Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.22 (cdc2)
 8,319 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Restenosis after percutaneous transluminal coronary angioplasty (PTCA) and coronary stenting remains a major clinical problem. Vascular smooth muscle cell (SMC) proliferation and migration from the arterial wall media into the intima are believed to play a critical role in the pathogenesis of restenosis. Several studies have demonstrated that phosphorothioate (PS) oligodeoxynucleotides targeted against genes involved in SMC proliferation inhibit in vitro SMC proliferation and migration. Moreover, PS oligodeoxynucleotides targeted against the genes c-myb, c-myc, cdc2 kinase, cdk2 kinase, and proliferating cell nuclear antigen (PCNA) when delivered adventitially or intraluminally inhibit in vivo neointimal formation after balloon injury in both the rat carotid and porcine coronary artery models. The inhibitory effects of these PS oligodeoxynucleotides may be the result of their suppression of migration of medial SMC rather than suppression of medial or intimal cell proliferation. Other studies have demonstrated the presence of the potent guanosine or G-quartet aptameric inhibitory effect of the PS oligodeoxynucleotides. Experiments with cytidine homopolymers such as S-dC28, which lack guanosines, reveal the presence of potent non-G-quartet, non-sequence-specific inhibitory effects on in vitro SMC proliferation, migration, and adhesion as well as in vivo neointimal formation after rat carotid artery balloon injury. This is owing to the avid binding of these PS oligodeoxynucleotides to the SMC mitogens and chemoattractants platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF). The extent to which hybridization-dependent antisense, G-quartet aptameric, or non-G-quartet, non-sequence-specific inhibitory effects occurs is the result of PS oligodeoxynucleotide sequence, length, and concentration. The 18-mer guanosine-rich PS oligodeoxynucleotide ZK10 is a more potent in vitro SMC proliferation inhibitor than S-dC28, although both compounds manifest comparable in vivo inhibitory effects on neointimal formation in the rat carotid artery model of balloon injury. PS oligodeoxynucleotides also possess non-sequence-specific immunomodulatory effects, including the induction of interferon-gamma and the unmethylated CpG motif, which exhibits numerous immunomodulatory effects. Novel strategies to inhibit restenosis include the development of E2F transcription decoys that inhibit several cell cycle regulatory genes and diminish neointimal lesion formation. In addition, antisense oligonucleotides targeted against the anti-apoptotic gene bcl-xL, which when transfected into the vessel wall inhibits bcl-xl expression, induce a five-fold increase in apoptotic SMC intimal cells, and effect a marked attenuation of in vivo lesion dimensions, thereby suggesting frank vascular lesion regression.
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PMID:Antisense strategies to inhibit restenosis. 1055 57

Large increases in cAMP concentration inside the cell are generally growth inhibitory for most cell lines of mesenchymal and epithelial origin. Moreover, recent data suggest a role of cAMP in survival of different cell types. Herein, the ability of forskolin (an adenylyl cyclase activator) and IBMX (3-isobutyl-1-methylxanthine) (a phosphodiesterase inhibitor) to modulate cell cycle progression and survival of human pancreatic cancer cells was evaluated. We showed that forskolin + IBMX inhibited serum-induced ERK activities, Rb hyperphosphorylation, Cdk2 activity, and p27(Kip1) downregulation and caused G1 arrest in MIA PaCa-2 cells. Furthermore, forskolin + IBMX protected pancreatic cells against apoptosis induced by prolonged inhibition of ERK activities by preventing Bcl-X(L) downregulation, activation of caspases 3, 6, 8, and 9, and PARP cleavage and by inducing Bad phosphorylation (ser112). Taken together, our data demonstrate for the first time that cAMP is an inhibitor of cell cycle progression and apoptosis in human pancreatic cancer cells.
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PMID:cAMP protection of pancreatic cancer cells against apoptosis induced by ERK inhibition. 1144 27

Specific phosphorylation of serine- and arginine-rich pre-mRNA splicing factors (SR proteins) is one of the key determinants regulating splicing events. Several kinases involved in SR protein phosphorylation have been identified and characterized, among which human DNA topoisomerase I is known to have DNA-relaxing activity. In this study, we have investigated the mechanism of splicing inhibition by a glycosylated indolocarbazole derivative (NB-506), a potent inhibitor of both kinase and relaxing activities of topoisomerase I. NB-506 completely inhibits the capacity of topoisomerase I to phosphorylate, in vitro, the human splicing factor 2/alternative splicing factor (SF2/ASF). This inhibition is specific, because NB-506 does not demonstrate activity against other kinases known to phosphorylate SF2/ASF such as SR protein kinase 1 and cdc2 kinase. Importantly, HeLa nuclear extracts competent in splicing but not splicing-deficient cytoplasmic S100 extracts treated with the drug fail to phosphorylate SF2/ASF and to support splicing of pre-mRNA substrates containing SF2/ASF-target sequences. Native gel analysis of splicing complexes revealed that the drug affects the formation of the spliceosome, a dynamic ribonucleoprotein structure where splicing takes place. In the presence of the drug, neither pre-spliceosome nor spliceosome is formed, demonstrating that splicing inhibition occurs at early steps of spliceosome assembly. Splicing inhibition can be relieved by adding phosphorylated SF2/ASF, showing that extracts treated with NB-506 lack a phosphorylating activity required for splicing. Moreover, NB-506 has a cytotoxic effect on murine P388 leukemia cells but not on P388CPT5 camptothecin-resistant cells that carry two point mutations in conserved regions of topoisomerase I gene (Gly361Val and Asp709Tyr). After drug treatment, P388 cells accumulated hypophosphorylated forms of SR proteins and polyadenylated RNA in the nucleus. In contrast, neither SR protein phosphorylation nor polyadenylated mRNA distribution was affected in P388 CPT5-treated cells. Consistently, NB506 treatment altered the mRNA levels and/or splicing pattern of several tested genes (Bcl-X, CD 44, SC35, and Sty) in P388 cells but not in P388 CPT5 cells. The study shows for the first time that indolocarbazole drugs targeting topoisomerase I can affect gene expression by modulating pre-mRNA splicing through inhibition of SR proteins phosphorylation.
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PMID:Specific inhibition of serine- and arginine-rich splicing factors phosphorylation, spliceosome assembly, and splicing by the antitumor drug NB-506. 1155 64

Aberrant overexpression of the c-rel protooncogene is associated with lymphoid malignancy, while c-rel deletion produces severe lymphoproliferative defects and immunodeficiency. To investigate the mechanism of c-rel-induced proliferation and cell cycle progression in B lymphocytes, we have compared signaling events elicited through the BCR in c-rel-/- and wild-type B cells. BCR stimulation of c-rel-/- B cells fails to induce proper cyclin expression, resulting in G1 phase arrest, but it is unclear whether these defects are in fact secondary events of decreased B-cell survival, since c-rel deletion also affects the expression of antiapoptotic genes such as bcl-xL. Here, we use the bcl-xL transgene to correct the viability of c-rel-deficient B cells, and show that the inhibition of apoptosis does not necessarily confer hyperproliferation of B cells activated through the BCR. c-rel-/- B cells still fail to enter the S phase despite improved survival by bcl-xL overexpression, suggesting that c-Rel-associated cell cycle progression is dependent on more than just enhanced cell viability. Overexpression of cyclin E protein, however, can cooperate with Bcl-xL to restore cell cycle progression to c-rel-/- B cells via induction of the cyclin-CDK/Rb-E2F pathway. Furthermore, we show that c-Rel can directly regulate transcription of the e2f3a promoter/enhancer, which is then likely to lead to transcriptional activation of the cyclin E promoter by E2F3a. Hence, these studies provide clear evidence that control of lymphocyte proliferation via c-Rel is linked to a cyclin-dependent process, and suggest that c-Rel not only activates antiapoptotic signaling but also the induction of cell cycle progression.
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PMID:Cyclin E and Bcl-xL cooperatively induce cell cycle progression in c-Rel-/- B cells. 1462 88

Prostate cancer is the most common invasive malignancy and the second leading cause of cancer-related deaths among U.S. males, with a similar trend in many Western countries. One approach to control this malignancy is its prevention through the use of agents present in diet consumed by humans. Pomegranate from the tree Punica granatum possesses strong antioxidant and antiinflammatory properties. We recently showed that pomegranate fruit extract (PFE) possesses remarkable antitumor-promoting effects in mouse skin. In this study, employing human prostate cancer cells, we evaluated the antiproliferative and proapoptotic properties of PFE. PFE (10-100 microg/ml; 48 h) treatment of highly aggressive human prostate cancer PC3 cells resulted in a dose-dependent inhibition of cell growth/cell viability and induction of apoptosis. Immunoblot analysis revealed that PFE treatment of PC3 cells resulted in (i) induction of Bax and Bak (proapoptotic); (ii) down-regulation of Bcl-X(L) and Bcl-2 (antiapoptotic); (iii) induction of WAF1/p21 and KIP1/p27; (iv) a decrease in cyclins D1, D2, and E; and (v) a decrease in cyclin-dependent kinase (cdk) 2, cdk4, and cdk6 expression. These data establish the involvement of the cyclin kinase inhibitor-cyclin-cdk network during the antiproliferative effects of PFE. Oral administration of PFE (0.1% and 0.2%, wt/vol) to athymic nude mice implanted with androgen-sensitive CWR22Rnu1 cells resulted in a significant inhibition in tumor growth concomitant with a significant decrease in serum prostate-specific antigen levels. We suggest that pomegranate juice may have cancer-chemopreventive as well as cancer-chemotherapeutic effects against prostate cancer in humans.
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PMID:Pomegranate fruit juice for chemoprevention and chemotherapy of prostate cancer. 1619 56

In this article, we studied the chemopreventive effects of sanguinarine on UVB-mediated responses in human HaCaT immortalized keratinocytes. For our studies, HaCaT cells were treated with a low dose (50 nmol/L) of sanguinarine for 24 hours followed by irradiation with UVB (15 or 30 mJ/cm2). Our data showed that UVB exposure, at both doses, resulted in decreased cell viability and increased apoptosis. Interestingly, pretreatment of the cells with sanguinarine caused a significant enhancement in the antiproliferative response of UVB. These responses on UVB and/or sanguinarine treatments were associated with (a) decrease in Bcl-2 and Bcl-X(L) and (b) increase in Bax, Bid, and Bak protein levels. Bax knockdown and Bcl-2 overexpression resulted in a rescue of HaCaT cells from sanguinarine-mediated apoptosis. DNA cell cycle analysis revealed that UVB treatment resulted in an accumulation of cells in the G2-M phase of the cell cycle, whereas pretreatment of sanguinarine resulted in a significant shift of cells in the S phase at a low UVB dose and a further accumulation of cells in the G2-M phase at a higher UVB dose. These effects on cell cycle were accompanied with modulations in the protein levels of cyclin (B1, E, and A) and cdc2 and cyclin-dependent kinase 1. Furthermore, sanguinarine treatment was found to result in significant modulations in p53, p66Shc, MsrA, and superoxide dismutase levels. Based on our data, we suggest the sanguinarine may protect skin cells from UVB-mediated damages via apoptotic elimination of damaged cells that escape programmed cell death and therefore possess a potential of clonal expansion.
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PMID:Enhancement of UVB radiation-mediated apoptosis by sanguinarine in HaCaT human immortalized keratinocytes. 1650 17

In this study, we first report the chemopreventive effect of rugosin E in human breast cancer cell line, MDA-MB-231. Treatment with rugosin E decreased the cell proliferation of MDA-MB-231 cells in a dose-dependent manner. Rugosin E treatment arrested MDA-MB-231 cells at G0/G1 phase. This effect was strongly associated with concomitant decrease in the level of cyclin D1, cyclin D2, cyclin E, cdk2, cdk4, and cdk6, and increase of p21/WAF1. In addition, rugosin E also induced apoptotic cell death. Rugosin E increased in the expression of Bax, Bak, and Bcl-Xs, but decreased the levels of Bcl-2 and Bcl-X(L), and subsequently triggered mitochondria apoptotic pathway (release of cytochrome c, activation of caspase-9, and caspase-3). In addition, pre-treatment of cells with caspase-9 inhibitor blocked rugosin E-induced cell proliferation and apoptosis, indicating caspase-9 activation was involved in rugosin E-mediated MDA-MB-231 cells apoptosis. Rugosin E inhibited the constitutively activated and inducible NF-kappaB in both its DNA-binding activity and transcriptional activity. Furthermore, rugosin E also inhibited the TNF-alpha-activated NF-kappaB-dependent reporter gene expression of cyclin D1, c-Myc, XIAP, Bcl-2, and Bcl-X(L) were all downregulated by rugosin E. Our results indicated that rugosin E inhibits the activation of NF-kappaB, and this may provide a molecular basis for drug development in the prevention and treatment of cancer by rugosin E.
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PMID:Rugosin E, an ellagitannin, inhibits MDA-MB-231 human breast cancer cell proliferation and induces apoptosis by inhibiting nuclear factor-kappaB signaling pathway. 1696 81

In vitro manipulation of hematopoietic stem cells (HSCs) is a key issue in both transplantation therapy and regenerative medicine, and thus new methods are required to achieve HSC expansion with self-renewal. GATA2 is a transcription factor controlling pool size of HSCs. Of interest, continuous overexpression of GATA2 does not induce HSC proliferation. In this report, we demonstrate that GATA2 expression, in leukemic and normal hematopoietic cells, oscillates during the cell cycle, such that expression is high in S phase but low in G(1)/S and M phase. GATA2 binding to target Bcl-X gene also oscillates in accordance with GATA2 expression. Using a green fluorescent protein (GFP)-GATA2 fusion protein, we demonstrate cell-cycle-specific activity of proteasome-dependent degradation of GATA2. Immunoprecipitation/immunoblotting analysis demonstrated phosphorylation of GATA2 at cyclin-dependent kinase (Cdk)-consensus motifs, S/T(0)P(+1), and interaction of GATA2 with Cdk2/cyclin A2-, Cdk2/cyclin A2-, and Cdk4/cyclin D1-phosphorylated GATA2 in vitro. Mutants in phosphorylation motifs exhibited altered expression profiles of GFP-GATA2 domain fusion proteins. These results indicate that GATA2 phosphorylation by Cdk/cyclin systems is responsible for the cell-cycle-dependent regulation of GATA2 expression, and suggest the possibility that a cell-cycle-specific "on-off" response of GATA2 expression may control hematopoietic-cell proliferation and survival.
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PMID:Cell-cycle-dependent oscillation of GATA2 expression in hematopoietic cells. 1725 59

In response to cancer chemotherapeutic drugs, cells rapidly trigger the apoptotic program or undergo growth arrest and senescence at specific phases of the cell cycle. Mitochondrial bcl-xL plays a central role in preventing alteration of mitochondrial dysfunction, cytochrome c release, caspase activation, DNA fragmentation and apoptosis. However, its pleitropic function depends on its subcellular localization. Here, we show that in addition to its mitochondrial effect that delays apoptosis, bcl-xL colocalizes and binds to cdk1(cdc2) during G(2)/M cell-cycle checkpoint and its overexpression stabilizes a G(2)/M-arrest senescence program in surviving cells after DNA damage. Bcl-xL potently inhibits cdk1(cdc2) kinase activity, which is reversible by a synthetic peptide between the 41st amino acid and 60th amino acid surrounding of the Thr47 and Ser62 phosphorylation sites, and Asn52 deamidation site, within the flexible loop domain of bcl-xL. A mutant deleted of this region does not alter the antiapoptotic function of bcl-xL, but impedes its effect on cdk1(cdc2) activity and on the G(2)/M-arrest senescence program after DNA damage. The nuclear interaction of bcl-xL and cdk1(cdc2) suggests that bcl-xL is coupled to the stabilization of a cell-cycle checkpoint induced by DNA damage, and this effect is genetically distinct from its function on apoptosis.
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PMID:Nuclear colocalization and interaction between bcl-xL and cdk1(cdc2) during G2/M cell-cycle checkpoint. 1736 48

In beta-thalassemia, the mechanism driving ineffective erythropoiesis (IE) is insufficiently understood. We analyzed mice affected by beta-thalassemia and observed, unexpectedly, a relatively small increase in apoptosis of their erythroid cells compared with healthy mice. Therefore, we sought to determine whether IE could also be characterized by limited erythroid cell differentiation. In thalassemic mice, we observed that a greater than normal percentage of erythroid cells was in S-phase, exhibiting an erythroblast-like morphology. Thalassemic cells were associated with expression of cell cycle-promoting genes such as EpoR, Jak2, Cyclin-A, Cdk2, and Ki-67 and the antiapoptotic protein Bcl-X(L). The cells also differentiated less than normal erythroid ones in vitro. To investigate whether Jak2 could be responsible for the limited cell differentiation, we administered a Jak2 inhibitor, TG101209, to healthy and thalassemic mice. Exposure to TG101209 dramatically decreased the spleen size but also affected anemia. Although our data do not exclude a role for apoptosis in IE, we propose that expansion of the erythroid pool followed by limited cell differentiation exacerbates IE in thalassemia. In addition, these results suggest that use of Jak2 inhibitors has the potential to profoundly change the management of this disorder.
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PMID:Decreased differentiation of erythroid cells exacerbates ineffective erythropoiesis in beta-thalassemia. 2909 81


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