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

HTLV-I is etiologically implicated with tropical spastic paraparesis/HTLV-I associated myelopathy, adult T-cell leukemia and certain other diseases. However, after infection the virus enters into a dormant state, whereas the characteristics of the HTLV-I related diseases indicate that their genesis requires activation of the dormant virus by a Tax-independent mechanism. In the present study we demonstrate that a variety of stress-inducing agents (TPA, cisplatin, etoposide, taxol, and 3-methylcholanthrene) are capable of Tax-independent activation of HTLV-I LTR and that this activation is detected mainly in cells that are undergoing through the apoptotic process. Furthermore, it is demonstrated that both apoptosis induction and HTLV-I LTR activation are inhibited by Bcl-2 and by PKC, indicating that these two processes are mechanistically cross-linked. In addition, using an HTLV-I producing human T-cell line which permanently express the negatively transdominant tax mutant, Delta58tax, under the Tet-Off control system, we prove that the virally encoded Tax protein protects the host cells from apoptosis. Together, these data suggest that activation of the dormant virus in the carriers' infected T-cells by certain stress-inducing conditions and protecting these cells from the consequent apoptotic death by the viral Tax protein emerging after this activation, might be the basis for switching the virus from latency to a pathogenic phase.
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PMID:Activation of HTLV-I long terminal repeat by stress-inducing agents and protection of HTLV-I-infected T-cells from apoptosis by the viral tax protein. 1169 93

TPA-1 is a subclone of B cell hybridomas established by somatic hybridization using B cells of A/J mice immunized with TNP-LPS, and expresses a receptor for TNP on the cell membrane. The present study showed that TPA-1 was induced to apoptotic cell death upon treatment with TNP-BSA. Therefore, TPA-1 is considered to provide a good model for the study on activation-induced cell death of mature B cells induced by soluble antigen. TNP-BSA treatment caused the generation of a large amount of intracellular reactive oxygen species (ROS) of TPA-1, and the addition of the monovalent thiol-reactive compound: monochlorobimane (MCB) rescued it from apoptosis as well as the antioxidant reagent: N-acetyl-L-cysteine. Furthermore, MCB markedly inhibited the generation of ROS and prevented the disruption of mitochondrial membrane potential that was induced by TNP-BSA treatment. In addition, it counteracted the effect of TNP-BSA on the expression of the Bcl-2 family, resulting in down-regulation of Bax and Bad and up-regulation of Bcl-XL. Taken together, these results suggest strongly that oxidative stress of mitochondria may be involved directly in apoptotic cell death by engagement of antigen receptors on mature B cells with soluble antigen.
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PMID:The molecular mechanism in activation-induced cell death of an Ag-reactive B cell clone. 1206 98

Pro-apoptotic functions of the BH3-only protein BAD are negatively regulated by survival signal-mediated phosphorylation at several serine residues. Recently, we found that the mutant BAD (BADD119G) with an amino acid substitution of Asp (Asp119 to Gly) within the BH3 domain displays strong pro-apoptotic activity in serum-starved COS-7 cells, although it cannot interact with Bcl-2. Here, we demonstrate that the BADD119G loses phosphorylation-mediated negative regulation. Importantly, pro-apoptotic activity of wild-type BAD (BADwt) was strongly suppressed by co-transfection with constitutively active Akt (CA-Akt) cDNA, whereas that of BADD119G was not. In these transfectants, BADD119G phosphorylation was barely detectable at serine residues (S75 and S99), although BADwt phosphorylation was clearly increased by CA-Akt. In addition, various external stimuli UV, TPA and forskolin could not phosphorylate BADD119G neither at S75, S99 nor S118 in COS-7 cells. However, in vitro kinase assay revealed that catalytic protein kinase A (PKA) strongly phosphorylated both BADs at S75 and S118, excluding the possibility that the target sequence of PKA was disrupted by mutation at S119. Furthermore, as a result of disrupted phosphorylation, BADD119G could not physically interact with 14-3-3. Taken together, disruption of phosphorylation-mediated negative regulation may explain, at least in part, the strong pro-apoptotic functions of BADD119G, and suggest a role for the BH3 domain in phosphorylation events.
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PMID:Mutation of BAD within the BH3 domain impairs its phosphorylation-mediated regulation. 1296 20

Curcumin (Diferuloylmethane) is a major chemical component of turmeric (curcuma longa) and is used as a spice to give a specific flavor and yellow color in Asian food. Curcumin exhibits growth inhibitory effects in a broad range of tumors as well as in TPA-induced skin tumors in mice. This study was undertaken to investigate the radiosensitizing effects of curcumin in p53 mutant prostate cancer cell line PC-3. Compared to cells that were irradiated alone (SF(2)=0.635; D(0)=231 cGy), curcumin at 2 and 4 microM concentrations in combination with radiation showed significant enhancement to radiation-induced clonogenic inhibition (SF(2)=0.224: D(0)=97 cGy and SF(2)=0.080: D(0)=38 cGy) and apoptosis. It has been reported that curcumin inhibits TNF-alpha-induced NFkappaB activity that is essential for Bcl-2 protein induction. In PC-3 cells, radiation upregulated TNF-alpha protein leading to an increase in NFkappaB activity resulting in the induction of Bcl-2 protein. However, curcumin in combination with radiation treated showed inhibition of TNF-alpha-mediated NFkappaB activity resulting in bcl-2 protein downregulation. Bax protein levels remained constant in these cells after radiation or curcumin plus radiation treatments. However, the downregulation of Bcl-2 and no changes in Bax protein levels in curcumin plus radiation-treated PC-3 cells, together, altered the Bcl2 : Bax ratio and this caused the enhanced radiosensitization effect. In addition, significant activation of cytochrome c and caspase-9 and -3 were observed in curcumin plus radiation treatments. Together, these mechanisms strongly suggest that the natural compound curcumin is a potent radiosesitizer, and it acts by overcoming the effects of radiation-induced prosurvival gene expression in prostate cancer.
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PMID:Curcumin confers radiosensitizing effect in prostate cancer cell line PC-3. 1498 1

Thymoquinone (TQ), the most abundant constituent in black seed, was shown to possess potent chemopreventive activities against DMBA-initiated TPA-promoted skin tumors in mice. Despite the potential interest in TQ as a skin antineoplastic agent, its mechanism of action has not been examined yet. Using primary mouse keratinocytes, papilloma (SP-1) and spindle (I7) carcinoma cells, we studied the cellular and molecular events involved in TQ's antineoplastic activity. We show that non-cytotoxic concentrations of TQ reduce the proliferation of neoplastic keratinocytes by 50%. The sensitivity of cells to TQ treatment appears to be stage dependent such that papilloma cells are twice as sensitive to the growth inhibitory effects of TQ as the spindle cancer cells. TQ treatment of SP-1 cells induced G0/G1 cell-cycle arrest, which correlated with sharp increases in the expression of the cyclin-dependent kinase inhibitor p16 and a decrease in cyclin D1 protein expression. TQ-induced growth inhibition in I7 cells by inducing G2/M cell-cycle arrest, which was associated with an increase in the expression of the tumor suppressor protein p53 and a decrease in cyclin B1 protein. At longer times of incubation, TQ induced apoptosis in both cell lines by remarkably increasing the ratio of Bax/Bcl-2 protein expression and decreasing Bcl-xL protein. The apoptotic effects of TQ were more pronounced in SP-1 than in I7 cells. Collectively, these findings support a potential role for TQ as a chemopreventive agent, particularly at the early stages of skin tumorigenesis.
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PMID:Molecular pathway for thymoquinone-induced cell-cycle arrest and apoptosis in neoplastic keratinocytes. 1505 44

S-100 proteins are calcium-binding proteins with important growth regulatory functions. Of these proteins, psoriasin and calgranulin-B have been shown to be highly upregulated in ductal carcinoma in situ (DCIS) of the breast and in psoriasis. The purpose of this study was to further elucidate the functional relevance of the overexpression of these two S-100 proteins in psoriasis and DCIS. We report the induction of both proteins by reactive oxygen species, phorbol ester TPA, and the induction of psoriasin in response to the PI3K inhibitor wortmannin. We also demonstrate that Bcl-2 overexpression represses the induction of psoriasin and calgranulin-B under these different conditions. The same effect was obtained with the antioxidant NAC, which indicates that the suppression of psoriasin and calgranulin-B induction is mediated by the antioxidant function of Bcl-2. Furthermore, we demonstrate that overexpression of a dominant negative IKKbeta also inhibits the induction of psoriasin suggesting that the NFkappaB pathway is involved in the induction of this protein. Also, we found NFkappaB responsive DNA elements in the upstream promoter region of psoriasin. MCF10A cells with a stable retroviral overexpression of psoriasin were significantly more resistant to H2O2-induced cell death than control cells further supporting the hypothesis that these S-100 proteins may play a role in oxidative stress response.
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PMID:Psoriasin (S100A7) and calgranulin-B (S100A9) induction is dependent on reactive oxygen species and is downregulated by Bcl-2 and antioxidants. 1608 88

The study was aimed to explore the role of gene JWA, a novel retinoic acid responsible and cytoskeleton associate gene, in regulating committed differentiation of HL-60 cell and the molecular mechanism in the course of differentiation and apoptosis of leukemic cells. By using FCM, the changes of CD13, CD14, CD15, CD11b and cell cycles were detected in HL-60 cells treated with ATRA (10(-6) mol/L), Ara-C (10 ng/ml) and TPA (10(-8) mol/L) respectively. The samples were determined by semi-quantitative reverse transcript-polymerase chain reaction (RT-PCR) and Western blot for the expression of JWA, Bcl-2, HSP27 and HSP70 at day 0, 2, 4, 6, 8. The results showed that HL-60 cells committedly differentiated into granulocyte-, monocyte-, macrophage-like cells. As a result, JWA was up-regulated in a time-dependent manner, while Bcl-2 was down- regulated at the same time. In ATRA and TPA group, the change of HSP70 had positive correlation with JWA, and negative correlation with Bcl-2. The expression of HSP27 was not detected. Contrast to the cells from APL patient, the expression of JWA need not be activated by ATRA in advance. In this study, we also exposed HL-60 cells in higher dose of Ara-C (20 ng/ml), and JWA expression underwent opposite trend comparing with in lower dose of Ara-C (10 ng/ml). It is concluded that JWA may play double important roles in regulating ATRA and TPA-induced differentiation and apoptosis in leukemic cells. The JWA expression had a negative correlation between induction and cytotoxic response. The difference of JWA expressions between HL-60 cell and ANLL patient cells would be involved in different leukemia pathogenesis.
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PMID:[JWA gene in regulating committed differentiation of HL-60 cells induced by ATRA, Ara-C and TPA]. 1627 46

PKC-delta is a serine/threonine kinase that mediates diverse signal transduction pathways. We previously demonstrated that overexpression of PKC-delta slowed the G1 progression of Caco-2 colon cancer cells, accelerated apoptosis, and induced cellular differentiation. In this study, we further characterized the PKC-delta dependent signaling pathways involved in these tumor suppressor actions in Caco-2 cells overexpressing PKC-delta using a Zn2+ inducible expression vector. Consistent with a G1 arrest, increased expression of PKC-delta caused rapid and significant downregulation of cyclin D1 and cyclin E proteins (50% decreases, P<0.05), while mRNA levels remained unchanged. The PKC agonist, phorbol 12-myristate 13-acetate (TPA, 100 nM, 4 h), induced two-fold higher protein and mRNA levels of p21(Waf1), a cyclin-dependent kinase (cdk) inhibitor in PKC-delta transfectants compared with empty vector (EV) transfected cells, whereas the PKC-delta specific inhibitor rottlerin (3 microM) or knockdown of this isoenzyme with specific siRNA oligonucleotides blocked p21(Waf1) expression. Concomitantly, compared to EV control cells, PKC-delta upregulation decreased cyclin D1 and cyclin E proteins co-immunoprecipitating with cdk6 and cdk2, respectively. In addition, overexpression of PKC-delta increased binding of cdk inhibitor p27(Kip1) to cdk4. These alterations in cyclin-cdks and their inhibitors are predicted to decrease G1 cyclin kinase activity. As an independent confirmation of the direct role PKC-delta plays in cell growth and cell cycle regulation, we knocked down PKC-delta using specific siRNA oligonucleotides. PKC-delta specific siRNA oligonucleotides, but not irrelevant control oligonucleotides, inhibited PKC-delta protein by more than 80% in Caco-2 cells. Moreover, PKC-delta knockdown enhanced cell proliferation ( approximately 1.4-2-fold, P<0.05) and concomitantly increased cyclin D1 and cyclin E expression ( approximately 1.7-fold, P<0.05). This was a specific effect, as nontargeted PKC-zeta was not changed by PKC-delta siRNA oligonucleotides. Consistent with accelerated apoptosis in PKC-delta transfectants, compared to EV cells, PKC-delta upregulation increased proapoptotic regulator Bax two-fold at mRNA and protein levels, while antiapoptotic Bcl-2 protein was decreased by 50% at a post-transcriptional level. PKC-delta specific siRNA oligonucleotides inhibited Bax protein expression by more than 50%, indicating that PKC-delta regulates apoptosis through Bax. Taken together, these results elucidate two critical mechanisms regulated by PKC-delta that inhibit cell cycle progression and enhance apoptosis in colon cancer cells. We postulate these antiproliferative pathways mediate an important tumor suppressor function for PKC-delta in colonic carcinogenesis.
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PMID:Protein kinase C delta inhibits Caco-2 cell proliferation by selective changes in cell cycle and cell death regulators. 1643 69

Proapoptotic nuclear receptor family member Nur77 translocates from the nucleus to the mitochondria, where it interacts with Bcl-2 to trigger apoptosis. Nur77 translocation is induced by certain apoptotic stimuli, including the synthetic retinoid-related 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalenecarboxylic acid (AHPN)/CD437 class. In this study, we investigated the molecular mechanism by which AHPN/CD437 analog (E)-4-[3-(1-adamantyl)-4-hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC) induces Nur77 nuclear export. Our results demonstrate that 3-Cl-AHPC effectively activated Jun N-terminal kinase (JNK), which phosphorylates Nur77. Inhibition of JNK activation by a JNK inhibitor suppressed 3-Cl-AHPC-induced Nur77 nuclear export and apoptosis. In addition, several JNK upstream activators, including the phorbol ester TPA, anisomycin and MAPK kinase kinase-1 (MEKK1), phosphorylated Nur77 and induced its nuclear export. However, Nur77 phosphorylation by JNK, although essential, was not sufficient for inducing Nur77 nuclear export. Induction of Nur77 nuclear export by MEKK1 required a prolonged MEKK1 activation and was attenuated by Akt activation. Expression of constitutively active Akt prevented MEKK1-induced Nur77 nuclear export. Conversely, transfection of dominant-negative Akt or treatment with a phosphatidylinositol 3-kinase (PI3-K) inhibitor accelerated MEKK1-induced Nur77 nuclear export. Furthermore, mutation of an Akt phosphorylation residue Ser351 in Nur77 abolished the effect of Akt or the PI3-K inhibitor. Together, our results demonstrate that both activation of JNK and inhibition of Akt play a role in translocation of Nur77 from the nucleus to the cytoplasm.
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PMID:Regulation of Nur77 nuclear export by c-Jun N-terminal kinase and Akt. 1643 70

In the present study, we found that baicalein (BE), but not its glycoside baicalin (BI), induced apoptosis in human leukemia HL-60 and Jurkat cells, but not in primary murine peritoneal macrophages (PMs) or human polymorphonuclear (PMN) cells, by the MTT assay, LDH release assay, and flow cytometric analysis. Activation of the caspase 3, but not caspase 1, enzyme via inducing protein processing was detected in BE-induced apoptosis. The ROS-scavenging activity of BE was identified by the anti-DPPH radical, DCHF-DA, and in vitro plasmid digestion assay, and none of chemical antioxidants including allpurinol (ALL), N-acetyl-cystein (NAC), and diphenylene iodonium (DPI) affected BE-induced apoptosis in HL-60 cells. This suggests that apoptosis induced by BE is independent of the production of ROS in HL-60 cells. Interestingly, the apoptotic events such as DNA ladders formation and activation of the caspase 3 cascade were significantly blocked by TPA addition in the presence of membrane translocation of PKCalpha, and TPA-induced protection was reduced by adding the PKC inhibitors, GF-109203X and staurosporin. TPA addition induces the phosphorylation of JNKs and ERKs, but not p38, protein in HL-60 cells, and incubation of HL-60 cells with JNKs inhibitor SP600125, but not ERKs inhibitor, PD98059 or the p38 inhibitor SB203580, suppressed the protective effect of TPA against BE-induced apoptotic events including DNA ladders, apoptotic bodies, caspase 3 and D4-GDI protein cleavage in according with blocking JNKs protein phosphorylation. In addition, PKC inhibitor GF-109203X treatment blocks TPA-induced ERKs and JNKs protein phosphorylation, which indicates that activation of PKC locates at upstream of MAPKs activation in TPA-treated HL-60 cells. Additionally, a loss in mitochondrial membrane potential with a reduction in Bcl-2 protein expression, the induction of Bad protein phosphorylation, and translocation of cytochrome c from mitochondria to the cytosol were observed in BE-treated HL-60 cells, and these events were prevented by the addition of TPA. GF-109203X and SP600125 suppression of TPA against cytochrome c release induced by BE was identified. This suggests that activation of PKC and JNKs participate in TPA's prevention of BE-induced apoptosis via suppressing mitochondrial dysfunction in HL-60 cells.
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PMID:12-o-Tetradecanoylphorbol 13-acetate prevents baicalein-induced apoptosis via activation of protein kinase C and JNKs in human leukemia cells. 1701 57


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