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)

Interactions between pharmacologic NF-kappaB inhibitors (eg, Bay 11-7082, SN-50) and the checkpoint abrogator UCN-01 have been examined in human multiple myeloma (MM) cells. Exposure of U266 cells to Bay 11-7082 (Bay) in combination with UCN-01 resulted in the abrogation of NF-kappaB/DNA binding activity and the synergistic induction of apoptosis. Comparable synergism was observed in other MM cell lines and patient-derived CD138+ cells and between an inhibitory peptide of NF-kappaB (SN50) and UCN-01. Bay/UCN-01-mediated lethality involved mitochondrial dysfunction, caspase cleavage, and poly adenosine diphosphate-ribose polymerase (PARP) degradation. Although Bay modestly blocked UCN-01-induced extracellular signal-regulated kinase (ERK) phosphorylation, coadministration activated c-Jun N-terminal kinase (JNK) and cdc2/cdk1 and down-regulated Mcl-1, XIAP, and Bcl-xL. Transfection with a constitutively activated mitogen-activated protein kinase kinase (MEK1)/green fluorescent protein (GFP) construct failed to block apoptosis induced by Bay/UCN-01 but significantly attenuated MEK inhibitor (U0126)/UCN-01-induced lethality. Inhibiting JNK activation with SP600125 or D-JNKI1 peptide markedly reduced Bay/UCN-01-mediated mitochondrial dysfunction and apoptosis and the down-regulation of Mcl-1, XIAP, and Bcl-xL but not of cdc2/cdk1 activation. Stable transfection of cells with dominant-negative caspase-9 dramatically diminished Bay/UCN-01 lethality without altering JNK or cdc2/cdk1 activation. Neither interleukin-6 (IL-6)- nor fibronectin-mediated adherence conferred resistance to Bay/UCN-01-induced apoptosis. Together, these findings suggest that a strategy combining UCN-01 with disruption of the IkappaB kinase (IKK)/IkappaB/NF-kappaB pathway warrants attention in MM.
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PMID:Interruption of the NF-kappaB pathway by Bay 11-7082 promotes UCN-01-mediated mitochondrial dysfunction and apoptosis in human multiple myeloma cells. 1464 3

Interactions between the histone deacetylase inhibitors (HDACIs) suberoylanilide hydroxamic acid (SAHA) and sodium butyrate (SB) and the heat shock protein (Hsp) 90 antagonist 17-allylamino-17-demethoxygeldanamycin (17-AAG) have been examined in human leukemia cells (U937). Coadministration of marginally toxic concentrations of 17-AAG with sublethal concentrations of SB or SAHA resulted in highly synergistic induction of mitochondrial damage (i.e., cytochrome c release), caspase-3 and -8 activation, and apoptosis. Similar interactions were noted in human promyelocytic (HL-60) and lymphoblastic (Jurkat) leukemia cells. These events were accompanied by multiple perturbations in signal transduction, cell cycle, and survival-related pathways, including early down-regulation of Raf-1, inactivation of extracellular signal-regulated kinase (ERK) 1/2 and mitogen-activated protein/ERK kinase (MEK) 1/2, diminished expression of phospho-Akt, and late activation of c-Jun-NH(2)-terminal kinase, but no changes in expression of phospho-p38 mitogen-activated protein kinase. Coadministration of 17-AAG blocked SAHA-mediated induction of the cyclin-dependent kinase inhibitor p21(CIP1) and resulted in reduced expression of p27(KIP1) and p34(cdc2). 17-AAG/SAHA-treated cells also displayed down-regulation of the antiapoptotic protein Mcl-1 and evidence of Bcl-2 cleavage. Enforced expression of doxycycline-inducible p21(CIP1) or constitutively active MEK1 significantly diminished 17-AAG/SAHA-mediated lethality, indicating that interference with ERK activation and p21(CIP1) induction play important functional roles in the lethal effects of this regimen. In contrast, enforced expression of constitutively active Akt failed to exert cytoprotective actions. Together, these findings indicate that coadministration of SAHA or SB with the Hsp90 antagonist 17-AAG in human leukemia cells leads to multiple perturbations in signaling, cell cycle, and survival pathways that culminate in mitochondrial injury and apoptosis. They also raise the possibility that combining such agents with Hsp90 antagonists may represent a novel antileukemic strategy.
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PMID:Coadministration of the heat shock protein 90 antagonist 17-allylamino- 17-demethoxygeldanamycin with suberoylanilide hydroxamic acid or sodium butyrate synergistically induces apoptosis in human leukemia cells. 1467 5

Heme plays a central role in oxygen utilization and in the generation of cellular energy. Here we examined the effect of heme and heme deficiency on cell cycle progression and the expression of key regulators in HeLa cells. We found that inhibition of heme synthesis causes cell cycle arrest and induces the expression of molecular markers associated with senescence and apoptosis, such as increased formation of PML nuclear bodies. Our data show that succinyl acetone-induced heme deficiency increases the protein levels of the tumor suppressor gene product p53 and CDK inhibitor p21, and decreases the protein levels of Cdk4, Cdc2, and cyclin D2. Further, we found that heme deficiency diminishes the activation/phosphorylation of Raf, MEK1/2, and ERK1/2-components of the MAP kinase signaling pathway. Our results show that heme is a versatile molecule that can effectively control cell growth and survival by acting on multiple regulators.
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PMID:Heme controls the expression of cell cycle regulators and cell growth in HeLa cells. 1497 35

Benign prostate hyperplasia and prostate cancer are major public health problems. We report herein that daily treatment of male rats with 50, 100 or 150 mg quercetin per kg body weight resulted in serum concentrations of quercetin equivalent to 25.3 microM, 43.3 microM and 54.3 microM respectively. Concomitantly, serum testosterone levels were increased by 1.79-, 1.83- and 3.48-fold, while serum dihydrotestosterone (DHT) levels were 125%, 92% and 73% of the control. A slight increase in prostate weight coupled with dilated prostate lumens full of secretory materials were observed. Finasteride alone caused a significant decrease in serum DHT level and prostate weight. Co-administration of quercetin with finasteride prevented the finasteride-induced decrease in serum DHT levels but significantly enhanced the reduction in wet prostate weight, which was reduced by 26.9% in finasteride-treated animals to 31.8%, 40.0% and 48.2% after finasteride given together with the three doses of quercetin. The combined treatment altered cell cycle-regulated proteins in a wide spectrum. The expressions of cyclin D1, CDK-4, cdc-2 and phospho-cdc-2 at tyrosine 15, phospho-MEK1/2, phospho-MAP kinase, phospho-pRb at serine 780 and serine 807/811 were significantly inhibited, while the levels of p15, p21 and p27 were increased. In conclusion, quercetin-finasteride treatments caused wide cell cycle deregulation in rat prostates, which, in turn, decreased the proliferation rate, changed the secretion activities of epithelial cells and resulted in a marked reduction in wet prostate weight. The results suggest that quercetin synergizes with finasteride to reduce the wet prostate weight through a cell cycle-related pathway, which may be androgen independent.
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PMID:Reduction of rat prostate weight by combined quercetin-finasteride treatment is associated with cell cycle deregulation. 1571 25

Several forms of human dwarfism are due to activating mutations in FGFR3 highlighting the role of FGF signaling in the growth attenuation of cartilage. Here, we studied the effects of FGF2 on RCS chondrocytes. Treatment with FGF2 induced growth arrest in the G1 phase of the cell cycle and partial de-differentiation of cells manifested by changes in cell morphology, loss of the cartilage-like extracellular matrix, and down-regulation of aggrecan expression. FGF2 activated phospholipase Cgamma, protein kinase B, and Erk and p38 MAP kinases. Chemical inhibition of FGFR3 and MEK1/2 antagonized FGF2-mediated growth arrest. Expression of a dominant-negative Ras mutant resulted in a partial reversal of growth inhibition while expression of constitutively activated Ras led to Erk-dependent growth arrest, further demonstrating the role of the Ras/Erk pathway in this phenotype. At the molecular level, FGF2-induced growth arrest was initiated by disintegration of cyclin D3-cdk6 complex followed by increased association of p21(WAF1) and p27(Kip1) with the cyclin-cdk2 and cyclin-cdk4 complexes leading to inhibition of their kinase activities and ultimately to underphosphorylation of the p107 and p130 pocket proteins. Both p21(WAF1) and p27(Kip1) accumulated upon FGF2 treatment, but this accumulation occurred at the protein level at least partially due to interaction with transcriptionally induced cyclin D1.
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PMID:FGF2 inhibits proliferation and alters the cartilage-like phenotype of RCS cells. 1519 33

CCAAT/enhancer binding protein beta (C/EBPbeta) is a widely expressed transcription factor whose activity is regulated by oncogenic Ha-RasV12 signaling. C/EBPbeta is essential for the development of mouse skin tumors containing Ras mutations and can cooperate with RasV12 to transform NIH 3T3 cells. Here we have investigated Ras-induced phosphorylation of C/EBPbeta in fibroblasts and report a novel proline-directed phosphoacceptor site at Ser64 within the transactivation domain. Ser64 phosphorylation was induced by activated Ras and Raf but was not blocked by chemical inhibitors of MEK1/2, phosphatidylinositol 3-kinase, JNK, or p38 mitogen-activated protein kinases. Ser64 was efficiently phosphorylated in vitro by the cyclin-dependent kinases Cdk2 and Cdc2. Thr189, previously identified as an ERK1/2 phosphorylation site that regulates C/EBPbeta activity, was also a substrate for Cdk phosphorylation. Ser64 and Thr189 phosphorylation was low in serum-starved (G0) cells but was strongly increased in mid-G1 cells and in cells arrested in S or M phase. In addition, phosphorylation on both sites was blocked by treating cells with the Cdk inhibitor roscovitine. In contrast to wild-type C/EBPbeta, which enhances transformation of NIH 3T3 cells, mutants bearing alanine substitutions at Ser64 and/or Thr189 inhibited RasV12-induced focus formation. Our findings support a role for C/EBPbeta as a nuclear effector of Ras signaling and transformation, and they indicate that cell cycle-dependent phosphorylation of C/EBPbeta on Ser64 and Thr189 is required to promote Ras-induced transformation of NIH 3T3 cells.
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PMID:Cell cycle-dependent phosphorylation of C/EBPbeta mediates oncogenic cooperativity between C/EBPbeta and H-RasV12. 1531 50

Green tea catechins, especially (-)-epigallocatechin gallate (EGCG), have been proposed as a chemopreventative for obesity, diabetes, cancer, and cardiovascular diseases. However, relatively little is known about the mechanism of the action of EGCG on fat cell function. This study was designed to investigate the pathways of EGCG's modulation of the mitogenesis of 3T3-L1 preadipocytes. Preadipocyte proliferation as indicated by an increased number of cells and greater incorporation of bromodeoxyuridine (BrdU) was inhibited by EGCG in dose-, time-, and growth phase-dependent manners. Also, EGCG dose and time dependently decreased levels of phospho-ERK1/2, Cdk2, and cyclin D(1) proteins, reduced Cdk2 activity, and increased levels of G(0)/G(1) growth arrest, p21(waf/cip), and p27(kip1), but not p18(ink), proteins and their associations to Cdk2. However, neither MEK1, ERK1/2, p38 MAPK, phospho-p38, JNK, nor phospho-JNK was changed. Increased phospho-ERK1/2 content and Cdk2 activity, respectively, via the transfection of MEK1 and Cdk2 cDNA into preadipocytes prevented EGCG from reducing cell numbers. These data demonstrate the ERK- and Cdk2-dependent antimitogenic effects of EGCG. Moreover, EGCG was more effective than epicatechin, epicatechin gallate, and epigallocatechin in changing the mitogenic signals. The signal of EGCG in reducing growth of 3T3-L1 preadipocytes differed from that of 3T3 fibroblasts. Results of this study may relate to the mechanism by which EGCG modulates body weight.
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PMID:Antimitogenic effect of green tea (-)-epigallocatechin gallate on 3T3-L1 preadipocytes depends on the ERK and Cdk2 pathways. 1564 88

Interactions between the protein kinase C and Chk1 inhibitor UCN-01 and rapamycin in human leukemia cells have been investigated in relation to apoptosis induction. Treatment of U937 monocytic leukemia cells with rapamycin (10 nmol/L) in conjunction with a minimally toxic concentration of UCN-01 (100 nmol/L) for 36 hours resulted in marked potentiation of mitochondrial injury (i.e., loss of mitochondrial membrane potential and cytosolic release of cytochrome c, AIF, and Smac/DIABLO), caspase activation, and apoptosis. The release of cytochrome c, AIF, and Smac/DIABLO were inhibited by BOC-D-fmk, indicating that their release was caspase dependent. These events were associated with marked down-regulation of Raf-1, MEK, and ERK phosphorylation, diminished Akt activation, and enhanced phosphorylation of c-Jun NH2-terminal kinase (JNK). Coadministration of UCN-01 and rapamycin reduced the expression levels of the antiapoptotic members of the Bcl-2 family Mcl-1 and Bcl-xL and diminished the expression of cyclin D1 and p34(cdc2). Furthermore, enforced expression of a constitutively active MEK1 or, to a lesser extent, myristoylated Akt construct partially but significantly attenuated UCN-01/rapamycin-mediated lethality in both U937 and Jurkat cell systems. Finally, inhibition of the stress-related JNK by SP600125 or by the expression of a dominant-negative mutant of c-Jun significantly attenuated apoptosis induced by rapamycin/UCN-01. Together, these findings indicate that the mammalian target of rapamycin inhibitor potentiates UCN-01 cytotoxicity in a variety of human leukemia cell types and suggest that inhibition of both Raf-1/MEK/ERK and Akt cytoprotective signaling pathways as well as JNK activation contribute to this phenomenon.
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PMID:Rapamycin and UCN-01 synergistically induce apoptosis in human leukemia cells through a process that is regulated by the Raf-1/MEK/ERK, Akt, and JNK signal transduction pathways. 1576 55

Male germ cell-associated kinase (MAK) and intestinal cell kinase (ICK) are nuclear Cdc2-related kinases with nearly identical N-terminal catalytic domains and more divergent C-terminal noncatalytic domains. The catalytic domain is also related to mitogen-activated protein kinases (MAPKs) and contains a corresponding TDY motif. Nuclear localization of ICK requires subdomain XI and interactions of the conserved Arg-272, but not kinase activity or, surprisingly, any of the noncatalytic domain. Further, nuclear localization of ICK is required for its activation. ICK is activated by dual phosphorylation of the TDY motif. Phosphorylation of Tyr-159 in the TDY motif requires ICK autokinase activity but confers only basal kinase activity. Full activation requires additional phosphorylation of Thr-157 in the TDY motif. Coexpression of ICK with constitutively active MEK1 or MEK5 fails to increase ICK phosphorylation or activity, suggesting that MEKs are not involved. ICK and MAK are related to Ime2p in budding yeast, and cyclin-dependent protein kinase-activating kinase Cak1p has been placed genetically upstream of Ime2p. Recombinant Cak1p phosphorylates Thr-157 in the TDY motif of recombinant ICK and activates its activity in vitro. Coexpression of ICK with wild-type CAK1 but not kinase-inactive CAK1 in cells also increases ICK phosphorylation and activity. Our studies establish ICK as the prototype for a new group of MAPK-like kinases requiring dual phosphorylation at TDY motifs.
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PMID:Activation of a nuclear Cdc2-related kinase within a mitogen-activated protein kinase-like TDY motif by autophosphorylation and cyclin-dependent protein kinase-activating kinase. 1598 18

MEK1/2 inhibitors like U0126 can potentiate or antagonize the antitumor activity of cytotoxic agents such as cisplatin, paclitaxel or vinblastine, depending on the drug or the target cells. We now investigated whether U0126, differentially regulates melanoma signaling in response to UV radiation or betulinic acid, a drug lethal against melanoma. This report shows that U0126 inhibits early response (ERK) kinase activation and cyclin A expression in wt p53 C8161 melanoma exposed to either UV radiation or betulinic acid. However, U0126 does not protect from UV damage, but counteracts betulinic acid-mediated apoptosis in the same cells. Protection from the latter drug by joint treatment with U0126 was also evident in wt p53 MelJuso melanoma and mutant p53 WM164 melanoma. The latter cells were the most responsive to betulinic acid, showing a selective decline in the cdk4 protein, without a comparable change in other key cell cycle proteins like cdc2, cdk2, cdk7 or cyclin A, prior to apoptosis-associated PARP fragmentation. Laser scanning cytometry also showed that betulinic acid induced a significant increase in chromatin condensation in WM164 melanoma irrespective of whether they were in adherent form or as multicellular spheroids. All these betulinic acid-induced changes were counteracted by U0126. Our data show for the first time that (a) cdk4 protein is an early target of betulinic acid-induced apoptosis and (b) unrestricted ERK signaling favours betulinic acid-induced apoptosis, but this is counteracted by U0126, partly through counteracting chromatin condensation and restoring Akt activation decreased by betulinic acid treatment.
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PMID:Signalling responses linked to betulinic acid-induced apoptosis are antagonized by MEK inhibitor U0126 in adherent or 3D spheroid melanoma irrespective of p53 status. 1615 20


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