Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.4.2.30 (PARP)
 13,611 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cell death by apoptosis is an efficient mechanism of eliminating unwanted or aberrant cells. Triggering of Fas, a member of the tumor necrosis factor (TNF) receptor superfamily, by anti-Fas antibodies or by the Fas ligand (FasL), has been shown to cause cell death by apoptosis. A recent study from our laboratory has demonstrated that Fas crosslinking leads to the dephosphorylation of the tumor suppressor retinoblastoma protein (Rb) and that this dephosphorylation is inhibited by calyculin A, a serine/threonine phosphatase inhibitor. In this investigation, we compared the effect of Fas crosslinking by CH11, an anti-Fas mAb, with two cyclin-dependent kinase (CDK) inhibitors, a peptide that specifically inhibits CDK2 (cdk2 inh) and roscovitine, which inhibits CDK2, CDC2, and CDK5. We illustrate that roscovitine induced DNA fragmentation, whereas cdk2 inh did not. In contrast to Fas-induced apoptosis, roscovitine-induced apoptosis was resistant to calyculin A. Both cdk2 inh and roscovitine induced cleavage of poly (ADP-ribose) polymerase (PARP) within 2 h. Roscovitine, however, led to the degradation of Rb, whereas cdk2 inh did not. Furthermore, both CH11 and roscovitine caused cell cycle arrest in S phase. In contrast, cdk2 inh did not have any effect on Jurkat cell cycle progression. Taken together, our results strongly suggest that the maintenance of Rb in its hyperphosphorylated form during S phase may be necessary for cell survival and that Rb dephosphorylation during S phase may constitute a crucial step in Fas-induced apoptosis.
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PMID:Evidence that Fas-induced apoptosis leads to S phase arrest. 1129 63

Previously, we reported that EB1089 inhibited the growth of NCI-H929 myeloma cells via cell cycle arrest and apoptosis. In the present study, we investigated whether a combined EB1089 and TGF-beta1 synergistically inhibited the cell proliferation of myeloma cell lines. While TGF-beta1 alone could not inhibit the proliferation of any of the tested myeloma cells, synergistic effect between EB1089 (1 x 10(-8) M) and TGF-beta1 (1 ng/ml) was observed in NCI-H929 cells. TGF-beta1 intensified the decreased expression of CDK2, CDK4, CDK6 and cyclin D1 in EB1089-treated NCI-H929 cells. However, these effects did not intensify to decrease CDK2 activity of EB1089-treated NCI-H929 cells, resulting in no difference in the extent of G1 arrest between EB1089- and both agents-treated cells. Remarkably, both agents synergistically induce apoptosis of NCI-H929 cells, which was accompanied with up-regulation of Bax, degradation of PARP and Rb proteins, and loss of mitochondrial transmembrane potential (deltapsim). EB1089 caused the induction of SMAD4, a mediator of TGF-beta1 signaling. In addition, a combined EB1089 and TGF-beta1 increased p21 and JNK/SAPK activity whereas neither EB1089 nor TGF-beta1 affected p21 and JNK/SAPK activity. Taken together, these results suggest that treatment with both EB1089 and TGF-beta1 synergistically inhibits the proliferation of NCI-H929 cells through apoptosis.
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PMID:The induction of apoptosis by a combined 1,25(OH)2D3 analog, EB1089 and TGF-beta1 in NCI-H929 multiple myeloma cells. 1183 65

We have examined the effects of the CDK1 inhibitor CGP74514A on cell cycle- and apoptosis-related events in human leukemia cells. An 18-hr exposure to 5 microM CGP74514A induced mitochondrial damage (i.e., loss of Delta psi(m)) and apoptosis in multiple human leukemia cell lines (e.g., U937, HL-60, KG-1, CCRF-CEM, Raji, and THP; range 30-95%). In U937 cells, CGP74514A- induced apoptosis (5 microM) became apparent within 4 hr and approached 100% by 24 hr. The pan- caspase inhibitor Boc-fmk and the caspase-8 inhibitor lETD-fmk opposed CGP74514A-induced caspase-9 activation and PARP degradation, but not cytochrome c or Smac/DIABLO release. CGP74514A-mediated apoptosis was substantially blocked by ectopic expression of full-length Bel- 2, a loop-deleted mutant Bcl-2, and Bcl-x(L). CGP74514A treatment (5 microM; 18 hr) resulted in increased p21(CIP1) expression, p27(KIP1) degradation, diminished E2F1 expression, and dephosphorylation of p34(CDC2). It also induced early (i.e., within 2 hr) inhibition of CDK1 activity and dephosphorylation of pRb, followed by pRb degradation, but did not block pRb phosphorylation at CDK2- and CDK4- specific sites. These findings indicate that the selective CDK1 inhibitor, CGP74514A, induces complex changes in cell cycle-related proteins in human leukemia cells accompanied by extensive mitochondrial damage, caspase activation, and apoptosis.
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PMID:Induction of apoptosis in human leukemia cells by the CDK1 inhibitor CGP74514A. 1242 20

Flavopiridol is a synthetic flavone that inhibits tumor growth by suppressing cyclin-dependent kinases (CDKs). We have investigated effects of flavopiridol in oral squamous cell carcinoma (OSCC). Flavopiridol was found to inhibit the growth of OSCC cells in a time- and dose-dependent manner. Induction of apoptosis was observed in all cells showing accumulated cells with sub-G(1) DNA contents, DNA fragmentations, and PARP cleavages. While Bcl-2 and Bax expression did not change, Bcl-x(L) was down regulated and Bcl-xs was up-regulated after being exposed to flavopiridol. Flavopiridol treatments also resulted in remarkable reductions of cyclin A, cyclin B, and cyclin D1 expressions. We also found that expression levels of CDK activation kinase and CDC25C were reduced, and p34 inactive form CDK2 were up-regulated. Our data indicate that flavopiridol has growth inhibition activities against OSCC. Flavopiridol not only inhibits CDKs directly, but it also inhibits the CDKs activation pathway and activates the Bcl-x apoptotic pathway.
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PMID:Flavopiridol, a cyclin dependent kinase (CDK) inhibitor, induces apoptosis by regulating Bcl-x in oral cancer cells. 1245 21

There is no effective treatment for advanced hepatocellular carcinoma (HCC). We therefore explored the molecular mechanisms of interferon-gamma (IFN-gamma)-mediated growth regulation in human HCC cell lines. IFN-gamma receptor expression, signal transduction, and regulation of effectors were examined by RT-PCR, immunoprecipitation, immunoblotting, and reporter gene assays. Growth and apoptosis were determined based on cell numbers, cell cycle analyses, kinase assays, DNA fragmentation, and PARP cleavage. HCC cell lines express functionally intact IFN-gamma receptors and downstream effectors. IFN-gamma profoundly inhibited growth of HCC cells via two different mechanisms: inhibition of G1 cell cycle progression and induction of apoptosis. Analyses in SK-Hep-1 cells revealed a deficient cyclin D induction in IFN-gamma-treated cells, resulting in reduced activity of CDK4 and CDK2 kinases and pRB hypophosphorylation. In contrast, apoptosis prevailed in IFN-gamma-treated HepG2 cultures. A survey of apoptosis relevant IFN-gamma effectors including IRF-1, caspase-1, caspase-3, and p21(waf/cip-1) documented a dramatic transcriptional downregulation of p21(waf/cip-1) exclusively in apoptosis-susceptible HepG2 cells. Reconstitution of p21(waf/cip-1) rescued HepG2 cells from IFN-gamma-induced apoptosis, indicating that p21(waf/cip-1) reduction was required for apoptosis execution. Inversely, downregulation of p21(waf/cip-1) sensitized SK-Hep-1 cells to IFN-gamma-induced apoptosis. Thus, downregulation of p21(waf/cip-1) in HCC cells functions as a novel, critical determinant of alternative growth inhibitory pathways in response to IFN-gamma.
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PMID:Downregulation of p21(waf/cip-1) mediates apoptosis of human hepatocellular carcinoma cells in response to interferon-gamma. 1253 94

Cancer chemopreventive effects of inositol hexaphosphate (IP6), a dietary constituent, have been demonstrated against a variety of experimental tumors, however, limited studies have been done against prostate cancer (PCA), and molecular mechanisms are not well defined. In the present study, we investigated the growth inhibitory effect and associated mechanisms of IP6 in advanced human PCA cells. Advanced human prostate carcinoma DU145 cells were used to study the anticancer effect of IP6. Flow cytometric analysis was performed for cell cycle progression and apoptosis studies. Western immunoblotting, immunoprecipitation and kinase assay were performed to investigate the involvement of G1 cell cycle regulators and their interplay, and end point markers of apoptosis. A significant dose- as well as time-dependent growth inhibition was observed in IP6-treated cells, which was associated with an increase in G1 arrest. IP6 strongly increased the expression of CDKIs (cyclin-dependent kinase inhibitors), Cip1/p21 and Kip1/p27, without any noticeable changes in G1 CDKs and cyclins, except a slight increase in cyclin D2. IP6 inhibited kinase activities associated with CDK2, 4 and 6, and cyclin E and D1. Further studies showed the increased binding of Kip1/p27 and Cip1/p21 with cyclin D1 and E. In down-stream of CDKI-CDK/cyclin cascade, IP6 increased hypophosphorylated levels of Rb-related proteins, pRb/p107 and pRb2/p130, and moderately decreased E2F4 but increased its binding to both pRb/p107 and pRb2/p130. At higher doses and longer treatment times, IP6 caused a marked increase in apoptosis, which was accompanied by increased levels of cleaved PARP and active caspase 3. IP6 modulates CDKI-CDK-cyclin complex, and decreases CDK-cyclin kinase activity, possibly leading to hypophosphorylation of Rb-related proteins and an increased sequestration of E2F4. Higher doses of IP6 could induce apoptosis and that might involve caspases activation. These molecular alterations provide an insight into IP6-caused growth inhibition, G1 arrest and apoptotic death of human prostate carcinoma DU145 cells.
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PMID:Inositol hexaphosphate inhibits growth, and induces G1 arrest and apoptotic death of prostate carcinoma DU145 cells: modulation of CDKI-CDK-cyclin and pRb-related protein-E2F complexes. 1266 18

Silymarin, a defined mixture of natural flavonoid, has recently been shown to have potent cancer chemopreventive efficacy against colon carcinogenesis in rat model; however, the mechanism of such efficacy is not elucidated. Here, using pure active agent in silymarin, namely silibinin, we show its antiproliferative and apoptotic effects, and associated molecular alterations in human colon carcinoma HT-29 cells. Silibinin treatment of cells at 50-100 microg/ml doses resulted in a moderate to very strong growth inhibition in a dose- and a time-dependent manner, which was largely due to a G0/G1 arrest in cell cycle progression; higher dose and longer treatment time also caused a G2/M arrest. In mechanistic studies related its effect on cell cycle progression, silibinin treatment resulted in an upregulation of Kip1/p27 and Cip1/p21 protein as well as mRNA levels, and decreased CDK2, CDK4, cyclin E and cyclin D1 protein levels together with an inhibition in CDK2 and CDK4 kinase activities. In other studies, we observed that G2/M arrest by silibinin was associated with a decrease in cdc25C, cdc2/p34 and cyclin B1 protein levels, as well as cdc2/p34 kinase activity. In the studies assessing biological fate of silibinin-treated cells, silibinin-induced cell cycle arrest and growth inhibition were not associated with cellular differentiation, but caused apoptotic death. The quantitative apoptosis analysis showed up to 15% apoptotic cell death after 48 h of silibinin treatment. Interestingly, silibinin-induced apoptosis in HT-29 cells was independent of caspases activation, as all caspases inhibitor did not reverse silibinin-induced apoptosis. This observation was further confirmed by the findings showing a lack in caspases activity increase and caspases and PARP cleavage as well as a lack in cytochrome c release in cytosol following silibinin treatment of HT-29 cells. Additional studies conducted in mice showed that silibinin doses found effective in HT-29 cells are achievable in plasma, which increases the significance of the present findings and their possible translation in in vivo anticancer efficacy of silibinin against colon cancer. Together, these results identify molecular mechanisms of silibinin efficacy as a cell cycle regulator and apoptosis inducer in human colon carcinoma HT-29 cells, and justify further studies to investigate potential usefulness of this nontoxic agent in colon cancer prevention and intervention.
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PMID:Silibinin upregulates the expression of cyclin-dependent kinase inhibitors and causes cell cycle arrest and apoptosis in human colon carcinoma HT-29 cells. 1461 51

In the present study the deacetylase inhibitor trichostatin A (TSA) was used to elucidate the effect of protein acetylation on cell cycle progression and survival in seven human malignant melanoma cell lines. It was shown that TSA treatment led to a transient G(2)/M phase delay and accumulation of unphosphorylated retinoblastoma protein (pRB) in all cases. TSA significantly induced protein expression of the cyclin-dependent kinase inhibitor p21(WAF1/CIP1) in a dose-dependent manner in all cell lines including those not expressing p21(WAF1/CIP1) constitutively, whereas the levels of both wild-type and mutated p53 protein were reduced. The effect on p53 was not a direct result of inhibition of extracellular signal-regulated kinase-1/2 (ERK1/2) activation by TSA, as treatment of the cells with the mitogen-activated protein kinase/extracellular signal-regulated kinase kinase-1 (MEK1) inhibitor PD98059 did not result in decreased p53 protein level. Furthermore, TSA treatment led to reduction in cyclin D1 whereas cyclin D3 accumulated, the latter due to increased protein stability. Similarly, cyclin A protein was reduced whereas cyclin E level was elevated. The effect on p27(Kip1), CDK4 and CDK2 was only marginal. In all the examined cell lines, TSA treatment resulted in a profound induction of apoptosis and cleavage of poly-(ADP-ribose)-polymerase (PARP) indicative of caspase activity. Similarly, TSA-mediated apoptosis was reversed by the caspase-inhibitor z-vad-fmk. Altogether, these results suggest that p21(WAF1/CIP1) in melanomas is silenced by deacetylation, and furthermore that inhibition of deacetylation may have potential in anticancer therapy of melanoma patients.
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PMID:Deacetylase inhibition in malignant melanomas: impact on cell cycle regulation and survival. 1517 85

Inactivation of poly(ADP-ribose) polymerase-1 (PARP-1) has been shown to potentiate the cytotoxicity of distinct DNA targeting agents including topoisomerase I inhibitors. On the other hand, the PARP-1 deficient cells exhibited resistance to conventional inhibitors of topoisomerase II such as etoposide or doxorubicin (DOX). Recently, we observed the extreme sensitivity of PARP-1 knock-out (KO) cells to C-1305, a new biologically active triazoloacridone compound. C-1305 permanently arrested the cells in G2-phase of the cell-cycle. These observations prompted us to investigate more thoroughly the susceptibility of PARP-1 KO cells to DOX and to examine the effect of DOX on the progression of cell-cycle. We determined the uptake of DOX and P-glycoprotein (P-gp) expression in mouse cells and compared it with that in human myeloma 8226/Dox40 cells overexpressing P-gp. Exposure of mouse cells to DOX revealed a reduced drug uptake in cells lacking PARP-1. However, combined treatment with verapamil, a potent MDR modulator increased the DOX accumulation. Detailed immunoblotting experiments revealed an approximately threefold higher P-gp level in PARP-1 KO cells as compared with normal counterparts. Interestingly, DOX induced in normal fibroblasts very rapidly G2 arrest whereas in PARP-1 KO cells it blocked primarily the transition between S and G2 resulting in the increase of cells remaining in S-phase. This coincided with the lack of the site-specific phosphorylation of CDK2. Simultaneous inhibition of P-gp in cells lacking PARP-1 resulted in an accumulation of cells in G2. Exposure of mouse cells to high DOX dose activated significantly caspase-3/7 in PARP-1 KO cells.
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PMID:Major contribution of the multidrug transporter P-glycoprotein to reduced susceptibility of poly(ADP-ribose) polymerase-1 knock-out cells to doxorubicin action. 1586 98

Proteins of the poly(ADP-ribose) polymerase (PARP) family play a wide array of functions, covering virtually every aspect of DNA metabolism and function, most notably with the response to DNA damage, transcription, and the maintenance of genomic stability. Here we report the identification and characterization of a novel PARP family member, PARP10 (FLJ14464 or hypothetical protein LOC84875). Overexpression of PARP10 results in loss of cell viability, although down-expression by short hairpin RNA leads to delayed G1 progression and concomitant cell death. PARP10 exists in both cytoplasm and nucleus, but only nucleolar PARP10 acquires CDK-dependent phosphorylation through late-G1 to S phase, and from prometaphase to cytokinesis in the nucleolar organizing regions. The PARP activity of PARP10 depends on phosphorylation by CDK2-cyclin E in vitro. CDK-phosphorylated PARP10 is absent in growth-arrested cells. These results suggest that PARP10 functions in cell proliferation and may serve as a marker for proliferating cells.
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PMID:CDK-dependent activation of poly(ADP-ribose) polymerase member 10 (PARP10). 1645 63


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