also required for its degradation. Mutations in this domain inhibit Wee1 degradation in somatic cell extracts and in cells without affecting the overall Wee1 structure or kinase activity. More broadly, these findings suggest that kinase activation domains may be previously unappreciated sites of recognition by the ubiquitin proteasome pathway. 相似文献
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越来越多的证据表明,Cdk5通过与大量蛋白相互作用而在学习和记忆过程中发挥重要作用。近来,关于Cdk5的研究结果不仅证实其参与药物成瘾过程中细胞间的通路改变,且其活性与一些神经退行性疾病的发生有关。本文就Cdk5对学习和记忆的影响及其相关机制的研究进展予以综述。 相似文献
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Yamada M Saito T Sato Y Kawai Y Sekigawa A Hamazumi Y Asada A Wada M Doi H Hisanaga S 《Journal of neurochemistry》2007,102(5):1477-1487
Cyclin-dependent kinase 5 (Cdk5) is a proline-directed Ser/Thr kinase that plays important roles in various neuronal activities, including neuronal migration, synaptic activity, and neuronal cell death. Cdk5 is activated by association with a neuron-specific activator, p35 or its isoform p39, but little is known about the kinase activity of Cdk5--p39. In fact, kinase-active Cdk5--p39 was not prepared from rat brain extracts nor from HEK293 cells expressing Cdk5 and p39 by immunoprecipitation in the presence of non-ionic detergent, under conditions with which active Cdk5--p35 could be isolated. p39 dissociated from Cdk5 in the presence of detergent, indicating that p39 has a lower binding affinity for Cdk5 than p35. We developed a method for purifying kinase-active Cdk5--p39 from Sf9 cells infected with baculovirus encoding Cdk5 and p39. The purified Cdk5--p39 complex showed similar substrate specificity to that of Cdk5--p35, but with opposite sensitivity to detergent. Cdk5--p39 was inactivated by Triton X-100, whereas Cdk5--p35 was activated. The N-terminal deletion from p35 and p39, the amino acid sequences of which are different, did not change the stability or substrate specificity of either Cdk5 complex. The different stability between Cdk5--p35 and Cdk5--p39 suggests their distinct roles under different regulation mechanisms in neurons. 相似文献
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An Unusual Member of the Cdk Family: Cdk5 总被引:1,自引:0,他引:1
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Complex mechanisms underlying impaired activation of Cdk4 and Cdk2 in replicative senescence: roles of p16, p21, and cyclin D1 总被引:3,自引:0,他引:3
Morisaki H Ando A Nagata Y Pereira-Smith O Smith JR Ikeda K Nakanishi M 《Experimental cell research》1999,253(2):503-510
Numerous changes in gene expression are known to occur during replicative senescence, including changes in genes involved in the cell cycle control. In the present study, we have found a severe impairment in the activation of Cdk2 and Cdk4 in response to mitogens in senescent human fibroblasts and determined the molecular basis for this. Although Cdk4 protein was constitutively expressed in senescent cells at the same level as in early-passage young cells, it was found to be complexed with a distinct set of Cdk inhibitors. Cdk4 derived from early passage quiescent cells was effectively activated by incubation with cyclin D1 and Cdk-activating kinase (CAK) in vitro, whereas Cdk4 from senescent cells was not. Cdk2 protein was dramatically decreased in senescent cells and complexed primarily with cyclin D1 and p21. This cyclin D1-bound Cdk2 was not activated by CAK either in vivo or in vitro, implicating cyclin D1 as an inhibitor of Cdk2 activation. Thus, one of the underlying molecular events involved in replicative senescence is the impaired activation of Cdk4 and Cdk2 due to increased binding of p16 to Cdk4 and increased association of Cdk2 with cyclin D1 and p21. 相似文献
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Abstract The Dictyostelium vegetative cell cycle is characterized by a short mitotic period followed immediately by a short S-phase (less than 30 min) and a long and variable G2 phase. The cell cycle continues during differentiation despite a decrease in cell mass: DNA replication and mitosis occur early in development and also at the tipped aggregate stage. Cells that are in mitosis, S-phase or early G2, when starved differentiate into prestalk cells and cells that are in the middle of G2 differentiate into prespore cells. We postulate that there is a restriction point late in the G2 phase, about 1–2 h before mitosis, where the cells can be arrested either by starvation and the initiation of development, by growing into stationary phase, or by prolonged incubation at low temperature. During development, this block persists to the tipped aggregate stage, where it is specifically released in prespore cells, and these cells then go through one more round of cell division. Genes encoding components of the cell cycle machinery have recently been isolated and attemps to specifically block the cell cycle by reverse genetics to study the effects on differentiation have been initiated. 相似文献
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The function of the c-myc proto-oncogene in cell cycle progression remains unclear. In order to examine the role c-myc may play in cell cycle progression, we have expressed the hormone-inducible MycER protein in the nontransformed, EGF-dependent mouse keratinocyte cell line BALB/MK. We have found that activation of MycER, but not a mutant MycER, Gal4ER, or FosER, leads to an EGF-dependent and hormone-dependent increased incorporation of labeled thymidine only during the S phase of the cell cycle in BALB/MK cells. A possible explanation for the increase in thymidine incorporation comes from flow cytometric analyses that reveal that activation of MycER leads to an increase in the total number of cells that enter S phase after EGF restimulation. Investigation of the intracellular effects of Myc activation shows that the expression of several putative Myc-sensitive proteins, cyclins A, E, and D1, and the E2F-1 protein are unaffected by Myc induction. Interestingly, we find that the histone H1 kinase activity associated with an E2F-1 complex containing Cyclin A and Cdk-2, but not that associated with Cyclin E, in late G1 and early S phases is increased in cells containing hormone-activated MycER, but not FosER. Although the mechanism for this Myc-dependent effect on E2F-1-associated kinase activity is still unknown, it does not appear to involve dissociation of the Cdk inhibitor p27Kip1 from the complexes as suggested by others. However, we have also found that hormone-treated cells actually show more p16INK4A inhibitor associated with another kinase, Cdk-4, as the cells are entering S phase. Altogether, the data suggest that the presence of excessive Myc protein in keratinocytes can stimulate otherwise noncycling cells to enter the cell cycle, and that this effect of Myc involves both positive effects on E2F-1-associated Cdk-2 and negative effects on Cdk-4 in late G1. J. Cell Biochem. 70:528–542, 1998. © 1998 Wiley-Liss, Inc. 相似文献
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We have recently developed a rapid protocol involving NT2 cell aggregation and treatment with retinoic acid (RA) to produce terminally differentiated CNS neurons. As a first step to explore the functional roles of cell-cycle regulatory proteins in the process of neuronal differentiation, the expression profiles of cyclin-dependent kinases (Cdks) and their regulators were examined in NT2 cells following treatment with RA. One of the Cdks, Cdk5, has been demonstrated to affect the process of neuronal differentiation and suggested to play an important role in development of the nervous system. We found that the expression of Cdk5 was gradually increased, while its activators (p35 and p39) as well as Cdk5 kinase activity were induced in NT2 cells during the process of neuronal differentiation. Moreover, both p35 and p39 were localized along the axons and varicosity-like structures of differentiated NT2 neurons. Taken together, our results demonstrated that NT2 cells provide a good in vitro model system to examine signaling pathways involved in the regulation of Cdk5 activators and to elucidate the functional roles of Cdk5 in neuronal differentiation. 相似文献
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Emergence of the cell cycle hypothesis in neurodegenerative disease comes from the numerous lines of evidence showing a tight link between "cell cycle-like reactivation" and neuronal death. Terminally differentiated neurons remain in G0 phase and display, compared to proliferating cells, an opposite regulation pattern of cell cycle markers in that most of the key activators and inhibitors are respectively down- and up-regulated. It has been clearly established that any experimental attempt to force terminally differentiated neurons to divide ultimately leads to their death. Conversely, cell cycle blockade in experimental models of neuronal death is able to rescue neurons. Hence, cell cycle deregulation is certainly among mechanisms governing neuronal death. However, many questions remain unresolved, especially those related to which molecular mechanisms trigger cell cycle deregulation and how this deregulation leads to cell death. In the present review, we focus on neurodegeneration in Alzheimer's disease and discuss the cell cycle deregulation related to this neurodegenerative pathology. Finally, we emphasize the role of p25/Cdk5 kinase complex in this pathological process through retinoblastoma protein phosphorylation and derepression of E2F-responsive genes and other actors such as cdc2, cyclins, and MCM proteins. 相似文献
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Uhlmann F Bouchoux C López-Avilés S 《Philosophical transactions of the Royal Society of London. Series B, Biological sciences》2011,366(1584):3572-3583
The eukaryotic cell division cycle encompasses an ordered series of events. Chromosomal DNA is replicated during S phase of the cell cycle before being distributed to daughter cells in mitosis. Both S phase and mitosis in turn consist of an intricately ordered sequence of molecular events. How cell cycle ordering is achieved, to promote healthy cell proliferation and avert insults on genomic integrity, has been a theme of Paul Nurse's research. To explain a key aspect of cell cycle ordering, sequential S phase and mitosis, Stern & Nurse proposed 'A quantitative model for cdc2 control of S phase and mitosis in fission yeast'. In this model, S phase and mitosis are ordered by their dependence on increasing levels of cyclin-dependent kinase (Cdk) activity. Alternative mechanisms for ordering have been proposed that rely on checkpoint controls or on sequential waves of cyclins with distinct substrate specificities. Here, we review these ideas in the light of experimental evidence that has meanwhile accumulated. Quantitative Cdk control emerges as the basis for cell cycle ordering, fine-tuned by cyclin specificity and checkpoints. We propose a molecular explanation for quantitative Cdk control, based on thresholds imposed by Cdk-counteracting phosphatases, and discuss its implications. 相似文献