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)

The p53 tumor suppressor controls a cell cycle arrest and apoptosis pathway that is central to tumor suppression and often disrupted in cancer. The accumulation and activity of p53 are positively controlled by the p14/ARF tumor suppressor and full restoration of the pathway in cancer cells may require that both p53 and p14ARF be supplied [corrected]. To address this issue, we have constructed a bicistronic adenoviral vector encoding the two proteins (Adp14/p53) and compared its tumor suppressor activity with that of a single gene vector for p53 (Adp53). We find that tumor cells treated with Adp14/p53 undergo a much sharper decrease in viability with increasing multiplicities of infection than do cells treated with Adp53, even when cells express endogenous p14ARF. Adp14/p53 is also more effective than is a combination of single gene vectors for p14 and p53. The sharper decrease in cell viability after treatment of cells with Adp14/p53 correlates with an increased rate of p53 protein synthesis and a decreased rate of p53 protein turnover, leading to increased steady-state levels of p53 protein and increased levels of p53 downstream targets mdm2, p21waf1, and bax. Adp14/p53 treatment leads to an elevated bax:bcl2 ratio and induction of apoptosis in vitro and in vivo, coupled with a failure of the tumor cells to induce neovascularization in vivo. The results indicate that endogenous p14ARF expression may be insufficient to ensure efficient accumulation of ectopic p53 after gene transfer and demonstrate that for tumor suppression, bicistronic coexpression of p14ARF and p53 is superior to p53 alone. The results show that in this setting, p14ARF promotes p53 accumulation by increasing p53 protein synthesis, in addition to its well-characterized ability to oppose mdm2-mediated degradation of p53.
 ...
PMID:Enhanced tumor suppression by a p14ARF/p53 bicistronic adenovirus through increased p53 protein translation and stability. 1283 54

We have recently shown that oral consumption of green tea polyphenols inhibits prostate carcinogenesis in transgenic mouse model of prostate cancer and suggested that induction of apoptosis in prostate cancer cells is responsible for these effects. Much of the chemopreventive effects of green tea are attributed to its major polyphenolic constituent (-) epigallocatechin-3-gallate (EGCG). In the present study, we report that EGCG-induced apoptosis in human prostate carcinoma LNCaP cells is mediated via modulation of two related pathways: (a) stabilization of p53 by phosphorylation on critical serine residues and p14ARF-mediated downregulation of murine double minute 2(MDM2) protein, and (b) negative regulation of NF-kappaB activity, thereby decreasing the expression of the proapoptotic protein Bcl-2. EGCG-induced stabilization of p53 caused an upregulation in its transcriptional activity, thereby resulting in activation of its downstream targets p21/WAF1 and Bax. Thus, EGCG had a concurrent effect on two important transcription factors p53 and NF-kappaB, causing a change in the ratio of Bax/Bcl-2 in a manner that favors apoptosis. This altered expression of Bcl-2 family members triggered the activation of initiator capsases 9 and 8 followed by activation of effector caspase 3. Activation of the caspases was followed by poly (ADP-ribose) polymerase cleavage and induction of apoptosis. Taken together, the data indicate that EGCG induces apoptosis in human prostate carcinoma cells by shifting the balance between pro- and antiapoptotic proteins in favor of apoptosis.
 ...
PMID:Role of p53 and NF-kappaB in epigallocatechin-3-gallate-induced apoptosis of LNCaP cells. 1289 26

p16(INK4a) (hereafter referred to as p16), a major cyclin-dependent kinase (CDK) inhibitor, is the product of a tumor-suppressor gene that has been found inactivated in different cancer types. In the present study, we sought to investigate the role of p16 in apoptosis induced by ultraviolet light (the most important etiological cause of skin cancer) and cisplatin (an anticancer DNA damaging agent). It is clearly shown that p16-compromised osteosarcoma U2OS cell line and p16-/- mouse embryo fibroblasts are sensitive to UV-induced apoptosis, as compared to their respective isogenic p16-expressing cells (EH1, EH2) and p16 +/+, indicating that p16 protects cells from undergoing apoptosis in response to UV light. Importantly, this reduction in UV-mediated apoptosis was associated with downregulation of the proapoptotic Bax protein, with no effect on Bcl-2 expression, suggesting that this antiapoptotic role of p16 is mediated via the intrinsic-mitochondrial pathway. On the other hand, p16 sensitized cells to cisplatin-mediated apoptosis through Bcl-2 decline. Interestingly, only proliferating but not G1-arrested EH1 cells underwent apoptosis in response to the anticancer drug. These novel findings provide further insight into the role of p16 in carcinogenesis, and has potential implications for future therapy strategies.
 ...
PMID:The tumor suppressor p16(INK4a) gene is a regulator of apoptosis induced by ultraviolet light and cisplatin. 1471 25

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.
 ...
PMID:Molecular pathway for thymoquinone-induced cell-cycle arrest and apoptosis in neoplastic keratinocytes. 1505 44

Bcl-2/adenovirus E1B 19 kDa interacting protein 2 like-1 (BNIPL-1) is a novel human protein identified in our laboratory, which can interact with Bcl-2 and Cdc42GAP and induce apoptosis via the BNIP-2 and Cdc42GAP homology (BCH) domain. In the present study, we established the Hep3B-Tet-on stable cell line in which expression of BNIPL-1 can be induced by doxycycline. The cell proliferation activity assay showed that the overexpression of BNIPL-1 suppresses Hep3B cell growth in vitro. The differential expression profiles of 588 known genes from BNIPL-1-transfected Hep3B-Tet-on and vector control cells were determined using the Atlas human cDNA expression array. Fifteen genes were differentially expressed between these two cell lines, among which seven genes were up-regulated and eight genes were down-regulated by BINPL-1. Furthermore, the differential expression result was confirmed by semiquantitative RT-PCR. Among these differentially expressed genes, p16INK4, IL-12, TRAIL and the lymphotoxin beta gene involved in growth suppression or cell apoptosis were up-regulated, and PTEN involved in cell proliferation was down-regulated by BNIPL-1. These results suggest that BNIPL-1 might inhibit cell growth though cell cycle arrest and/or apoptotic cell death pathway(s).
 ...
PMID:cDNA expression array analysis of gene expression in human hepatocarcinoma Hep3B cells induced by BNIPL-1. 1614 17

Human Ag-specific CD8(+) T lymphocytes are heterogeneous and include functionally distinct populations. In this study, we report that at least two distinct mechanisms control the expansion of circulating naive, memory, and effector CD8(+) T lymphocytes when exposed to mitogen or Ag stimulation. The first one leads to apoptosis and occurs shortly after in vitro stimulation. Susceptibility to cell death is prominent among primed T cell subsets, and it is inversely correlated with the size of the ex vivo Bcl-2(high) population within these subsets. Importantly, the Bcl-2(high) phenotype is associated to the proportion of responsive CD8(+) T cells, independently of their differentiation stage. The second one depends on the expression of newly synthesized cyclin-dependent kinase inhibitor p16(INK4a) that occurs in a significant fraction of T cells that had been actively cycling, leading to their cell cycle arrest upon stimulation. Strikingly, accumulation of p16(INK4a) protein preferentially occurs in naive as opposed to primed derived T lymphocytes and is not related to apoptosis. Significant levels of p16 are readily detectable in a small number of ex vivo CD8(+) T cells. Our observations reveal that activation-induced p16 expression represents an alternative process to apoptosis, limiting the proliferation potential of activated naive derived T lymphocytes.
 ...
PMID:Distinct mechanisms control human naive and antigen-experienced CD8+ T lymphocyte proliferation. 1645 73

A cell line, TW2.6, has been established from the surgically resected specimen of an untreated primary squamous cell carcinoma of the buccal mucosa from a 48-year-old man who was an areca quid chewer and tobacco smoker. TW2.6 cells exhibited morphological features of keratinocytes and replicated rapidly in culture with a doubling time of 24h. The karyotype showed human chromosomes with high hyperdiploidy and complex rearrangements. Western blotting showed pronounced expression of p53 and moderate expression of p21(CIP1). The baseline expressions of p27(KIP1) and p16(INK4a) were barely detectable. Low levels of Bax and Fas were found in TW2.6 cells but Bcl-2 expression was more readily observed. Mutational analysis of p53 gene revealed an A-->G transition at the second base of codon 220, resulting in amino acid substitution from tyrosine to cysteine in the protein. Functional analysis showed that TW2.6 was unable to activate the p53-specific PUMA promoter. Lipofectamine 2000 and calcium phosphate precipitation technique offer good transfection efficiencies for TW2.6 cells and may be used in future transfection experiments. A xenograft-SCID mouse tumor model was established for TW2.6. Histological examination demonstrated that the engrafted tumors maintained the morphological features of a squamous cell carcinoma. It is thought that the establishment of tumorigenic TW2.6 cell line provides a valuable model for AQ and tobacco smoke-associated buccal carcinoma.
 ...
PMID:Establishment and characterization of a tumorigenic cell line from areca quid and tobacco smoke-associated buccal carcinoma. 1707 96

The INK4 and CIP cyclin-dependent kinase (Cdk) inhibitors (CKI) activate pocket protein function by suppressing Cdk4 and Cdk2, respectively. Although these inhibitors are lost in tumors, deletion of individual CKIs results in modest proliferation defects in murine models. We have evaluated cooperativity between loss of all INK4 family members (using cdk4r24c mutant alleles that confer resistant to INK4 inhibitors) and p21(Waf1/Cip1) in senescence and transformation of mouse embryo fibroblasts (MEF). We show that mutant cdk4r24c and p21 loss cooperate in pRb inactivation and MEF immortalization. Our studies suggest that cdk4r24c mediates resistance to p15(INK4B)/p16(INK4A) that accumulates over passage, whereas loss of p21 suppresses hyperoxia-induced Cdk2 inhibition and pRb dephosphorylation on MEF explantation in culture. Although cdk4r24c and p21 loss cooperate in H-ras(V12)/c-myc-induced foci formation, they are insufficient for oncogene-induced anchorage-independent growth. Interestingly, p21(-/-); cdk4r24c MEFs expressing H-ras(V12) and c-myc display detachment-induced apoptosis and are transformed by c-myc, H-ras(V12), and Bcl-2. We conclude that the INK4 family and p21 loss cooperate in promoting pRb inactivation, cell immortalization, and H-ras(V12)/c-myc-induced loss of contact inhibition. In addition, absence of pRb function renders H-ras(V12) + c-myc-transduced fibroblasts prone to apoptosis when deprived of the extracellular matrix, and oncogene-induced anchorage-independent growth of pocket protein-deficient cells requires apoptotic suppression.
 ...
PMID:p21 loss cooperates with INK4 inactivation facilitating immortalization and Bcl-2-mediated anchorage-independent growth of oncogene-transduced primary mouse fibroblasts. 1748 23

Apigenin, a plant flavone, potentially activates wild-type p53 and induces apoptosis in cancer cells. We conducted detailed studies to understand its mechanism of action. Exposure of human prostate cancer 22Rv1 cells, harboring wild-type p53, to growth-suppressive concentrations (10-80 microM) of apigenin resulted in the stabilization of p53 by phosphorylation on critical serine sites, p14ARF-mediated downregulation of MDM2 protein, inhibition of NF-kappaB/p65 transcriptional activity, and induction of p21/WAF-1 in a dose- and time-dependent manner. Apigenin at these doses resulted in ROS generation, which was accompanied by rapid glutathione depletion, disruption of mitochondrial membrane potential, cytosolic release of cytochrome c, and apoptosis. Interestingly, we observed accumulation of a p53 fraction to the mitochondria, which was rapid and occurred between 1 and 3 h after apigenin treatment. All these effects were significantly blocked by pretreatment of cells with the antioxidant N-acetylcysteine, p53 inhibitor pifithrin-alpha, and enzyme catalase. Apigenin-mediated p53 activation and apoptosis were further attenuated by p53 antisense oligonucleotide treatment. Exposure of cells to apigenin led to a decrease in the levels of Bcl-XL and Bcl-2 and increase in Bax, triggering caspase activation. Treatment with the caspase inhibitors Z-VAD-FMK and DEVD-CHO partially rescued these cells from apigenin-induced apoptosis. In vivo, apigenin administration demonstrated p53-mediated induction of apoptosis in 22Rv1 tumors. These results indicate that apigenin-induced apoptosis in 22Rv1 cells is initiated by a ROS-dependent disruption of the mitochondrial membrane potential through transcriptional-dependent and -independent p53 pathways.
 ...
PMID:Apigenin-induced prostate cancer cell death is initiated by reactive oxygen species and p53 activation. 1834 37

Paclitaxel (PTX) is an anticancer drug currently in phase II clinical trials. This study shows for the first time that low doses of PTX (5 nM) potently induce apoptosis in human retinoblastoma Y79 cells. The effect of PTX is accompanied by a potent induction of E2F1 which appears to play a critical role in the effects induced by PTX. PTX induced a dose- and time-dependent effect, with G2/M arrest, cyclines A, E and B1 accumulation and a marked modification in the status of Cdc2-cyclin B1 complex, the major player of the G2/M checkpoint. Apoptosis followed G2/M arrest. An early and prolonged increase in p53 expression with its stabilization by phosphorylation and acetylation and its nuclear translocation occurred. Consistently, PTX increased p21WAF1, bax and MDM2 levels, suggesting that p53 is transcriptionally active. p53 accumulated following both E2F1 up-regulation and increase in the levels of p14ARF which interacts with MDM2 preventing ubiquitination and proteosomal degradation of p53. Both extrinsic (E2F1/Fas/JNK/caspase-2 activation) and intrinsic (Bcl-2 phosphorylation, Bid fragmentation and Bax increase) pathways seemed to be involved. Loss of mitochondrial potential and activation of apoptosome and executive caspase-3,-6 and-7 was shown. Incubation with either the irreversible pan-caspase inhibitors Z-VAD-FMK, or SP600125, a selective inhibitor of JNK, or pifithrin alpha, a potent p53 inhibitor, significantly inhibited the effects induced by PTX.
 ...
PMID:Low doses of paclitaxel potently induce apoptosis in human retinoblastoma Y79 cells by up-regulating E2F1. 1881 80


<< Previous 1 2 3 4 Next >>