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

This review attempts to provide current information on the role played by the p53 gene in normal and leukemic hematopoiesis with particular emphasis on chronic myeloid leukemia. On the basis of the currently available data we can argue that p53 acts as a negative regulator of proliferation of myeloid mature cells and CD34+ progenitors, and its action is mediated through changes in cell cycle kinetics, mainly before the S phase. The p53-dependent pathway is also regulated by several proteins, including p16, p21, p27 (cyclin-dependent kinase [CDK] inhibitors), and a few oncogenes (bcl-2, bax, MDM-2). Although there is some information about the changes in the p53 gene seen in various types of leukemia, the functions and biological importance of these changes in the pathogenesis of leukemia are still largely elusive. During the past several years, accumulated evidence suggests that changes in the p53 gene are commonly associated with blast crisis of chronic myeloid leukemia (CML) but rarely with chronic phase, and they are represented by rearrangements, deletions and point mutations. As for most of the tumors, the majority of point mutations occur between exons 4 and 8 (hot regions). In patients with CML in blastic crisis the most frequent mechanism of p53 inactivation is complete deletion of one allele in association with a point mutation in the remaining allele.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of p53 in leukemogenesis of chronic myeloid leukemia. 754 4

It is generally recognized that bcl-2 gene strongly protects cells from apoptosis in various situations. But its function is still to be examined. We analyzed the effect of bcl-2 gene using growth factor dependent cell line, TF-1, derived from an erythroleukemia patient. On GM-CSF removal TF-1 (bcl-2) cells which were transfected with bcl-2 cDNA by retrovirus vector system survived and arrested in G0-1 phase of the cell cycle, while TF-1 (mock) cells which were transfected with vector only also arrested in G0-1 but decreased in number in several days and showed typical apoptosis. N-acetylcysteine, one of antioxidants, did not show such anti-apoptotic effect as bcl-2 in the preincubation experiment. By centrifugal elutriation system the G0-1 arrested subfraction of TF-1 (bcl-2) showed time delay at the re-entry into cell after GM-CSF re-addition when compared with the G0-1 arrested subfraction of TF-1 (mock). Similar delay in cell cycle progression was observed after 24hs-exposure of staurosporine, a protein kinase C (PKC) inhibitor. The expression of cell cycle genes including cyclin A, C, D1, E, cdk2, 4, c-myc, bax and bcl-x showed no difference between these two cell lines upon growth factor removal. These results imply that the functional commitment of bcl-2 into cell cycle progression under the situation of apoptosis especially at the restriction point of G1-S transition.
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PMID:[Overexpression of bcl-2 suppresses apoptosis in the human leukemia cell line TF-1]. 925 8

Time-dependent ladder-type DNA fragmentation and morphological alterations consistent with apoptosis were observed among A253 human head and neck squamous cell carcinoma (HNSCC) cells in nude mice from 15 to 18 days after transplantation, without any drug treatment. No evidence of ladder-type DNA fragmentation was detected in A253 cells in vitro or in normal nude mouse tissues (skin and muscle). Our aim was to explore molecular factors associated with such spontaneous apoptosis. Bcl-2 protein expression decreased, while bax protein expression increased from day 9 after transplantation. Moreover, altered expression of bcl-2 and bax was accompanied by the increased proteolytic cleavage of poly(ADP-ribose) polymerase (PARP). Time-dependent dephosphorylation of Rb, followed by proteolytic cleavage, was also observed from day 9 after transplantation. The data indicate that the caspase-3 activation and cleavage of Rb protein may represent important steps in the regulation pathway of bax-mediated spontaneous apoptosis. Interestingly, the time-dependent activation of spontaneous apoptosis was almost simultaneous with the induction of differentiation and increased expression of several differentiation-associated regulatory proteins. An increased expression of cyclin D1 and cyclin-dependent kinase-5 (cdk5) was observed from day 9 after transplantation, whereas only slight alteration of cdk4 expression was found. The time-dependent activation of cyclin D1 and cdk5 preceded both the induction of ladder-type DNA fragmentation and increased keratin pearl formation. Furthermore, MCM3 was cleaved early in spontaneous apoptosis and differentiation. Our observations suggest the involvement of cyclin D1-cdk5 overexpression and MCM3 cleavage in bax-mediated spontaneous apoptosis and differentiation in A253 xenografts. P53 and WAF1 proteins were not expressed in the xenografts, indicating that the changes in the regulatory proteins during apoptosis and differentiation were not p53 or WAF1 dependent.
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PMID:Involvement of cyclin D1-cdk5 overexpression and MCM3 cleavage in bax-associated spontaneous apoptosis and differentiation in an A253 human head and neck carcinoma xenograft model. 1049 26

Mechanisms of resistance to Tomudex include increased thymidylate synthase activity, as well as reduced intracellular drug uptake and polyglutamation. However, little is known about other mechanisms of resistance, such as a possible protection against Tomudex-induced apoptosis mediated by bcl-2. We transfected the MDA-MB-435 human breast cancer cell line, which is characterized by a mutated p53 gene, with cDNA of the bcl-2 gene and generated two clones (MDA-bcl4 and MDA-bcl7) characterized by bcl-2 expression twofold and fourfold that observed in the control cell clone (MDAneo). A concomitant overexpression of p21wafl was also detected in the MDA-bcl7 clone. The MDA-bcl4 clone was three times more resistant to a 24-h Tomudex exposure than the MDAneo clone, whereas the MDA-bcl7 clone was as sensitive to Tomudex as the control cell clone. A lower sensitivity of the MDA-bcl4 clone than MDAneo and MDA-bcl7 clones to 5-fluorouracil and gemcitabine was also observed. No significant difference was noted in the susceptibility of clones to fludarabine and methothrexate. Basal levels of thymidylate synthase activity were superimposable in the three clones. Tomudex induced a marked accumulation of cells in the S phase in all the clones. However, an apoptotic hypodiploid DNA peak and the characteristic nuclear morphology of apoptosis were observed only in the MDA-bcl7 clone after exposure to Tomudex. No difference in the treatment-induced modulation of proteins involved in cell cycle progression (cyclin A, cdk2, pRB, E2F-1) and apoptosis (bcl-2, bax) was observed in the three clones. The only exception was that the expression of p21wafl in the MDA-bcl4 clone was inducible at a Tomudex concentration much higher than that required to induce the protein in the other clones. Overall, the results indicate that bcl-2 and p21wafl proteins concur in determining the cellular profile of sensitivity/resistance to Tomudex.
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PMID:Involvement of bcl-2 and p21waf1 proteins in response of human breast cancer cell clones to Tomudex. 1049 50

In an attempt to gain more insight into the events of leukaemic transformation, a cell line overexpressing MHC class II (DR) was generated by transfecting an early CD34-negative haematopoietic progenitor stem cell line with the appropriate constructs. The stable transfection with genes for DR antigens leads to cellular transformation. The DR(+) transformed cell clones express a tyrosine-phosphorylated DR heterodimer and show a significantly different morphology. DR(+) clones present the morphology of an immature myeloid neoplasia expressing alpha-naphthyl-acetate-esterase (ANAE), but neither myeloperoxidase nor CD34. While D064 cells predominately grow adherent as fibroblast-like cells, the DR(+) clones display a decrease in adherent growth. Although both cell lines express similar amounts of the interleukin-6 (IL-6) signal transducer gp130, the DR-transfected cells still show activation of STAT factors by IL-6, whereas D064 cells do not. Although the transformed clones present acceleration of cell-cycle transition and growth, the G(0)/G(1) progression inhibitor p27(kip-1) is up-regulated, while the expression of proteins involved in the S/G(2) phase transition, such as cyclin B and cdc2 (p34), is suppressed. Instead cyclin D3, one of the G(0)/G(1) progression factors, is up-regulated, as well as tyrosine-phosphorylated p62(dok), suggesting dysregulation of cell cycle-controlling proteins. In addition, DR(+) leukaemia-like cells also overexpress Bcl-2, while bax expression is suppressed, compared with the wild-type (wt) parental haematopoietic stem cell line.
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PMID:In vitro-generated stem cell leukaemia showing altered cell cycle progression with distinct signalling of the tyrosine-phosphorylated rasGAP-associated p62(dok) protein. 1105 20

The effects of liposome-encapsulated annamycin (L-Ann) were investigated in two human breast cancer cell lines, MCF7 and MDA-MB-435. For comparative purposes, doxorubicin (Dx) was used throughout the study. A 4-hour treatment with L-Ann was significantly more active in MDA-MB-435 than in MCF7 cells (IC(50) values of 0.03 and 0.08 microg/ml, respectively), whereas Dx was equally active in the two cell lines (IC(50) 0.12 microg/ml). L-Ann induced an accumulation of cells in G2M phases which was dose-dependent in MDA-MB-435 but not in MCF7 cells. Dx also caused a dose-dependent increase of G2M cell fraction in MDA-MB-435 cells, whereas a G2M cell accumulation was observed only after treatment with the highest Dx concentration in MCF7 cells. G2M phase cell accumulations induced in MCF7 cells by L-Ann or Dx were accompanied by a decrease in cdc2 kinase activity and in cyclin B1 and cdc2 expression. Conversely, in MDA-MB-435 cells exposed to L-Ann or Dx, cdc2 kinase activity, cyclin B1 and cdc2 expression increased in parallel to the increase in the number of cells accumulated in the G2M phase. L-Ann and Dx induced apoptosis in MDA-MB-435 but not in MCF7 cells. In MDA-MB-435 cells exposed to L-Ann or Dx, no change was observed in the expression of bax, but there was a p53-independent increase in p21(waf1) expression. In MCF7 cells, treatment with L-Ann or Dx induced an increase in p53 expression with a consequent transactivation of p21(waf1) and bax. Our results indicate that L-Ann is more cytotoxic than Dx in breast cancer cells and is able to induce apoptosis through p53-independent mechanisms.
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PMID:Effects of liposome-entrapped annamycin in human breast cancer cells: interference with cell cycle progression and induction of apoptosis. 1118 Mar 94

Promotion of apoptosis may potentiate the sensitivity of tumor cells to chemotherapeutic agents, thus improving the efficacy of cancer treatment. The transfection of the proapoptotic bax gene, which results in the overexpression of bax protein, augments the growth inhibition of A253 cells by BNP1350. Increased drug response was associated with the induction of DNA fragmentation in the size of 30-200 Kb, generating a cleaved fragment of 18 kDa from full-length 21 kDa bax and the cleavage of PARP. A253/vec cells treated with 0.07 microM(IC50) of BNP1350 accumulated in G2 phase at 24 h after drug removal. In contrast, A253/Bax cells treated with an equimolar concentration of BNP1350 primarily displayed a G1 phase accumulation with a concurrent decrease in G2 phase. Certain cell cycle regulatory protein expression and activities were altered following drug exposure in both cell lines under similar conditions. Cdk2- and cdc2-associated H1 kinase activities were markedly increased in the A253/Bax cell line with marginal increased activity in the A253/vec cell line. A chk1 activity assay was performed with GST-cdc25C (200-256) or GST-cdc25C(S216A) (200-256) fusion proteins as the substrate. Increased chk1 activity was observed in the A253/vec cell line, with little change in the A253/Bax cell line, when exposed to equimolar concentrations of BNP1350 (0.07 microM). A Western blot of immunoprecipitated chk1 indicated that increased chk1 phosphorylation following DNA damage induced by BNP1350 was accompanied by the observed G2 accumulation in the A253/vec cell line, while only a slight increase in chk1 phosphorylation was seen in the A253/Bax cell line. A decreased expression of cdc25C was observed in the BNP1350-treated A253/Bax cells, but not in the A253/vec cell line. Following exposure to BNP1350, increased binding of 14-3-3 proteins to chk1 occurred in both cell lines, with more being observed in the A253/vec cell line. The data have shown that inhibition of the chk1 pathway accompanied by the abrogation of G2 arrest is involved in sensitizing A253 cells to BNP1350 by bax gene transfer. These findings suggest that bax gene transfer sensitizes A253 cells to BNP1350 through apoptosis promoting and G2/M DNA damage checkpoint regulatory pathways.
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PMID:The Chk1-Cdc25C regulation is involved in sensitizing A253 cells to a novel topoisomerase I inhibitor BNP1350 by bax gene transfer. 1153 38

We have previously reported that combretastatin-A4 prodrug (CA4P), anantitubulin/antiangiogenic agent isolated from the South African willow tree Combretum caffrum, induced cell death primarily through mitotic catastrophe in a panel of human B-lymphoid tumors. In this study, we investigated the molecular aspects of the mitotic catastrophe and whether or not it shares the same pathways of apoptosis. For this we studied the effect of CA4P on selected markers of apoptosis [caspases 9 and 3, poly(ADP-ribose) polymerase (PARP), bcl-2, and bax] and G2-M protein regulators (p53, MDM2, 14-3-3sigma, GADD45, cdc2, cdc25, chk1, wee1, p21, and cyclin B1). The chronic lymphocytic leukemia cell line WSU-CLL was used for this purpose. Western blot analysis showed that 24 h of CA4P (5 nM) exposure induces caspase 9 activation and PARP cleavage. However, the addition of Z-Val-Ala-Asp-fluoromethylketone (a general caspase inhibitor) or Z-Leu-Glu(OMe)-His-Asp(OMe)-CH2F (a caspase 9 inhibitor) before CA4P treatment did not block cell death. No change in bcl-2 or bax protein expression was observed. Exposure of WSU-CLL cells to 4 and 5 nM CA4P was associated with overproduction of total p53 and no dramatic change in MDM2, 14-3-3sigma, GADD45, the cyclin-dependent kinase cdc2, its inhibitory phosphorylation, the cdc2-inhibitory kinase (wee1), chk1, or cdc25 hyperphosphorylation. The overaccumulation of p21 and cyclin B1 protein was obvious at 24 h. Furthermore, CA4P treatment showed an increase in the expression of a marker of mitosis (mitotic protein monoclonal-2 antibody) and an overaccumulation of the cyclin B in the nucleus. Our findings suggest that CA4P induces mitotic catastrophe and arrest of WSU-CLL cells mostly in the M phase independent of p53 and independent of chk1 and cdc2 phosphorylation pathways. Apoptosis is a secondary mechanism of death in a small proportion of cells through activation of caspase 9 and PARP cleavage. The two mechanisms of cell death, i.e., mitotic catastrophe and apoptosis, are independent of each other in our model.
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PMID:Combretastatin-A4 prodrug induces mitotic catastrophe in chronic lymphocytic leukemia cell line independent of caspase activation and poly(ADP-ribose) polymerase cleavage. 1217 7

For hormone resistant prostate cancer (HRPC), chemotherapy is used but the mortality is 100% with a mean survival time of 7-8 months. Our previous studies have shown the chemotherapeutic effect of ciprofloxacin in bladder cancer. At doses 50-400 micro g/ml ciprofloxacin, the concentrations that are normally achieved at doses currently used for the treatment of anti-bacterial infections, inhibited bladder cancer cell growth and induced S/G2M arrest with modulation of key cell cycle regulatory genes and ultimately activated apoptotic processes. In this study, we investigated the effect of ciprofloxacin on androgen independent prostate carcinoma, PC3 cells and compared our results with non-tumorigenic prostate epithelial cells. The main advantage of this fluroquinolone antibiotic is its relative non-toxicity as compared to current chemotherapy, which is not very effective, for the treatment of advanced hormone resistant prostate cancer. PC3 cells as well as normal prostate epithelial cells (MLC8891) were treated with 25-400 micro g/ml ciprofloxacin, and cell counting was done during 3 days of treatment. The cell death was determined using DAPI staining of cell nuclei, 7AAD-staining followed by flow cytometric analysis as well as by activation of caspase-3, a member of the ICE family of enzymes involved in the apoptotic cascade. The cell lysates were analyzed by immunoblotting techniques for the expression of key genes targeted by ciprofloxacin (p21WAF1, Bax and Bcl-2). Translocation of bax was visualized using a fluorescence staining procedure followed by laser confocal microscopic imaging. Treatment of prostate cancer cells with ciprofloxacin resulted in a dose- and time-dependent inhibition of cell growth (70-100% with 50-400 micro g/ml of the drug). There was a concomitant induction of cell cycle arrest at the S and G2/M phases of the cell cycle as well as induction of apoptosis. The CDK inhibitor p21WAF1 was down-regulated as early as 12 h following ciprofloxacin treatment (100-200 micro g/ml for 12-24 h). There was a significant increase in the Bax/Bcl-2 ratio with translocation of Bax, a pro-apoptotic protein, to mitochondria with concomitant activation of caspase 3. These results suggest the potential usefulness of the fluroquinolone, ciprofloxacin as a chemotherapeutic agent for advanced prostate cancer. The fluroquinolone ciprofloxacin showed anti-proliferative and apoptosis inducing activity on prostate cancer cells but not on non-tumorigenic prostate epithelial cells. These effects of ciprofloxacin were mediated by cell cycle arrest at S-G2/M phase of the cell cycle, Bax translocation to mitochondrial membrane and by increasing the Bax/Bcl-2 ratio in PC3 prostate cancer cells. Based on our in vitro results, further in-depth in vivo animal or human investigations are warranted.
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PMID:Suppression of human prostate cancer cell growth by ciprofloxacin is associated with cell cycle arrest and apoptosis. 1263 69

The aim of our study was to examine the involvement of IGF-II, tyrosine kinases (TK)- and MAP kinases (MAPK)-dependent intracellular mechanisms in the control of ovarian functions in the domestic fowl, as well as the role of these kinases in mediating the IGF-II effect on this process. For this purpose, we studied the influence of IGF-II (0,1,10 or 100 ng/ml), inhibitors of TK (AG1024, 1 microg/ml), MAPK (PD98059, 5 microg/ml), and their combinations, on proliferation (expression of proliferation-related substances PCNA), apoptosis (apoptosis-associated protein bax), TK (phosphotyrosine), MAPK (ERK1,2), cyclin-dependent protein kinase 2 (p34/cdc2) and transcription factor CREB-1, as well as on the release of progesterone (P), testosterone (T), estradiol (E) and arginine-vasotocin (AVT) in cultured fragments of ovarian follicles. The presence of substances within ovarian cells was evaluated by SDS PAGE-Western immunoblotting, and release of the substances was measured by using RIA/EIA of ovarian fragments-conditioned medium. It was found, that the addition of IGF-II to the culture medium (1-100 ng/ml) substantially increased expression of PCNA, MAPK and CREB, and decreased the level of p34/cdc2 and bax, but not TK. Furthermore, exogenous IGF-II inhibited P (at a concentration of 100 ng IGF-II/ml medium), and stimulated T (1,10,100 ng/ml), E (10,100 ng/ml) and AVT (1 ng/ml) release by cultured ovarian cells. Inhibitor of TK, when given alone, increased MAPK and E, inhibited p34/cdc2 and AVT, and did not affect accumulation of TK, P or T. Furthermore, TK blocker prevented effects of IGF-II on T, E and AVT, but not on TK, MAPK, p34/cdc2 and P. MAPK blocker augmented PCNA, MAPK, T and AVT expression, but not P or E, and suppressed expression of p34/cdc2 and bax. Furthermore, MAPK inhibitor, given together with IGF-II, prevented or even reversed the action of IGF-II on PCNA, P, T and AVT, but not on MAPK, p34/cdc2, CREB, bax or E. These observations suggest the involvement of IGF-II, TK and MAPK in the control of proliferation, apoptosis, steroid and peptide hormones by avian ovarian cells, as well as of the involvement of these kinases in mediation of some IGF-II effects on ovarian cells.
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PMID:Role of tyrosine kinase- and MAP kinase-dependent intracellular mechanisms in control of ovarian functions in the domestic fowl (Gallus domesticus) and in mediating effects of IGF-II. 1496 54


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