Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Effects of the PI-3 kinase inhibitor LY294002 (LY) have been examined in relation to responses of human leukemia cells to histone deacetylase inhibitors (HDIs). Coexposure of U937 cells for 24 h to marginally toxic concentrations of LY294002 (e.g., 30 microM) and sodium butyrate (SB; 1 mM) resulted in a marked increase in mitochondrial damage (e.g., cytochrome c and Smac/DIABLO release, loss of DeltaPsi(m)), caspase activation, and apoptosis. Similar results were observed in Jurkat, HL-60, and K562 leukemic cells and with other HDIs (e.g., SAHA, MS-275). Exposure of cells to SB/LY was associated with Bcl-2 and Bid cleavage, XIAP and Mcl-1 downregulation, and diminished CD11b expression. While LY blocked SB-mediated Akt activation, enforced expression of a constitutively active (myristolated) Akt failed to attenuate SB/LY-mediated lethality. Unexpectedly, treatment of cells with SB+/-LY resulted in a marked reduction in phosphorylation (activation) of p44/42 mitogen-activated protein (MAP) kinase. Moreover, enforced expression of a constitutively active MEK1 construct partially but significantly attenuated SB/LY-induced apoptosis. Lastly, cotreatment with LY blocked SB-mediated induction of p21(CIP1/WAF1); moreover, enforced expression of p21(CIP1/WAF1) significantly reduced SB/LY-mediated apoptosis. Together, these findings indicate that LY promotes SB-mediated apoptosis through an AKT-independent process that involves MEK/MAP kinase inactivation and interference with p21(CIP1/WAF1) induction.
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PMID:Inhibition of PI-3 kinase sensitizes human leukemic cells to histone deacetylase inhibitor-mediated apoptosis through p44/42 MAP kinase inactivation and abrogation of p21(CIP1/WAF1) induction rather than AKT inhibition. 1367 62

The effect of conjugated docosahexaenoic acid (CDHA) on the inhibition of colon cancer cell growth was examined in the colo 201 human colon cancer cell line, and the effect was compared with docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). CDHA was a more potent tumor cell growth inhibitor than DHA and EPA by colorimetric 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay (IC50 for 72 h: 31.6 microM, 46.8 microM, and 56.6 microM, respectively). CDHA inhibited cell cycle progression, due to accumulation of cells in G1 phase, which involved increased p21Cip1/Waf1 and decreased cyclin D1, cyclin E, and proliferating cell nuclear antigen expression; the p53 and cyclin A levels were unchanged. Induction of apoptosis was confirmed by the appearance of sub-G1 populations, and apoptosis cascade involved upregulation of the apoptosis-enhancing proteins (Bak and Bcl-xS) and downregulation of the apoptosis-suppressing proteins (Bcl-xL and Bcl-2). CDHA modulated cell cycle regulatory proteins and apoptosis-related proteins, similar to the effects of DHA. CDHA at a dietary dose of 1.0% significantly inhibited growth of colo 201 cells transplanted in nude mice.
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PMID:Conjugated docosahexaenoic acid is a potent inducer of cell cycle arrest and apoptosis and inhibits growth of colo 201 human colon cancer cells. 1557

The cyclin-dependent kinase inhibitor p21Cip1/Waf1/Sdi1 protects the lung against hyperoxia, but the mechanism of protection remains unclear because loss of p21 does not lead to aberrant cell proliferation. Because some members of the Bcl-2 gene family have been implicated in hyperoxia-induced cell death, the current study investigated their expression as well as p21-dependent growth suppression and cytoprotection. Conditional overexpression of full-length p21, its amino-terminal cyclin-binding (p211-82NLS) domain or its carboxy-terminal PCNA-binding (p2176-164) domain inhibited growth of human lung adenocarcinoma H1299 cells, but only the full-length protein was cytoprotective. Low levels of p21 inhibited cell proliferation, whereas higher levels were required for protection. Expression of the anti-apoptotic protein Bcl-XL declined during hyperoxia but was maintained in cells expressing p21. RNA interference (RNAi) knockdown of Bcl-XL enhanced hyperoxic death of cells expressing p21, whereas overexpression of Bcl-XL increased cell survival. Consistent with growth suppression and cytoprotection requiring different levels of p21, hyperoxia inhibited PCNA expression in p21+/+ and p21+/- mice but not in p21-/- mice. In contrast, p21 was haplo-insufficient for maintaining expression of Bcl-XL and protection against hyperoxia. Taken together, these data show that p21-mediated cytoprotection against hyperoxia involves regulation of Bcl-XL and is uncoupled from its ability to inhibit proliferation.
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PMID:p21Cip1 protection against hyperoxia requires Bcl-XL and is uncoupled from its ability to suppress growth. 1672 99

Lymphocyte production in bone marrow (BM) requires substantial cell division, but the relationship between largely quiescent stem cells and dividing lymphoid progenitors is poorly understood. Therefore, the proliferation and cell cycle status of murine hematopoietic progenitors that have just initiated the lymphoid differentiation program represented the focus of this study. Continuous bromo-2'-deoxyuridine (BrdU) incorporation and DNA/RNA analysis by flow cytometry revealed that a surprisingly large fraction of RAG-1(+)c-kit(hi) early lymphoid progenitors (ELPs) and RAG-1(+)c-kit(lo) pro-lymphocytes (Pro-Ls) in adult BM were in cell cycle quiescence. In contrast, their counterparts in 14-day fetal liver actively proliferated. Indeed, the growth fraction (cells in G(1)-S-G(2)-M phases) of fetal ELPs was on average 80% versus only 30% for adult ELPs. After 5-fluorouracil treatment, as many as 60% of the adult ELP-enriched population was in G(1)-S-G(2)-M and 34% incorporated BrdU in 6 hours. Transcripts for Bcl-2, p21Cip1/Waf1, and p27 Kip1 cell cycle regulatory genes correlated inversely well with proliferative activity. Interestingly, adult lymphoid progenitors in rebound had the high potential for B lymphopoiesis in culture typical of their fetal counterparts. Thus, lymphocyte production is sustained during adult life by quiescent primitive progenitors that divide intermittently. Some, but not all, aspects of the fetal differentiation program are reacquired after chemotherapy.
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PMID:Cell cycle quiescence of early lymphoid progenitors in adult bone marrow. 1693 72

The overexpression of the antiapoptotic gene Bcl-2 has been previously shown to protect cells from undergoing apoptosis during exposure to environmental stress. There is strong evidence that, in addition to its well-known effects on apoptosis, Bcl-2 is involved in antioxidant protection and regulation of cell cycle progression. To determine if the overexpression of Bcl-2 could improve the process of adaptation to suspension and protein-free growth environments, we have studied the growth and viability of anchorage-dependent Chinese hamster ovary cell lines that differ only in there expression of Bcl-2. In addition, we examined the effect of combining Bcl-2 and p21CIP1 expression during adaptation to suspension and protein-free environments. The results of this study provide evidence of a clear reduction in the overall time required for the process of adaptation to both suspension and protein-free environments in Bcl-2 expressing cultures and that through the combined expression of p21CIP1 and Bcl-2, it is possible to further reduce the time. The Bcl-2 results support the well-demonstrated concept that this protein plays an important role in apoptotic signaling pathways and suggest that it may also provide more diverse functions beside its death-inhibiting role.
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PMID:The role of Bcl-2 and its combined effect with p21CIP1 in adaptation of CHO cells to suspension and protein-free culture. 1818 37

Pancreatic cancer cells are resistant to the growth-inhibitory and apoptosis-inducing effects of conventional chemotherapeutic agents. There are multiple genetic and epigenetic events during the process of carcinogenesis that enable the cancer cells to avoid normal growth constraints and apoptosis. Investigation of the mechanisms involved has led to multiple strategies that encourage cell death and apoptosis to occur. The pathways involved are summarized in this review, together with some recently developed strategies to promote cell death in this cancer and with a particular focus on the frondoside A, a novel triterpenoid glycoside isolated from the Atlantic sea cucumber, Cucumaria frondosa. Frondoside A inhibited proliferation of AsPC-1 human pancreatic cancer cells in a concentration- and time-dependent manner, as measured by (3)H-thymidine incorporation and cell counting. In concert with inhibition of cell growth, frondoside A induced significant morphological changes consistent with apoptosis. Propidium iodide DNA staining showed an increase of sub-G0/G1 cell population of apoptotic cells induced by frondoside A. Frondoside A-induced apoptosis was confirmed by annexin V binding and TUNEL assay. Furthermore, western blotting showed a decrease in expression of Bcl-2 and Mcl-1, an increase in Bax expression, activation of caspases 3, 7, and 9, and an increase in the expression of the cyclin-dependent kinase inhibitor, p21. These findings show that frondoside A induced apoptosis in human pancreatic cancer cells through the mitochondrial pathway and activation of the caspase cascade. Finally, a very low concentration of frondoside A (10 mug/kg/day) inhibited growth of AsPC-1 xenografts in athymic mice. In conclusion, new chemotherapeutic agents are desperately needed for pancreatic cancer because of the poor responsiveness to currently available treatment options. Frondoside A has potent growth inhibitory effects on human pancreatic cancer cells, and the inhibition of proliferation is accompanied by marked apoptosis. Frondoside A may be valuable for the treatment or chemoprevention of this devastating disease.
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PMID:Review of the apoptosis pathways in pancreatic cancer and the anti-apoptotic effects of the novel sea cucumber compound, Frondoside A. 1883 99

Resistance to growth suppression by TGF-beta1 is common in cancer; however, mutations in this pathway are rare in hematopoietic malignancies. In multiple myeloma, a fatal cancer of plasma cells, malignant cells accumulate in the TGF-beta-rich bone marrow due to loss of both cell cycle and apoptotic controls. Herein we show that TGF-beta activates Smad2 but fails to induce cell cycle arrest or apoptosis in primary bone marrow myeloma and human myeloma cell lines due to its inability to activate G(1) cyclin-dependent kinase (CDK) inhibitors (p15(INK4b), p21(CIP1/WAF1), p27(KIP1), p57(KIP2)) or to repress c-myc and Bcl-2 transcription. Correlating with aberrant activation of CDKs, CDK-dependent phosphorylation of Smad2 on Thr(8) (pT8), a modification linked to impaired Smad activity, is elevated in primary bone marrow myeloma cells, even in asymptomatic monoclonal gammopathy of undetermined significance. Moreover, CDK2 is the predominant CDK that phosphorylates Smad2 on T8 in myeloma cells, leading to inhibition of Smad2-Smad4 association that precludes transcriptional regulation by Smad2. Our findings provide the first direct evidence that pT8 Smad2 couples dysregulation of CDK2 to TGF-beta resistance in primary cancer cells, and they suggest that disruption of Smad2 function by CDK2 phosphorylation acts as a mechanism for TGF-beta resistance in multiple myeloma.
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PMID:CDK2 phosphorylation of Smad2 disrupts TGF-beta transcriptional regulation in resistant primary bone marrow myeloma cells. 1920 32

It is well known that Phellinus linteus has a variety of biological functions, such as antitumor and immunomodulating activities. In our previous studies, we developed a P. linteus grown on germinated brown rice (PBR) and found that organic solvent extracts of PBR possessed immunomodulating activity to regulate a balance of cytokine network in mice. The components of PBR are ergosterol peroxide, gamma-aminobutyric acid (GABA) and Beta-glucan. In this study, we demonstrate that an organic solvent extract of P. linteus grown on PBR induced apoptotic cell death through the induction of G(0)/G(1) arrest of cell cycle and the apoptosis via DNA fragmentation in human colon carcinoma HT-29 cells. Cell death induced by the extract of P. linteus grown on PBR was shown to be associated with the upregulation of p21(CIP1/WAF1), the downregulation of cyclin D1, anti-apoptotic protein, Bcl-2, the release of cytochrome c, and the activation of caspase-9, caspase-3 and caspase-8. This study suggests that the ethyl acetate extract of P. linteus grown on PBR induces apoptosis accompanied by cell cycle arrest at G(0)/G(1) phase and regulates apoptosis-regulatory proteins, which may be applicable to anticancer therapy.
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PMID:The ethyl acetate extract of Phellinus linteus grown on germinated brown rice induces G0/G1 cell cycle arrest and apoptosis in human colon carcinoma HT29 cells. 1999 18

Protein p53 plays an essential role in the induction of apoptosis by ionizing radiation in haemopoietic cells, the damage of which is the main reason for the development of bone marrow post-irradiation syndrome. p53 activation leads to an increase in the Bcl-2 family pro-apoptotic protein PUMA level. PUMA inhibits all the five anti-apoptotic proteins (Mcl-1, Bcl-2, Bcl-XL, Bcl-W and A1) and directly triggers apoptosis mediated by pro-apoptotic proteins Bax/Bak. In proliferating cells, knockout of p53 inhibits apoptosis on the one hand, but on the other disables the cellular division arrest moderated by p21Cip1/Waf1. The radioprotective effect of p53 inhibitor pifithrin was obvious at radiation doses causing the bone marrow syndrome. Knockout of PUMA also exerts its radioprotective effect through blocking the apoptosis induction, but the arrest of cells in the cell cycle through p21 induction is not abolished. PUMA -/- mice are radioresistant in terms of the development of post-irradiation syndrome after all radiation doses. Small molecules are being searched for that could prevent binding of PUMA with Bcl-2 family anti-apoptotic proteins. This would result in apoptosis inhibition and radioprotective or mitigating effects of these inhibitors.
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PMID:Importance of proapoptotic protein PUMA in cell radioresistance. 2478 7

Triptolide is a traditional Chinese medicinal herb-derived antineoplastic agent. However, its antitumor activity against gynecologic carcinomas has not yet been well described. It is the purpose of this article to investigate the effect and mechanism of triptolide in human ovarian cancer using both A2780 (p53 wild) and OVCAR-3 (p53 mutated) cells. Our results showed that triptolide exerted a potent inhibitory effect on the growth and proliferation of both cell lines in a dose- and time-dependent manner and that the effect was independent of the expression of p53. In contrast, triptolide had only a marginal cytotoxicity in noncancerous ovary cells, lung fibroblast cells, and macrophage cells, indicating differential inhibitory effects of the drug on cell growth between ovarian cancer cells and normal tissue cells. Exposure of the ovarian cancer cells to triptolide induced apoptosis, as evaluated by annexin V/propidium iodide-labeled flow cytometry. Triptolide-induced apoptosis was accompanied by cytochrome c release and caspase-3 activation and was associated with downregulation of Bcl-2 and upregulation of Bax. Cell cycle analysis demonstrated that treatment with triptolide induced cell cycle S phase arrest in A2780 cells and G2/M phase arrest in OVCAR-3 cells. Further detection by Western blotting revealed that the cell cycle arrest by triptolide in both cell lines occurred in concert with increased expression of p21(CIP1/WAF1). This study shows that triptolide selectively kills ovarian cancer cells with different p53 status predominantly through regulating the coordinate and dynamic cellular processes of proliferation and apoptosis, thereby making it a promising chemotherapeutic agent against a broad spectrum of ovarian carcinomas.
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PMID:Selective tumor cell killing by triptolide in p53 wild-type and p53 mutant ovarian carcinomas. 2488 Apr 64


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