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)

Activins, members of the transforming growth factor-beta family, have been implicated in the regulation of growth and differentiation of various types of cells. We have recently found that activin A induces apoptotic cell death of plasmacytic cells including B cell hybridoma cells and myeloma cells. In the present study, we demonstrated that activin A caused cell-cycle arrest in the G1 phase before appearance of apoptotic cells in mouse B cell hybridoma cells. Phosphorylation of retinoblastoma protein (Rb) and in vitro Rb kinase activity of cyclin-dependent kinase (CDK)4 was inhibited in activin A-treated cells. Analysis of expression of genes regulating Rb phosphorylation revealed that activin A suppressed cyclin D2, the sole D-type cyclin gene expressed in the hybridoma cells, and activated p21CIP1/WAF1 but had no effect on expression of cyclin-dependent kinases (CDK2, CDK4, CDK6) and other CDK inhibitors (p27KIP1, p16INK4a, p15INK4b). Modulation of cyclin D2 and p21CIP1/WAF1 expression resulted in a decrease in level of cyclin D2-CDK4 complex and an increase in level of CDK4 complexed with p21CIP1/WAF1. Moreover, overexpression of cyclin D2 partially abrogated inhibition of Rb phosphorylation and G1 arrest in the hybridoma cells.
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PMID:Activin A induction of cell-cycle arrest involves modulation of cyclin D2 and p21CIP1/WAF1 in plasmacytic cells. 921 52

We have cloned an alternatively spliced form of cyclin-dependent kinase (CDK) inhibitor p15 from human placenta. The alternative splice arises from an alternative 5' donor site in intron 1. An in-frame stop codon within the new exon, called exon 1beta, leads to translation of a Mr 10,000 protein identical to the NH2 terminus of p15 but contains a novel, basic COOH terminus. The alternatively spliced form, termed here as p10, is ubiquitously expressed in normal and tumor cell lines as shown by Northern hybridization and reverse transcription-PCR. Transforming growth factor beta1 induces the expression of p10 similarly to p15 in human HaCaT keratinocytes. Expression and analysis of p15 and epitope-tagged p10 in cells by immunohistochemistry showed similar localization of both to the cytoplasm and nucleus in mink epithelial cells and cytoplasmic localization in mouse fibroblasts. Analysis of the effects of p10 and p15 on cell growth indicated that both were transiently growth inhibitory in Mv1Lu and NIH 3T3 cells, but their stable expression did not significantly reduce the number of cell colonies. In contrast to p15, CDK4 and CDK6 did not coimmunoprecipitate p10 in transient expression assays in COS-7 cells. Furthermore, overexpression of p10 together with p15 in COS-7 cells did not interfere with the complex formation of p15 with CDK4 or CDK6. Thus, in the absence of detectable CDK binding, p10 is transiently able to restrain cell cycling, indicating that the alternative splicing of the CDK inhibitors presents further complexity in their regulation and functions.
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PMID:Cloning and characterization of p10, an alternatively spliced form of p15 cyclin-dependent kinase inhibitor. 923 Feb 10

It is well documented that Ras functions as a molecular switch for reentry into the cell cycle at the border between G0 and G1 by transducing extracellular growth stimuli into early G1 mitogenic signals. In the present study, we investigated the role of Ras during the late stage of the G1 phase by using NIH 3T3 (M17) fibroblasts in which the expression of a dominant negative Ras mutant, p21(Ha-Ras[Asn17]), is induced in response to dexamethasone treatment. We found that delaying the expression of Ras(Asn17) until late in the G1 phase by introducing dexamethasone 3 h after the addition of epidermal growth factor (EGF) abolished the downregulation of the p27kip1 cyclin-dependent kinase (CDK) inhibitor which normally occurred during this period, with resultant suppression of cyclin Ds/CDK4 and cyclin E/CDK2 and G1 arrest. The immunodepletion of p27kip1 completely eliminated the CDK inhibitor activity from EGF-stimulated, dexamethasone-treated cell lysate. The failure of p27kip1 downregulation and G1 arrest was also observed in cells in which Ras(Asn17) was induced after growth stimulation with a phorbol ester or alpha-thrombin and was mimicked by the addition late in the G1 phase of inhibitors for phosphatidylinositol-3-kinase. Ras-mediated downregulation of p27kip1 involved both the suppression of synthesis and the stimulation of the degradation of the protein. Unlike the earlier expression of Ras(Asn17) at the border between G0 and G1, its delayed expression did not compromise the EGF-stimulated transient activation of extracellular signal-regulated kinases or inhibit the stimulated expression of a principal D-type cyclin, cyclin D1, until close to the border between G1 and S. We conclude that Ras plays temporally distinct, phase-specific roles throughout the G1 phase and that Ras function late in G1 is required for p27kip1 downregulation and passage through the restriction point, a prerequisite for entry into the S phase.
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PMID:Ras activity late in G1 phase required for p27kip1 downregulation, passage through the restriction point, and entry into S phase in growth factor-stimulated NIH 3T3 fibroblasts. 927 12

Cytokines are growth inhibitory in a target cell specific manner. The signaling pathways that characterize each cell type play a crucial role in determining the responsiveness to cytokine triggering. Activin A has been shown to suppress the growth of primary hepatocytes. Similarly, the human HepG2 hepatoma cell line was growth arrested by activin A as judged by lack of cell proliferation and suppression of DNA synthesis. In HepG2 cells activin A further induced accumulation of retinoblastoma protein in the hypophosphorylated form known to prevent entrance into S phase. This finding implies the involvement of cyclin dependent kinases and CDK inhibitors. Examination of HepG2 cells following addition of activin A revealed reduced expression of CDK4 and conversely, an increase in the CKI p21(WAF1/Cip1). This accumulation of p21(WAF1/Cip1) protein was partly due to increased transcriptional activity. Functional inactivation of p53, using a miniprotein that oligomerizes with p53 and abrogates DNA binding, abolished the ability of activin A to induce transcriptional activation from the p21(WAF1/Cip1) promoter. Thus, activin A, like transforming growth factor beta, seems to suppress cell growth through the downstream target Rb. However, each of these cytokines seem to operate through a distinct pathway.
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PMID:Involvement of p21(WAF1/Cip1), CDK4 and Rb in activin A mediated signaling leading to hepatoma cell growth inhibition. 934 4

Cyclins contain two characteristic cyclin folds, each consisting of five alpha-helical bundles, which are connected to one another by a short linker peptide. The first repeat makes direct contact with cyclin-dependent kinase (CDK) subunits in assembled holoenzyme complexes, whereas the second does not contribute directly to the CDK interface. Although threonine 156 in mouse cyclin D1 is predicted to lie at the carboxyl terminus of the linker peptide that separates the two cyclin folds and is buried within the cyclin subunit, mutation of this residue to alanine has profound effects on the behavior of the derived cyclin D1-CDK4 complexes. CDK4 in complexes with mutant cyclin D1 (T156A or T156E but not T156S) is not phosphorylated by recombinant CDK-activating kinase (CAK) in vitro, fails to undergo activating T-loop phosphorylation in vivo, and remains catalytically inactive and unable to phosphorylate the retinoblastoma protein. Moreover, when it is ectopically overexpressed in mammalian cells, cyclin D1 (T156A) assembles with CDK4 in the cytoplasm but is not imported into the cell nucleus. CAK phosphorylation is not required for nuclear transport of cyclin D1-CDK4 complexes, because complexes containing wild-type cyclin D1 and a CDK4 (T172A) mutant lacking the CAK phosphorylation site are efficiently imported. In contrast, enforced overexpression of the CDK inhibitor p21Cip1 together with mutant cyclin D1 (T156A)-CDK4 complexes enhanced their nuclear localization. These results suggest that cyclin D1 (T156A or T156E) forms abortive complexes with CDK4 that prevent recognition by CAK and by other cellular factors that are required for their nuclear localization. These properties enable ectopically overexpressed cyclin D1 (T156A), or a more stable T156A/T286A double mutant that is resistant to ubiquitination, to compete with endogenous cyclin D1 in mammalian cells, thereby mobilizing CDK4 into cytoplasmic, catalytically inactive complexes and dominantly inhibiting the ability of transfected NIH 3T3 fibroblasts to enter S phase.
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PMID:A dominant-negative cyclin D1 mutant prevents nuclear import of cyclin-dependent kinase 4 (CDK4) and its phosphorylation by CDK-activating kinase. 937 67

Growth of prostatic epithelial cells is androgen-dependent; however, the mechanism of androgen action on cell growth is not well defined. We investigated whether androgen-dependent prostatic epithelial cell growth is mediated by androgen regulation of expression of genes controlling cell cycle progression. For this purpose, we used an androgen-dependent prostatic cancer cell line, LNCaP-FGC, as an in vitro model. We found that expression of CDK2 and CDK4 genes were up-regulated within hours of androgen treatment as detected in Northern and Western blot analyses. Kinase assay also confirmed that there was increased CDK2 kinase activity upon androgen stimulation. Moreover, androgen down-regulated expression of the cyclin-dependent kinase inhibitor p16 (MTS1, CDKN2) gene. The overall effects of these androgen actions result in an increased cyclin-dependent kinase activity and stimulation of the cell to enter S phase of the cell cycle, thereby enhancing cell proliferation. In contrast, an androgen-independent PC-3 cell line lost its response to androgen stimulation, and higher basal levels of CDK2, CDK4, and p16 genes were constitutively expressed in PC-3 cells. Collectively, these data suggest a possible signaling pathway of androgen in stimulating cell growth. These results also imply that in androgen-dependent prostate cancer, increased androgen receptor (AR) activity, resulting from AR gain-of-function mutations, AR gene amplification, or AR gene overexpression, malignantly stimulates proliferation of prostatic epithelial cells and constitutes one possible mechanism of androgen-dependent tumorigenesis.
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PMID:Regulation of androgen-dependent prostatic cancer cell growth: androgen regulation of CDK2, CDK4, and CKI p16 genes. 937 62

Small DNA viruses (adenoviruses, simian virus 40, or human papillomaviruses) induce S-phase progression but prevent cell division to provide precursors for viral DNA replication. Herpes simplex viruses types 1 or 2 (HSV-1 or HSV-2) contain genes which encode DNA-metabolizing enzymes, for example, ribonucleotide reductase, thymidine kinase and dUTPase, suggesting that S-phase factors are not required for an efficient infection. However, several studies indicated that HSV induces some events that occur during cell-cycle progression. To determine if HSV-2 induces S-phase entry, we examined serum-arrested African green monkey kidney cells (CV-1) after infection. Two hours after infection steady-state levels of the S-phase-specific cyclin, cyclin A, increased. S-phase cyclin-dependent kinase activity (CDK2) was stimulated 10-fold 8 h after infection but decreased at 16 or 24 h after infection. Mitotic CDK activity (CDC2) was not activated after infection, in part due to decreases in CDC2 protein levels and inactivation of enzymatic activity resulting from tyrosine phosphorylation of CDC2. Furthermore, CDK4 activity was not dramatically affected by infection. These studies indicate that HSV-2 infection selectively activates CDK2 after infection but cell-cycle progression does not occur. We hypothesize that infection activates certain components of the cell cycle which enhance viral gene expression and DNA replication.
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PMID:Analysis of cyclin-dependent kinase activity after herpes simplex virus type 2 infection. 940 Sep 86

The cyclin-dependent kinases (CDKs) promote cell cycle transitions in mammalian cells by phosphorylation of key substrates. To characterize substrates of the G1 and S phase cyclin-CDK complexes, including cyclin D1-CDK4, cyclin D3-CDK4, cyclin D3-CDK6, cyclin E-CDK2, and cyclin A-CDK2, which are largely undefined, we phosphorylated T-47D breast cancer cell nuclear lysates partially purified by ion-exchange chromatography with purified baculovirus expressed cyclin-CDK complexes. A comparison of the substrates that were phosphorylated by the different cyclin D-CDKs revealed some common as well as specific substrates. Hence, cyclin D1-CDK4 specifically phosphorylated a 38-kDa protein while cyclin D3-CDK4 specifically phosphorylated proteins of 105, 102, and 42 kDa. A 24-kDa protein was phosphorylated by both complexes. Cyclin D3-CDK6 exhibited similar substrate preferences to cyclin D3-CDK4, phosphorylating the 105- and 102-kDa proteins but not the 24-kDa protein. Hence, both the cyclin D1 and D3 as well as CDK4 and CDK6 subunits can confer substrate specificity on the overall cyclin D-CDK complex. Cyclin E-CDK2 and cyclin A-CDK2 phosphorylated a greater number of substrates than the cyclin D-CDKs, ranging in size from 10 kDa to over 200 kDa. Twenty-two substrates were common to both complexes, while six were specific for cyclin A-CDK2 and only one protein of 34 kDa was specific for cyclin E-CDK2. These studies indicate that cyclins E and A modulate the specificity of CDK2 and have demonstrated substrates that may be important for the specific roles of these cyclin-CDKs during G1 and S phase progression. Protein sequencing of one of the cyclin-CDK substrates characterized in this study identified this protein as nucleolin, a previously characterized CDC2 (CDK1) substrate, thus indicating the utility of this approach in identifying cyclin-CDK targets. These results show that both the cyclin and CDK subunits can regulate the substrate specificity of the overall cyclin-CDK complex and have demonstrated numerous substrates of D-, E-, and A-type cyclin-CDK complexes potentially involved in regulating transit through the G1 and S phases of the cell cycle.
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PMID:Differential phosphorylation of T-47D human breast cancer cell substrates by D1-, D3-, E-, and A-type cyclin-CDK complexes. 940 25

Tyr-Phe and Met limitation in vitro inhibited cell proliferation and proliferating cell nuclear antigen (PCNA) expression to a greater extent than serum limitation. Tyr-Phe and serum limitation arrested cells in the G0/G1 phase; Met limitation blocked cells in the G0/G1 and S phases. Tyr-Phe limitation progressively decreased cyclin D1 expression to 30% of control within four days and did not affect expression of cyclin D3 or cyclin-dependent kinase (CDK2, CDK4, and CDK5) expression, Met limitation decreased cyclin D3 expression to 25% of control and CDK2 expression to 32% of control by Day 4 and did not affect expression of cyclin D1, CDK4, and CDK5. Serum limitation inhibited cyclin D1 and cyclin D3 expression to 24% of control after four days and did not effect CDK expression. Expression of two CDK inhibitors, p21WAF1/Cip1 and p27Kip1, was not changed by amino acid or serum limitation. Dietary restriction of Tyr-Phe in mice bearing subcutaneous B16BL6 melanoma tumors decreased tumor growth rate compared with mice fed a normal diet. Tumors from Tyr-Phe-restricted mice exhibited decreased PCNA expression, G0/G1 phase cell cycle arrest, and reduced cyclin D1 expression. These data indicate that decreased tumor growth in vivo associated with dietary restriction of Tyr and Phe is cell cycle specific.
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PMID:Tyrosine and phenylalanine restriction induces G0/G1 cell cycle arrest in murine melanoma in vitro and in vivo. 942 72

The alpha 5 alpha 1 integrin, a fibronectin receptor, has been implicated in the control of cell growth and the regulation of gene expression. We report that disruption of ligation between alpha 5 alpha 1 and fibronectin by integrin alpha 5 subunit or fibronectin monoclonal antibodies stimulated DNA synthesis in growth-arrested FET human colon carcinoma cells. This stimulation only occurred when monoclonal antibody was added in the early G1 phase of the cell cycle after release from quiescence by fresh medium. Stimulation of DNA synthesis by alpha 5 or fibronectin antibody was concentration- and time-dependent. FET cells expressed alpha 4 beta 1 integrin (another fibronectin receptor); however, addition of anti-human integrin alpha 4 monoclonal antibody had no effect on DNA synthesis. Treatment with alpha 5 monoclonal antibody led to a marked increase in the expression of CDK4 in G1 phase of the cell cycle and consequently increased the phosphorylation of retinoblastoma protein. alpha 5 monoclonal antibody treatment increased both cyclin A- and cyclin E-associated kinase activity which was accompanied by increased protein levels of CDK2 and cyclin A. Western blotting of immunoprecipitates demonstrated increased CDK2-cyclin E and CDK2-cyclin A complexes in cells treated with alpha 5 monoclonal antibody. Furthermore, disruption of alpha 5 alpha 1/fibronectin ligation activated mitogen-activated protein kinase p44 and p42 (extracellular signal-regulated kinase 1 and 2). Pretreatment of the cells with a specific inhibitor of MEK-1, PD98059, blocked the alpha 5 monoclonal antibody-induced mitogen-activated protein kinase activity. In addition PD98059 prevented alpha 5 monoclonal antibody-induced DNA synthesis. Since alpha 5 alpha 1 ligation to fibronectin is associated with decreased growth parameters, our results indicate that ligation of alpha 5 alpha 1 integrin to fibronectin results in suppressed mitogen-activated protein kinase activity which in turn inhibits cyclin-dependent kinase activity in growth-arrested cells.
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PMID:Disruption of fibronectin binding to the alpha 5 beta 1 integrin stimulates the expression of cyclin-dependent kinases and DNA synthesis through activation of extracellular signal-regulated kinase. 943 Jul 10


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