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

---

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

It was recently demonstrated that ectopic expression of cyclin D1 inhibits skeletal muscle differentiation and, conversely, that expression of cyclin-dependent kinase (cdk) inhibitors facilitates activation of this differentiation program (S. S. Rao, C. Chu, and D. S. Kohtz, Mol. Cell. Biol. 14:5259-5267, 1994; S. S. Rao and D. S. Kohtz, J. Biol. Chem. 270:4093-4100, 1995; S. X. Skapek, J. Rhee, D. B. Spicer, and A. B. Lassar, Science 267:1022-1024, 1995). Here we demonstrate that cyclin D1 inhibits muscle gene expression without affecting MyoD DNA binding activity. Ectopic expression of cyclin D1 inhibits muscle gene activation by both MyoD and myogenin, including a mutated form of myogenin in which two potential inhibitory cdk phosphorylation sites are absent. Because the retinoblastoma gene product, pRB, is a known target for cyclin D1-cdk phosphorylation, we determined whether cyclin D1-mediated inhibition of myogenesis was due to hyperphosphorylation of pRB. In pRB-deficient fibroblasts, the ability of MyoD to activate the expression of muscle-specific genes requires coexpression of ectopic pRB (B. G. Novitch, G. J. Mulligan, T. Jacks, and A. B. Lassar, J. Cell Biol., 135:441-456, 1996). In these cells, the expression of cyclins A and E can lead to pRB hyperphosphorylation and can inhibit muscle gene expression. The negative effects of cyclins A or E on muscle gene expression are, however, reversed by the presence of a mutated form of pRB which cannot be hyperphosphorylated. In contrast, cyclin D1 can inhibit muscle gene expression in the presence of the nonhyperphosphorylatable form of pRB. On the basis of these results we propose that G1 cyclin-cdk activity blocks the initiation of skeletal muscle differentiation by two distinct mechanisms: one that is dependent on pRB hyperphosphorylation and one that is independent of pRB hyperphosphorylation.
...
PMID:Cyclin-mediated inhibition of muscle gene expression via a mechanism that is independent of pRB hyperphosphorylation. 894 59

The retinoblastoma gene product (RB protein) plays a key role in the progression of the cell cycle from G1 to S phase in normal and neoplastic cells. The activity of RB is regulated by phosphorylation and dephosphorylation with cell-cycle-dependent protein kinases. We investigated the effect of the protein kinase inhibitors, staurosporine and 7-hydroxy-staurosporine (UCN-01), on RB protein expression of N417 small cell lung cancer cells (absent RB), H209 small cell lung cancer cells (mutant RB), and Ma-31 non-small cell lung cancer cells (wild-type RB), using immunologic blotting. Staurosporine and UCN-01 each suppressed the growth of N417, H209 and Ma-31 cells in a dose-dependent manner in MTT assay. IC50 values of staurosporine for N417, H209 and Ma-31 cells were 54, 29 and 602 nM, respectively. IC50 values of UCN-01 for N417, H209 and Ma-31 cells were 737, 181 and 2,197 nM, respectively. Exposure to staurosporine and UCN-01 for 72 h each suppressed the level of expression and altered the ratio of phosphorylated/dephosphorylated RB protein (ppRB/pRB) of Ma-31 cells. Conversely, these agents increased the expression level of RB protein at concentrations less than IC50, and did not change phosphorylation status of mutant RB protein of H209 cells at the concentrations studied. A time course study demonstrated that exposure to the IC50 concentration of staurosporine for 48-72 h increased the ratio of ppRB/ pRB of Ma-31 cells, while exposure to the IC50 concentration of UCN-01 decreased that ratio. UCN-01 increased % cells in G2 + M phase and decreased % cells in S phase, while staurosporine increased % cells in G1 phase and decreased % cells in G2 + M phase. UCN-01 did not induce apoptosis (DNA content < 2 N) of Ma-31 cells, but staurosporine induced it. These findings suggest that the differing effects of staurosporine and UCN-01 on RB protein expression and cell cycle phases of lung cancer cells may explain their differing in vivo antitumor effect of staurosporine and UCN-01 despite their similar chemical structures.
...
PMID:Differing effects of staurosporine and UCN-01 on RB protein phosphorylation and expression of lung cancer cell lines. 896 Jan 46

We postulated that contact inhibition and transforming growth factor (TGF)-beta 1 may target the same molecules to negatively regulate the Mv1Lu cell cycle in G0/G1. Both contact inhibition and TGF-beta 1 suppressed the expression of a 45-kDa protein (p45); cyclins D2 and B1; cyclin-dependent protein kinase (Cdk)-4, Cdc-2, and Cdc-2-associated activity; and the phosphorylation of retinoblastoma tumor-suppressor protein (pRb) but did not affect the expression of cyclins D1, E, and A or the expression of Cdk-2 and Cdk-5. Expression of p45 reappeared 12 h after release from contact inhibition and 6-8 h after release from TGF-beta 1, while TGF-beta 1 prevented release from contact inhibition and maintained suppression of both p45 and cyclin D2. Additionally, cyclin D2 phosphorylation and its associated kinase activity were strongly inhibited by contact inhibition and TGF-beta 1. Thus suppression of p45, cyclin D2/Cdk-4, and cyclin B1/Cdc-2 expression and/or activities is targeted both by contact inhibition and by TGF-beta 1 and may define common mechanisms through which these negative growth signals are integrated.
...
PMID:Cell cycle arrest in G0/G1 phase by contact inhibition and TGF-beta 1 in mink Mv1Lu lung epithelial cells. 896 24

Understanding the growth constraints imposed on normal human melanocytes may help to elucidate the processes conferring growth advantage to melanoma cells. Several synergistic growth factors have been identified for normal human melanocytes. They include fibroblast growth factors (FGF), hepatocyte growth factor/scatter factor, mast/stem cell growth factor, and the neuropeptides endothelin-1, 2 and 3 (ET-1, ET-2, ET-3). From this group of peptides, only basic FGF (bFGF/FGF2) appears, so far, to play a role in autonomous growth of melanoma cells. Aberrant expression of FGF2 is due to activation of an otherwise repressed gene by a mechanism that may involve the transcriptional activity of wild-type p53. The growth factors and activated receptors aberrantly expressed in melanoma cells act in concert with molecules that control cell cycle progression. These proteins bind to, and regulate cyclin-dependent kinase (CDK), such as CDK4, responsible for phosphorylation of retinoblastoma (RB) and dissociation of RB-E2F1 inhibitory complexes, thereby allowing progression through the cell cycle. Constitutive CDK4 activity in melanomas may be the results of inactivation of the negative regulators known as CDK inhibitor p16INK4, and/or p21; and/or overexpression of cyclin D, the positive CDK4 regulator. This complex set of changes in melanoma cells can lift growth constraints by inducing unregulated expression of genes promoting transition from GI to S phase of the cell cycle.
...
PMID:Growth factors and melanomas. 897 May 86

Cyclin E is an important regulator of cell cycle progression that together with cyclin-dependent kinase (cdk) 2 is crucial for the G1/S transition during the mammalian cell cycle. Previously, we showed that severe overexpression of cyclin E protein in tumor cells and tissues results in the appearance of lower molecular weight isoforms of cyclin E, which together with cdk2 can form a kinase complex active throughout the cell cycle. In this study, we report that one of the substrates of this constitutively active cyclin E/cdk2 complex is retinoblastoma susceptibility gene product (pRb) in populations of breast cancer cells and tissues that also overexpress p16. In these tumor cells and tissues, we show that the expression of p16 and pRb is not mutually exclusive. Overexpression of p16 in these cells results in sequestering of cdk4 and cdk6, rendering cyclin D1/cdk complexes inactive. However, pRb appears to be phosphorylated throughout the cell cycle following an initial lag, revealing a time course similar to phosphorylation of glutathione S-transferase retinoblastoma by cyclin E immunoprecipitates prepared from these synchronized cells. Hence, cyclin E kinase complexes can function redundantly and replace the loss of cyclin D-dependent kinase complexes that functionally inactivate pRb. In addition, the constitutively overexpressed cyclin E is also the predominant cyclin found in p107/E2F complexes throughout the tumor, but not the normal, cell cycle. These observations suggest that overexpression of cyclin E in tumor cells, which also overexpress p16, can bypass the cyclin D/cdk4-cdk6/p16/pRb feedback loop, providing yet another mechanism by which tumors can gain a growth advantage.
...
PMID:Cyclin E, a redundant cyclin in breast cancer. 898 90

Abnormalities of several cell-cycle regulatory genes including cyclin D1, p16CDKN2 and p15CDKN2B have been described in B cell non-Hodgkin's lymphoma (B-NHL). We describe a new B-NHL cell line (Granta 519), with concurrent abnormalities of the cyclin D1, pl6CDKN2 and pl5CDKN2B genes. An independent clinical case of mantle cell NHL (Mc-NHL) with concomitant overexpression of cyclin D1, and deletion of the p16CDKN2 gene was also identified, suggesting that this combination of oncogenic aberration is a pathophysiologic contribution to a subset of NHL cases. More in-depth functional studies of this concept were facilitated by the availability of the cell line Granta 519 which was derived from a case of high-grade NHL and has a mature B cell immunophenotype. Cytogenetic analysis identified translocation t(11;14)(q13;q32) and complex rearrangements involving chromosomes 9p22, 13p21, 17pl1, and 18q21. Molecular analysis identified overexpression of cyclin D1 mRNA and biallelic deletion of the p16CDKN2 and p15CDKN2B genes. To elucidate the effect of these genetic abnormalities on the G1 control of Granta 519 cells, the level and function of the major components of the cyclinD/retinoblastoma (RB) pathway were investigated. Cyclin D1 was dominant among the D-type cyclins, formed abundant complexes with cyclin-dependent kinase (Cdk) Cdk4 rather than Cdk6, and the immunoprecipitated cyclin D1/Cdk4 holoenzyme was active as a pRB kinase. Electroporation of wild-type pl6CDKN2 arrested the Granta 519 cells in G1, consistent with the p16CDKN2 loss as a biologically relevant event during multistep evolution of the tumor, and with the expression of functional pRB. Direct cooperation of these distinct abnormalities to cell-cycle, deregulation in NHL cells was suggested by G1 acceleration upon inducible overexpression of cyclin D1 in a control breast cancer cell line lacking p16CDKN2, an effect which could be prevented by ectopic expression of p16CDKN2. Taken together, these data suggest that concurrent overexpression of cyclin D1 and functional elimination of p16CDKN2 and p15CDKN2B may characterize certain cases of mantle cell NHL, and that cooperation of the abnormalities is likely to provide a growth advantage of the tumour cells through more efficient inactivation of the RB tumor suppressor. Further clinicopathologic studies of this possibility are warranted.
...
PMID:Potential role for concurrent abnormalities of the cyclin D1, p16CDKN2 and p15CDKN2B genes in certain B cell non-Hodgkin's lymphomas. Functional studies in a cell line (Granta 519). 900 20

PITALRE is a human protein kinase belonging to the cell division cycle 2 (CDC2) kinase family, and is the catalytic subunit of a multimeric complex that contains several cellular proteins. PITALRE complexes from several cell lines and tissues phosphorylate retinoblastoma protein and myelin basic protein (MBP). In the present work, we have found that MBP is phosphorylated by PITALRE complexes on both Ser and Thr residues. Two different antibodies raised to PITALRE purified virtually identical kinase activities, as analysed by MBP phosphopeptide mapping and phosphoamino acid analysis. We have identified the proline-directed residue Ser-162 of MBP as a major phosphorylation site for PITALRE. In addition, our results suggest that one of the two MBP proline-directed threonine residues, Thr-97, is also selectively phosphorylated by PITALRE. These data, together with analysis of different peptide substrates derived from sites on MBP that are phosphorylated by PITALRE, indicate that PITALRE is a Ser/Thr proline-directed kinase. In addition, our results show that PITALRE has a substrate site specificity distinguishable from those of the CDC2 and cyclin-dependent kinase 2 (CDK2).
...
PMID:Phosphorylation site specificity of the CDC2-related kinase PITALRE. 900 89

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.
...
PMID:Inhibition of G1 cyclin expression in normal rat kidney cells by inostamycin, a phosphatidylinositol synthesis inhibitor. 901 Jul 59

Among the p53-regulated genes that have been identified thus far, cyclin G is a relatively recent one. We conducted a series of experiments aimed at elucidating cyclin G function. Ectopic overexpression of cyclin G in human RKO colon carcinoma cells accelerated cell growth. Transfection of normal human fibroblasts with the cyclin G expression vector promoted clonal expansion. Cyclin G immune complexes isolated from the transfected cells exhibited appreciable levels of cyclin-dependent kinase activity, as evidenced using histone H1 as a substrate. The retinoblastoma protein, pRb, was detectable in cyclin G immune complexes, raising the possibility that Rb may be one mediator of cyclin G action. Cyclin G-overexpressing cells were more sensitive to cisplatin cytotoxicity than the parent cells, probably because cyclin G overexpression overrides cell cycle checkpoint(s). Overexpression of another p53-regulated gene, GADD45, by contrast, protected cells from cisplatin killing. These findings suggest that different downstream effectors of the p53 pathway may exert different effects on cellular survival after treatment with cancer chemotherapy drugs such as cisplatin.
...
PMID:The p53-regulated cyclin G gene promotes cell growth: p53 downstream effectors cyclin G and Gadd45 exert different effects on cisplatin chemosensitivity. 901 7

Estrogens play a critical role in the etiology of found breast cancer. Estradiol promotes the growth of breast cancer cells in vivo and in vitro. Exogenous estrogens in both the environment and in the human diet increase the growth of breast cancer cells in vitro. A role for xenoestrogens in breast cancer etiology has been proposed but remains controversial. We examined the effects of the xenoestrogenic pesticide 1,1,1-trichloro-2,2-bis(chlorophenyl)ethane (DDT) on estrogen-receptor (ER)-positive MCF-7 and T-47D human breast cancer cells as well as on ER-negative HS 578Bst breast cancer cells and rat liver cells. Estradiol and DDT were found to increase the growth of MCF-7 cells in the presence of insulin. The activity of cyclin-dependent kinase (Cdk)2 increased in growth-arrested T-47D and MCF-7 cells treated with beta-estradiol or DDT. The steroidal antiestrogen ICI 182,780 prevented both growth and Cdk2 activation induced by estradiol or DDT. Increased phosphorylation of Cdk2 and the retinoblastoma protein (pRb1O5) was observed in ER-positive cells treated with DDT or estradiol. Cdk2 activity was not affected by DDT or estradiol in ER-negative HS 578Bst breast cancer cells or in rat liver epithelial cells. Cyclin D1 protein synthesis was increased by DDT and estradiol in MCF-7 cells. DDT and estradiol-induced ER-dependent transcriptional activation of estrogen response elements (EREs) in stably transfected MVLN cells, and ERE activation by low doses of DDT was increased by insulin. These findings suggest that DDT can stimulate breast cancer cells to enter into the cell cycle by directly affecting key regulatory elements. The relative potency of DDT in inducing cell-cycle progression appears to be only 100-300 times less than that of estradiol when measured in the presence of insulin. Therefore, the cancer risks associated with DDT exposure may be greater than first thought, especially when additional mitogenic stimuli are present.
...
PMID:DDT mimicks estradiol stimulation of breast cancer cells to enter the cell cycle. 904 86


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---