Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We previously reported that inostamycin, an inhibitor of CDP-DG: inositol transferase, inhibited cell proliferation in normal rat kidney (NRK) cells by blocking cell cycle progression at the G1 phase. In the present paper, we report the effect of inostamycin on the serum-induced activation of Ser/Thr protein kinases that are involved in G1 progression. In quiescent NRK cells mitogen-activated protein kinase (MAP kinase) and casein kinase II were activated within 15 min after serum addition. Neither activation was affected by the treatment with inostamycin. However, in the inostamycin-treated cell, cyclin-dependent kinase 2 (CDK2) failed to be activated after serum stimulation. Since serum-induced expression of cyclin E was also suppressed by inostamycin, this inhibitor would appear to block CDK2 activation by inhibiting cyclin E expression. Furthermore, inostamycin also inhibited cyclin D1 expression induced by serum; and consequently, hyperphosphorylation of retinoblastoma protein (pRB) by RB-kinases such as CDK4 and CDK2 was abolished, which would result in elimination of functional inactivation of pRB. Thus, early G1 arrest in NRK cells by inostamycin is due to the inhibition of cyclin D1 and E expressions.
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PMID:Inhibition of G1 cyclin expression in normal rat kidney cells by inostamycin, a phosphatidylinositol synthesis inhibitor. 901 Jul 59

The mitogen-activated protein kinase (MAPK) cascade plays a crucial role in the transduction of extracellular signals into responses governing growth and differentiation. The effects of a specific inhibitor of the MAPK kinase (MEK)/MAPK pathway (PD98059) on nerve growth factor (NGF)-induced growth arrest and inhibition of cell cycle-dependent kinases (CDKs) have been examined. Treatment of NIH 3T3 cells expressing TRKA with PD98059 dramatically reversed the complete inhibition of growth of these cells caused by NGF. PD98059 also blocked the ability of NGF to inhibit the activities of CDK4 and CDK2, while partially preventing NGF induction of p21Cip1/WAF1. To independently evaluate the involvement of the MEK/MAPK pathway in growth arrest, an inducible activated form of the Raf-1 protooncogene (delta RAF-1:ER) was expressed in these cells. Activation of delta RAF-1:ER resulted in a prolonged increase in MAPK activity and growth arrest of these cells, with concomitant induction of p21Cip1/WAF1 and inhibition of CDK2 activity. These effects of delta RAF-1:ER activation were all reversed by treatment of cells with PD98059. These data indicate that in addition to functioning as a positive effector of growth, stimulation of the MEK/MAPK pathway can result in an inhibition of CDK activity and cell cycle arrest.
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PMID:Cell cycle arrest mediated by the MEK/mitogen-activated protein kinase pathway. 901 3

In this study, we isolated and characterized a human cyclin A-like gene that we named cyclin A1. Cyclin A1 has 48% identity with human cyclin A and is more related to the recently cloned murine cyclin A1 (84% identity). The human cyclin A1 is specifically expressed in testis and brain among all of the normal tissues that we studied by Northern blot analysis; in addition, it is expressed in several myeloid leukemia cell lines, including ML-1, U937, NB4, KG-1, and THP1. A sensitive reverse transcription-PCR-Southern blot method also detected low-level expression of this gene in many other hematopoietic and nonhematopoietic cell lines. The expression of cyclin A1 mRNA is differentiation- and cell cycle-regulated in the ML-1 cells. We raised polyclonal antibodies against a glutathione S-transferase-cyclin A1 fusion protein produced in Escherichia coli. In immunoblot analyses, the antibodies recognized the Mr 65,000 cyclin A1 protein in ML-1 cells. The anti-cyclin A1 also immunoprecipitated the Mr 65,000 cyclin A1, along with the Mr 33,000 cyclin-dependent kinase (CDK) 2 and other proteins at Mr 39,000, 42,000, 45,000, 95,000, and 110,000. In an in vitro kinase assay, the CDK2-cyclin A1 complex precipitated by anti-cyclin A1 showed kinase activities against histone H1. In a yeast two-hybrid assay, cyclin A1 can bind to CDK2 but not to CDC2, CDK4, and CDK5. We mapped the human cyclin A1 gene to chromosome 13q12.3-q13, approximately 1000 kb from the sequence-tagged site marker WI-3374.
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PMID:Characterization of a second human cyclin A that is highly expressed in testis and in several leukemic cell lines. 904 Nov 94

The expression of cyclins (A, B1, D1, D3, E), cyclin-dependent kinases (CDK2(3), CDK4), and the cyclin-dependent kinase inhibitors (CDKIs) p16(INK4A) and p21(CIP1) was studied in 9 malignant human astrocytoma cell lines using northern blot analysis, immunocytochemistry, and immunoblotting to see if their altered expression contributed to astrocytoma proliferation. Steady state cell cycle mRNA expression was analyzed in unsynchronized tumor cells, and cell cycle phase-specific gene expression was analyzed in 3 synchronized cell lines. Analysis of steady state expression revealed increased levels of several different cyclin transcripts and CDKs in a number of astrocytoma cell lines compared with normal human brain tissue or cultured fibroblasts. We confirm previous reports identifying loss of p16(INK4A) in astrocytomas, as a p16(INK4A) transcript was identified in only 2 cell lines and protein in 1 cell line. However, we now show that p21(CIP1) expression was also diminished relative to normal fibroblasts in all astrocytoma cell lines studied regardless of p53 mutation status. Analysis of synchronized astrocytoma cells revealed altered timing of mRNA expression of several cyclins. Immunocytochemistry revealed a generalized increase in immunoreactivity of astrocytoma cells for most cyclins and CDKs compared with human fibroblasts. Immunoblotting also revealed increased expression of cyclin proteins in a number of astrocytoma cell lines. These data suggest that increased expression of cyclins and CDKs, and decreased expression of CDKIs by human astrocytoma cell lines may contribute to their increased proliferative state. In addition, our data show that alterations in cell cycle genes in astrocytomas are not confined to the cyclin D1-CDK4-pRb axis.
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PMID:Cyclin and cyclin-dependent kinase expression in human astrocytoma cell lines. 905 43

Characterization of proteins that control the passage through the G1 phase of the cell cycle is of particular interest because virtually all stimuli regulating cell proliferation or differentiation act primarily during this phase. We have analyzed the G1 phase proteic machinery, including cyclin D types, cyclin-dependent kinases (CDKs) and CDK inhibitors, of cell populations obtained at different stages of hematopoietic cell lineage. In particular, five cellular phenotypes, namely CD34+ cells (which contain stem cells), BFU-E, CFU-E, CFU-GM and peripheral lymphocytes were studied as representatives of distinct differentiation pathways. The results obtained indicated that all the cellular preparations express cyclin D2 and D3, while cyclin D1, which is the major cyclin D occurring in mesenchimal tissues, is not expressed. Moreover, CDK6 (but not CDK4) was detectable in all the populations investigated. Among the CDK inhibitors studied, p18INK4C and p19INK4D signals were clearly evidentiable in the various cell types. Interestingly, high levels of p15INK4B, a putative tumor suppressor protein, were detectable especially in granulocyte-monocyte precursors. Our results indicate that a specific hematopoietic G1 phase machinery occurs, which is conserved during the various steps of the different maturation processes.
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PMID:Expression of G1-phase cell cycle genes during hematopoietic lineage. 907 Feb 22

The cyclin D/cyclin-dependent kinase (CDK)/CDK-inhibitory proteins/retinoblastoma protein (pRb) pathway is hypothesized to control the G1-S check point. The role of this pathway is reported to be different depending on the status of pRb. In the present study, we examined nine human urological tumor cell lines. Cells lacking functional pRb expressed p16, instead of forming cyclin D/ CDK4 complex. In the LNCaP prostatic cancer cell line, however, both p16/CDK4 and cyclin D/ CDK4 complexes were present independently, probably because of partial loss of pRb. In view of the concomitant presence of the incompatible complexes, LNCaP should provide us with a valuable model for the study of this pathway in cancer cells.
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PMID:Concomitant presence of p16/cyclin-dependent kinase 4 and cyclin D/cyclin-dependent kinase 4 complexes in LNCaP prostatic cancer cell line. 914 Jan 5

To provide a state-of-the-art summary of currently available data about the genetics of cutaneous melanoma and nevi, we reviewed the pertinent literature and outlined the important findings on genetic analyses. Although the first English-language report of melanoma in 1820 contained a description of a melanoma-prone family, seminal studies by investigators at the National Cancer Institute and the University of Pennsylvania identified dysplastic nevi (DN) as an important melanoma precursor, suggested an autosomal dominant mode of inheritance for both melanoma and DN, and proposed that a melanoma-susceptibility gene (CMM1) was located on chromosome 1p36. This gene assignment has not yet been confirmed by independent investigators. A second melanoma gene, designated CMM2, has been mapped to chromosome 9p21. This gene assignment has been confirmed independently, and the cell cycle regulator p16INK4a has been proposed as a candidate gene; germline mutations in this gene have been identified in about half of melanoma-prone families. Germline mutations in the cyclin-dependent kinase gene CDK4 (chromosome 12q14) have recently been described in two melanoma kindreds; this finding likely represents a third melanoma gene. A heritable determinant for total nevus number has been suggested, as has the presence of a major gene responsible for total nevus density in melanoma-prone families. An autosomal dominant mode of inheritance for DN has been proposed, and evidence suggests that DN may be a pleiotropic manifestation of the 1p36 familial melanoma gene. Several studies have shown a surprisingly high prevalence of DN on the skin of family members of probands with DN. In light of the extensive evidence documenting that persons with DN (both sporadic and familial) have an increased prospective risk for melanoma, these family studies suggest that relatives of persons with DN should be examined for DN and for melanoma. Overall, genetic determinants have a major role in the pathogenesis of normal nevi, DN, and melanoma. Elucidating the molecular basis of these genetic events promises to enhance melanoma risk reduction strategies and thereby reduce melanoma-associated mortality.
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PMID:Genetics of cutaneous melanoma and nevi. 914 91

Glucocorticoids inhibit proliferation of many cell types, but the events leading from the activated glucocorticoid receptor (GR) to growth arrest are not understood. Ectopic expression and activation of GR in human osteosarcoma cell lines U2OS and SAOS2, which lack endogenous receptors, result in a G1 cell cycle arrest. GR activation in U2OS cells represses expression of the cyclin-dependent kinases (CDKs) CDK4 and CDK6 as well as their regulatory partner, cyclin D3, leading to hypophosphorylation of the retinoblastoma protein (Rb). We also demonstrate a ligand-dependent reduction in the expression of E2F-1 and c-Myc, transcription factors involved in the G1-to-S-phase transition. Mitogen-activated protein kinase, CDK2, cyclin E, and the CDK inhibitors (CDIs) p27 and p21 are unaffected by receptor activation in U2OS cells. The receptor's N-terminal transcriptional activation domain is not required for growth arrest in U2OS cells. In Rb-deficient SAOS2 cells, however, the expression of p27 and p21 is induced upon receptor activation. Remarkably, in SAOS2 cells that express a GR deletion derivative lacking the N-terminal transcriptional activation domain, induction of CDI expression is abolished and the cells fail to undergo ligand-dependent cell cycle arrest. Similarly, murine S49 lymphoma cells, which, like SAOS2 cells, lack Rb, require the N-terminal activation domain for growth arrest and induce CDI expression upon GR activation. These cell-type-specific differences in receptor domains and cellular targets linking GR activation to cell cycle machinery suggest two distinct regulatory mechanisms of GR-mediated cell cycle arrest: one involving transcriptional repression of G1 cyclins and CDKs and the other involving enhanced transcription of CDIs by the activated receptor.
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PMID:Glucocorticoid receptor-mediated cell cycle arrest is achieved through distinct cell-specific transcriptional regulatory mechanisms. 915 17

D-type cyclin/cyclin-dependent kinase (CDK) complexes regulate transit through the restriction point of the cell cycle, and thus are required for the initiation of DNA synthesis. Transgenic mice which overexpress cyclin D1 in the heart were produced to determine if D-type cyclin deregulation would alter myocardial development. Cyclin D1 overexpression resulted in a concomitant increase in CDK4 levels in the adult myocardium, as well as modest increases in proliferating cell nuclear antigen and CDK2 levels. Flow cytometric and morphologic analyses of dispersed cell preparations indicated that the adult transgenic cardiomyocytes had abnormal patterns of multinucleation. Histochemical analyses confirmed a marked increase in number of cardiomyocyte nuclei in sections prepared from the transgenic mice as compared with those from control animals. Tritiated thymidine incorporation analyses revealed sustained cardiomyocyte DNA synthesis in adult transgenic hearts.
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PMID:Cyclin D1 overexpression promotes cardiomyocyte DNA synthesis and multinucleation in transgenic mice. 916 94

Interleukin-6 (IL-6) is a growth factor for multiple myeloma (MM) cells and can inhibit MM cell apoptosis. Our recent studies show that IL-6 facilitates MM cell growth via phosphorylation of retinoblastoma protein (pRB); however, the effects of IL-6 on those cyclins, cyclin-dependent kinases (CDKs), and CDK inhibitors (CDIs) that are known to regulate phosphorylation of pRB have not been defined in MM cells. In the present report, we cultured MM cell lines and patient cells with IL-6 and/or dexamethasone (Dex) and characterized changes in cell cycle; expression and association of cyclins, CDKs, and CDIs; and phosphorylation of pRB. Dex induced G1 growth arrest in MM cells, whereas IL-6 facilitated G1 to S phase transition; moreover, the effect of Dex was blocked by IL-6. p21WAF1 (p21) protein was constitutively expressed in the majority of MM cells independent of the status of p53. Its expression was upregulated by Dex and downregulated by IL-6; again, IL-6 inhibited the increase in p21 triggered by Dex. These alterations in p21 expression in MM cells were associated with changes in p21 binding to CDK2, CDK4, and CDK6; CDK2, CDK4, and CDK6 kinase activities; and phosphorylation of pRB. In contrast, expression of G1 cell cycle regulatory proteins, including p27KIP1, cyclin D2, and cyclin E, was not altered in MM cells cultured with Dex and/or IL-6. Finally, interferon-gamma (IFN-gamma) also induced G1 growth arrest and upregulated p21 protein expression; as with Dex, affects of IFN-gamma were inhibited by IL-6. Our results therefore show that changes in cell cycle distribution in MM cells triggered by Dex, IL-6, and IFN-gamma correlate with changes in p21 protein expression and implicate p21 in the coupling of Dex-, IL-6-, and IFN-gamma-related signals to G1 cell cycle regulation in MM cells.
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PMID:Interleukin-6 overcomes p21WAF1 upregulation and G1 growth arrest induced by dexamethasone and interferon-gamma in multiple myeloma cells. 920 63


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