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)

The enamel knot, a transient epithelial structure, appears at the onset of mammalian tooth shape development. Until now, the morphological, cellular and molecular events leading to the formation and disappearance of the enamel knot have not been described. Here we report that the cessation of cell proliferation in the enamel knot in mouse molar teeth is linked with the expression of the cyclin-dependent kinase inhibitor p21. We show that p21 expression is induced by bone morphogenetic protein 4 (BMP-4) in isolated dental epithelia. As Bmp-4 is expressed only in the underlying dental mesenchyme at the onset of the enamel knot formation, these results support the role of the cyclin-dependent kinase inhibitors as inducible cell differentiation factors in epithelial-mesenchymal interactions. Furthermore, we show that the expression of p21 in the enamel knot is followed by Bmp-4 expression, and subsequently by apoptosis of the differentiated enamel knot cells. Three-dimensional reconstructions of serial sections after in situ hybridization and Tunel-staining indicated an exact codistribution of Bmp-4 transcripts and apoptotic cells. Apoptosis was stimulated by BMP-4 in isolated dental epithelia, but only in one third of the explants. We conclude that Bmp-4 may be involved both in the induction of the epithelial enamel knot, as a mesenchymal inducer of epithelial cyclin-dependent kinase inhibitors, and later in the termination of the enamel knot signaling functions by participating in the regulation of programmed cell death. These results show that the life history of the enamel knot is intimately linked to the initiation of tooth shape development and support the role of the enamel knot as an embryonic signaling center.
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PMID:The life history of an embryonic signaling center: BMP-4 induces p21 and is associated with apoptosis in the mouse tooth enamel knot. 948 90

Previous studies have indicated that certain members of the cyclin-dependent kinase/mitogen-activated protein kinase superfamily are involved in apoptosis of neuronal cells. Here, we have examined programmed cell death induced by withdrawal of neurotrophic support from CNS (rat retinal) and PNS (chick sympathetic, sensory, and ciliary) neurons. All four neuron types were equally rescued by the purine analogues olomoucine and roscovitine. Olomoucine inhibits multiple cyclin-dependent and mitogen-activated protein kinases with similar potency. Roscovitine is a more selective cyclin-dependent kinase inhibitor; but, so is butyrolactone I, which did not prevent retinal ganglion cell death. The specific p38MAPK inhibitor SB-203580 did not prevent apoptosis in retinal ganglion cells. Death of these cells in the absence of neurotrophic factors was accompanied by morphological changes indicative of apoptosis, including nuclear condensation and fragmentation. Treatment with olomoucine or roscovitine not only prevented these apoptotic changes in retinal ganglion cells but also blocked neurite outgrowth. The survival-promoting activity of olomoucine correlated with its in vitro IC50 for c-Jun N-terminal kinase-1 and its potency to repress c-jun induction in live PC12 cells. Roscovitine was more potent in rescuing neurons than in inhibiting Jun kinase. Thus, the antiapoptotic action of roscovitine might be due to inhibition of additional kinases.
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PMID:Apoptosis of central and peripheral neurons can be prevented with cyclin-dependent kinase/mitogen-activated protein kinase inhibitors. 952 56

The selection of NIH 3T3 cells expressing a hydroxytamoxifen-inducible c-Raf-1-estrogen receptor fusion protein (c-Raf-1-BxB-ER) in the absence or presence of the inducer results in dramatic differences in the expression levels of the fusion protein. Hydroxytamoxifen-mediated constitutive activation of the Raf signal favors the selection of cells expressing low levels of c-Raf-1-BxB-ER. Cells selected in the absence of hydroxytamoxifen express up to 20 times higher levels of the inducible Raf kinase. Activation of the oncogenic Raf kinase in cells expressing low levels leads to a weak activation of the Raf/Mek/Erk cascade and the induction of S phase in confluent cells. The activation of cells expressing high levels of the kinase leads to a strong persistent signal and inhibits DNA synthesis and mitosis in proliferating cells. The inhibition of DNA synthesis and cell division is presumably due to the elevated expression of the cyclin-dependent kinase inhibitor p21cip1, similar to cells exposed to ionizing radiation. Despite the inhibition of DNA synthesis and mitosis, the constitutive activity of the Raf signaling pathway is still able to initiate cell growth. Activation of the high-intensity Raf signal in arrested serum-starved cells induces cell growth up to a size corresponding to that of M-phase cells in the absence of DNA synthesis. High-intensity Raf signals in proliferating cells consistently lead to an accumulation of cells with the size of M-phase cells and the DNA content of G1 cells or G2-M-phase cells. Therefore, the activation of Raf kinase is sufficient to drive cell growth, even in the presence of high levels of the cyclin-dependent kinase inhibitor p21cip1.
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PMID:High-intensity Raf signals convert mitotic cell cycling into cellular growth. 956 74

The cyclin-dependent kinase inhibitor p21(WAF1/CIP1/SDI1/CAP20) exists in normal human fibroblasts in a quaternary complex with a cyclin, a cyclin-dependent kinase, and proliferating cell nuclear antigen. A model was proposed in which, during p53-mediated suppression of cell proliferation following treatment with 254 nm UV radiation (UVC), the enhanced expression of p21 might inhibit DNA replication by virtue of its interactions with proliferating cell nuclear antigen. To test this model, we examined the mechanisms of inhibition of DNA replication in diploid human fibroblasts that express human papillomavirus type 16 E6, which inactivates p53. E6-expressing cells were defective in G1 checkpoint responses of induction of p21 and G1 arrest after ionizing radiation-induced damage to DNA. Accordingly, E6-expressing cells were resistant to inactivation of single-cell colony formation by ionizing radiation. E6 cells also displayed normal S-phase checkpoint responses of inhibition and recovery of replicon initiation following exposure to ionizing radiation and normal ability to bypass pyrimidine dimers during DNA replication soon after UVC irradiation (i.e., postreplication repair). However, DNA replication 6 h after UVC exposure was significantly inhibited in E6 cells in comparison to isogenic controls. This failure to maintain DNA replication in S-phase cells was associated with enhanced sensitivity to inactivation of single-cell colony formation by UVC. These results indicate that the p53-induced p21 pathway is not involved in the immediate S-phase responses to radiation-induced DNA damage of inhibition of replicon initiation and translesion bypass. However, our results demonstrate that p53 and, conceivably, p21 contribute to the ability of normal human fibroblasts to sustain DNA replication activity and form colonies following UVC irradiation.
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PMID:p53-dependent signaling sustains DNA replication and enhances clonogenic survival in 254 nm ultraviolet-irradiated human fibroblasts. 958 44

The blocking of G1 progression by fission yeast pheromones requires inhibition of the cyclin-dependent kinase cdc2p associated with the B-cyclins cdc13p and cig2p. We show that cyclosome-mediated degradation of cdc13p and cig2p is necessary for down-regulation of B-cyclin-associated cdc2p kinase activity and for phermone-induced G1 arrest. The cyclin-dependent kinase inhibitor rum1p is also required to maintain this G1 arrest; it binds both cdc13p and cig2p and is specifically required for cdc13p proteolysis. We propose that rum1p acts as an adaptor targeting cdc13p for degradation by the cyclosome. In contrast, the cig2p-cdc2p kinase can be down-regulated, and the cyclin cig2p can be proteolyzed independently of rum1p. We suggest that pheromone signaling inhibits the cig2p-cdc2p kinase, bringing about a transient G1 arrest. As a consequence, rum1p levels increase, thus inhibiting and inducing proteolysis of the cdc13p-cdc2p kinase; this is necessary to maintain G1 arrest. We have also shown that pheromone-induced transcription occurs only in G1 and is independent of rum1p.
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PMID:Cyclin B proteolysis and the cyclin-dependent kinase inhibitor rum1p are required for pheromone-induced G1 arrest in fission yeast. 961 76

The tumor-suppressor protein p53 has been implicated in cell cycle arrest and apoptotic cell death in dividing cells (Yonish-Rouach et al. [1991] Nature 352:342-347. To elucidate possible functions of p53 in the regulation of cell division and cell death during development of the rat central nervous system, we compared the spatial and temporal expressions of p53 mRNA and protein with those of its transcriptional targets Bax, p21Waf1, and cyclin G1 and with the cyclin-dependent kinase inhibitors p27Kip1, p57Kip2, and p16Ink4a. From embryonic day 14 until the second postnatal week, p53 mRNA and protein were found predominantly in proliferating zones, including the cells of the emerging external granular layer of the cerebellum, and the ventricular and the subventricular zones of the forebrain. At all postnatal ages, there was a high expression of p53 mRNA and protein in cells of the rostral migratory stream, a well-defined pathway along which precursor cells of olfactory interneurons migrate from the ventricular and subventricular zones toward the olfactory bulb. In addition to its expression in proliferating cell populations, p53 was expressed in postmitotic cells of the cerebral cortex and hippocampus at embryonic and early postnatal stages. p53, p27Kip1, p16Ink4a, and bax alpha mRNA colocalized in the ventricular and subventricular zones at embryonic and early postnatal stages, but the distribution of p53 differed from that of its transcriptional targets cyclin G1 and p21Waf1 and from that of the cyclin-dependent kinase inhibitor p57Kip2, which were predominantly expressed in fully differentiated neurons. Double-labeling studies showed that p53 mRNA and protein were absent in cells undergoing developmental cell death, as identified by the presence of single- or double-stranded nuclear DNA breaks. Protein levels of p53 decreased during development in all brain areas studied. These results indicate a role for p53 in the control of cell division and early differentiation rather than in the control of cell death during rat brain development. The nonoverlapping temporal and spatial expression patterns of p53 and its transcriptional targets Bax, cyclin G1 and p21Waf1 suggest that each of these gene products fulfill independent roles in brain morphogenesis.
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PMID:Tumor-suppressor p53 is expressed in proliferating and newly formed neurons of the embryonic and postnatal rat brain: comparison with expression of the cell cycle regulators p21Waf1/Cip1, p27Kip1, p57Kip2, p16Ink4a, cyclin G1, and the proto-oncogene Bax. 965 83

When treated with millimolar concentrations of butyrate, many cell types undergo growth arrest in the G1 phase of the cell cycle. However, the molecular basis of butyrate-induced G1 arrest has not been elucidated. We have investigated the molecular mechanisms of butyrate-induced G1 arrest in synchronized cultures of untransformed 3T3 fibroblasts. We tested the hypothesis that butyrate-induced growth arrest might be mediated by the p21 cyclin-dependent kinase inhibitor. Sodium butyrate-treated 3T3 cells did, indeed, express elevated levels of p21 mRNA under conditions of G1 arrest. Surprisingly, however, primary cultures of fibroblasts from transgenic p21 "knockout" (p21-/-) mice and fibroblasts from wild-type p21-proficient (p21+/+) mice underwent butyrate-induced G1 arrest with similar dose dependencies. Therefore, p21 expression was not necessary for butyrate-induced G1 arrest. To identify other potential mechanisms of butyrate-induced growth arrest, we analyzed the butyrate sensitivity of key mitogenic signaling events during G1. We found that butyrate inhibited the mitogen-dependent transcriptional induction of cyclin D1 and phosphorylation of retinoblastoma (Rb), both in p21-proficient 3T3 cells and in p21+/+ and p21-/- mouse embryo fibroblasts. Butyrate treatment also prevented mitogen-dependent transcriptional induction of cyclin E and expression of cyclin A, cell cycle events that are temporally distal to expression of cyclin D and are necessary for entry into S phase. Abrogation of a requirement for cyclin D/cyclin-dependent kinase-dependent phosphorylation of Rb (by ectopic expression of the human papilloma virus E7 oncoprotein in 3T3 cells) resulted in decreased sensitivity to the antiproliferative actions of butyrate. Overall, these data show that butyrate-induced G1 arrest is, in large part, independent of p21 induction. Instead, butyrate-induced growth arrest appears to result from perturbation of the Rb signaling axis at the level of or at a stage prior to cyclin D1 expression.
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PMID:Butyrate-induced G1 arrest results from p21-independent disruption of retinoblastoma protein-mediated signals. 966 65

We have used c-Fos transgenic mice which develop osteosarcomas to determine the expression patterns of cyclins, cyclin-dependent kinases (CDKs), and cyclin-dependent kinase inhibitors (CKIs) in different bone cell populations in order to define the potential mechanisms of c-Fos transformation. Immunohistochemical analysis in embryonic and early postnatal bone demonstrated that cyclin E and its kinase partner CDK2 were expressed specifically in bone-forming osteoblasts. Cyclin D1 expression was absent despite high levels of CDK4 and CDK6, and the CKI p27 was expressed in chondrocytes, osteoclasts, and at lower levels in osteoblasts. Following activation of the c-fos transgene in vivo and before overt tumor formation, cyclin D1 expression increased dramatically and was colocalized with exogenous c-Fos protein specifically in osteoblasts and chondrocytes, but not in osteoclasts. Prolonged activation of c-Fos resulted in osteosarcoma formation wherein the levels of cyclin D1, cyclin E, and CDKs 2, 4, and 6 were high in a wide spectrum of malignant cell types, especially in transformed osteoblasts. The CKI p27 was expressed at very high levels in bone-resorbing osteoclasts, and to a lesser extent in chondrocytes and osteoblasts. These in vivo observations suggest that cyclin D1 may be a target for c-Fos action and that elevation of cyclin D1 in osteoblasts which already express cyclin E/CDK2 and the cyclin D1 partners CDKs-4 and 6, may predispose cells to uncontrolled cell growth leading to osteosarcoma development. This study implicates altered cell cycle control as a potential mechanism through which c-Fos causes osteoblast transformation and bone tumor formation.
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PMID:Control of cell cycle gene expression in bone development and during c-Fos-induced osteosarcoma formation. 966 90

p27Kip1 is a cyclin-dependent kinase inhibitor that regulates the decision to enter S phase or withdraw from the cell cycle. In resting cells, the level of p27Kip1 provides an inhibitory threshold above which G1 cyclin D/E/cyclin-dependent kinases accumulate before activation; however, in cycling cells, p27Kip1 protein is sequestered by high levels of active cyclin D/cyclin-dependent kinase 4 complexes. As a group, the cyclin-dependent kinase inhibitors have been proposed to act as tumor suppressor genes, and several members have been implicated in the pathogenesis of a variety of human cancers. We examined p27Kip1 expression in 116 non-Hodgkin's lymphomas including 50 cases of MCL (40 typical and 10 blastic variants), 21 follicular lymphomas, 20 diffuse large B-cell lymphomas, 16 chronic lymphocytic leukemias, 8 marginal zone B-cell lymphomas, and 1 splenic marginal zone lymphoma, and correlated its expression with that of the proliferation marker Ki67 (MiB1) and with p53. p27Kip1 gene structure was analyzed by Southern blot in the group of MCLs. In all cases of non-Hodgkin's lymphoma other than MCL, p27Kip1 expression was inversely related to the proliferation index as measured by Ki67. In contrast, in typical MCL, p27Kip1 expression was negative in 35 of 40 (88%) cases, irrespective of the proliferative rate (median 15%; range 2 to 90%). Paradoxically, in the blastic variant of MCL, 8 of 10 (80%) cases showed expression of p27Kip1, despite a high proliferation rate (median 60%; range 32 to 100%). However, the staining in most of the cases was less intense than in the reactive T lymphocytes. Deletions of p27Kip1 gene were not found in any of the 25 cases examined. p53 expression was found in 15 of 50 cases of MCL: 7 of 10 (70%) in the blastic variant and 8 of 40 (20%) in the typical MCL (70% vs. 20%, P < 0.0045). These results demonstrate that MCLs, in contrast to other non-Hodgkin's lymphomas and normal lymphoid tissue, fail to correlate p27Kip1 expression with the proliferation rate. This peculiar uncoupling of p27Kip1 protein expression from the proliferation rate may be related to the high levels of cyclin D1 expressed in MCL and is likely to have profound effects on cell cycle regulation and contribute to the pathogenesis of MCL.
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PMID:Mantle cell lymphomas lack expression of p27Kip1, a cyclin-dependent kinase inhibitor. 966 78

UCN-01, a protein kinase C/cyclin-dependent kinase inhibitor, suppressed thymidylate synthase (TS) protein expression in a dose-dependent manner with near complete suppression at 1 microM after a 24-h exposure in human gastric cancer cell line SK-GT5. Other protein kinase C/cyclin-dependent kinase inhibitors, including flavopiridol and safingol, had a similar effect on TS protein expression, but to a lesser degree. Moreover, UCN-01 repressed the induction of TS after 5-fluorouracil (FU) exposure by 90-95% and significantly enhanced the induction of apoptosis by FU from 4-8% with either FU or UCN-01 alone to 46+/-1% (P < 0.005 versus either single drug, reverse sequence, or the combination) when UCN-01 was given after FU. The effect of UCN-01 on TS was associated with a dose-dependent suppression of the E2F-1 protein, a transcriptional activator of TS. Northern blot analysis revealed that TS mRNA levels decreased gradually as the concentration of UCN-01 increased, but that E2F-1 mRNA levels remained relatively unchanged. UCN-01 may provide a novel way to enhance cellular sensitivity toward FU by means of suppressing TS expression mediated mainly by down-regulation of E2F-1.
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PMID:UCN-01 suppresses thymidylate synthase gene expression and enhances 5-fluorouracil-induced apoptosis in a sequence-dependent manner. 974 40


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