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)

Bax alpha can heterodimerize with Bcl-2 and Bcl-X(L), countering their effects, as well as promoting apoptosis on overexpression. We show that bax alpha transgenic mice have greatly reduced numbers of mature T cells, which results from an impaired positive selection in the thymus. This perturbation in positive selection is accompanied by an increase in the number of cycling thymocytes. Further to this, mature T cells overexpressing Bax alpha have lower levels of p27Kip1 and enter S phase more rapidly in response to interleukin-2 stimulation than do control T cells, while the converse is true of bcl-2 transgenic T cells. These data indicate that apoptotic regulatory proteins can modulate the level of cell cycle-controlling proteins and thereby directly impact on the cell cycle.
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PMID:Bax alpha perturbs T cell development and affects cell cycle entry of T cells. 900 75

p27KiP1, a member of the Cip/Kip family of cyclin-dependent kinase (cdk) inhibitors, has been implicated in mediating G1 arrest in response to a variety of growth inhibitory signals. Its importance in regulating cell growth is emphasized by the fact that mice lacking p27Kip1 are abnormally large and display hyperplasia of multiple tissues. However, these mice retain the ability to undergo G1 arrest in response to growth inhibitory signals, suggesting that p27KiP1 may serve other functions important for controlling tissue growth. In the present study, we utilized an adenoviral vector-based expression system to examine the consequences of p27Kip1 overexpression in the human carcinoma cell lines A549, HeLa and RKO, in human melanoma SK-MEL-110 cells, in human lung fibroblasts IMR90 and in the rat fibroblast line Rat1. We demonstrate that overexpression of p27Kip1 leads to apoptotic cell death in all cell types, and further show that ectopic expression of Bcl-2 can protect HeLa cells from apoptosis mediated by p27Kip1 overexpression. To our knowledge, this is the first study demonstrating that p27Kip1 can induce apoptosis. Our findings provide new insight into the possible functions of this growth regulatory protein, and support the potential utility of gene therapeutic approaches aimed at elevating p27Kip1 expression for treatment of human cancers.
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PMID:p27Kip1 overexpression causes apoptotic death of mammalian cells. 941 43

To examine the biochemical pathways by which activated Ha-Ras(G12V) (Ha-RasV12) induces factor-independent growth of myeloid cells, Ha-Ras effector loop mutations, including Y40C, T35S, and E37G, were analysed in a mouse factor-dependent myeloid cell line, WT19. Expression of a single effector loop mutant, Ha-Ras(G12V, Y40C) (Ha-RasV12C40), inhibited factor-withdrawal apoptosis, suggesting that activation of the phosphatidylinositol 3'-kinase (Pl3K) pathway is essential to prevent cell death. Neither Ha-Ras (G12V, T35S) (Ha-RasV12S35), which activates the Rafl signaling pathway, nor Ha-Ras(G12V, E37G) (Ha-RasV12G37), which stimulates the RalGDS pathway, did not have significant effects on factor-withdrawal apoptosis of myeloid cells. Although Ha-RasV12C40 inhibited apoptosis, it did not stimulate entry into the cell cycle. Cell lines containing the combination of Ha-RasV12G37 and Ha-RasV12C40 were capable of factor-independent cell growth, while expression of the other combinations of the Ha-Ras effector mutants were not. The combined expression of Bcl-2 and Ha-RasV12G37 was not sufficient to stimulate factor independent growth, suggesting that Ha-RasV12C40 activates additional signals, besides blocking apoptosis, which are critical for factor-independent growth of myeloid cells. In factor-starved myeloid cells, inducible expression of Ha-RasV12G37 results in decreased level of p27Kip1 protein, a cyclin-dependent kinase inhibitor (CKI). These data suggest that the factor-independent growth of myeloid cells requires the activation of at least two pathways, one inhibiting factor-withdrawal apoptosis, and another causing cell cycle progression.
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PMID:Regulation of myeloid cell growth by distinct effectors of Ras. 984 Sep 34

The proteasome inhibitors lactacystin and AcLLNal induced p53-independent apoptosis in two human glioma cell lines, and the apoptosis was accompanied by up-regulation of immunoreactive wild-type p53, p21Waf1, Mdm2, and p27Kip1. Pretreatment with cycloheximide decreased the induction of cell death independently of p53 protein status, suggesting that the up-regulation of short-lived proteins is associated with proteasome inhibitor-induced apoptosis. Caspase-3-like proteases were activated in the proteasome inhibitor-mediated apoptosis, and the induction of cell death was inhibited more effectively in the presence of z-VAD.fmk than in the presence of Ac-DEVD.fmk, suggesting that caspases other than caspase-3 are involved. Nonetheless, there were no significant alterations in levels of immunoreactive Bcl-2, Bcl-X(L), Bax, Bad, and Bak, nor any evidence of cytochrome c release into cytosol and dissipation of delta(psi)m. Thus, the proteasome inhibitor-induced apoptosis is mediated by a mitochondria-independent mechanism, and the once activated caspase-3 does not cause the cytochrome c release and the delta(psi)m disruption.
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PMID:Proteasome inhibitors induce mitochondria-independent apoptosis in human glioma cells. 998 1

The cyclin-dependent kinase inhibitor p27Kip1 has been implicated as a drug resistance factor in tumor cells grown as spheroids or confluent monolayers. Here, we show that p27Kip1 overexpression also induces resistance to drug-induced apoptosis and cytotoxicity in human leukemic cells growing in suspension. The anti-apoptotic effect of p27Kip1 is not restricted to DNA-damaging agents but extends to the tubulin poison vinblastin, agonistic anti-Fas antibodies and macromolecule synthesis inhibitors. To further identify at which level this protein interferes with the cell death pathway, we investigated its influence on caspase activation and mitochondrial changes. Exposure of mock-transfected U937 cells to 50 microm etoposide activates procaspase-3 and the long isoform of procaspase-2 and induces mitochondrial potential decrease and cytochrome c release from mitochondria to the cytosol. All these events are prevented by p27Kip1 overexpression. p27Kip1 does not modulate Bcl-2, Bcl-X(L), Mcl-1 and Bax protein level in leukemic cells but suppresses Mcl-1 expression decrease observed in mock-transfected U937 cells undergoing etoposide-induced cell death. We conclude that p27Kip1 prevents cell death upstream of the final pathway common to many apoptotic stimuli that involves cytochrome c release from mitochondria and activation of downstream caspases.
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PMID:p27Kip1 induces drug resistance by preventing apoptosis upstream of cytochrome c release and procaspase-3 activation in leukemic cells. 1005 Aug 78

p27Kip1, a cyclin-dependent kinase inhibitor, is a negative regulator of the cell cycle, and apoptosis is a genetically encoded program of cell death. To clarify the relationship between the cell cycle and apoptosis, we investigated expression of p27, cyclin D1 and apoptosis-related proteins (p53, Bax, Bcl-2 and c-Myc) in 60 cases of oral and oropharyngeal squamous-cell carcinoma (SCC) using an immuno-histochemical approach, and evaluated spontaneous apoptosis in vivo. Our most notable finding was that spontaneous apoptosis in the p27-positive group was significantly higher than that in the p27-negative group (p = 0.028). In addition, the percentage of p27-positive cells was clearly correlated with that of Bax-positive cells (gamma = 0.288, p = 0.028) and with that of cyclin D1-positive cells (gamma = 0.416, p = 0.002). Expression of p27 was inversely associated with the clinical stage of total tumor progression (p = 0.027). However, no correlation was found between p27 expression and the following parameters: gender, tumor size, lymph node metastasis, overall survival and disease-free survival. Our results give evidence that the action of the cell-cycle regulator p27 is closely linked with apoptosis in clinical samples from patients and indicate that over-expression of p27 might induce apoptosis in cancer cells through elevation of Bax expression, thereby acting on tumor progression.
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PMID:Expression of p27 is associated with Bax expression and spontaneous apoptosis in oral and oropharyngeal carcinoma. 1037 53

To characterize the TGF-beta1 response of monocytic leukemia cells, we analyzed the effects of TGF-beta1 on cell proliferation, differentiation, and apoptosis of human monoblastic U937 cells. Treatment of cells with TGF-beta1 in the absence of growth factors significantly enhanced cell viability. Flow cytometric analysis of DNA content and CD14 expression revealed that TGF-beta1 does not affect cell proliferation and differentiation. Consistent with these results was the finding that no transcriptional induction of Cdk inhibitors such as p21Waf1, p15Ink4b, and p27Kip1 was detected following TGF-beta1 treatment. Interestingly, however, pretreatment of TGF-beta1 significantly inhibited Fas-, DNA damage-, and growth factor deprivation-induced apoptosis. This antiapoptotic effect was totally abrogated by anti-TGF-beta1 antibody. Quantitative RT-PCR analysis demonstrated a dose- and time-dependent transcriptional up-regulation of Bcl-X(L), suggesting its implication in the TGF-1-mediated antiapoptotic pathway. We also observed elevated expression of c-Fos and PTEN/MMAC1. But, no detectable change was recognized in expression of c-Jun, Fas, Fadd, Fap-1, Bcl-2, and Bax. Taken together, our study shows that TGF-beta1 enhancement of cellular viability is associated with its antiapoptotic effect, which may result from the transcriptional up-regulation of Bcl-X(L).
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PMID:TGF-beta1 inhibition of apoptosis through the transcriptional up-regulation of Bcl-X(L) in human monocytic leukemia U937 cells. 1055 Dec 60

B cell chronic lymphocytic leukemia (B-CLL) cannot be cured with conventional chemotherapy. This clinical enigma appears to be at least partially due to the fact that B-CLL cells are resistant to programmed cell death (apoptosis) and that they are arrested in G0/G1 phase of the cell cycle. The reasons for the dysregulation of these two key cellular events in B-CLL are unclear. The present study aimed at determining correlations between the expression levels of proteins regulating apoptosis, cell cycle and DNA repair in B-CLL cells and normal B cells. In addition, the differential sensitivity of B-CLL cells to drug-induced apoptosis was quantified. We show that in B-CLL cells levels of the death-suppressor Bcl-2 correlated positively with those of the pro-apoptotic protein Bax and of the cyclin-dependent kinase (cdk) inhibitor p27Kip1. In B-CLL cells levels of the anti-apoptotic Bcl-xL showed a positive correlation with levels of the 80 kDa regulatory component (Ku80) of the DNA-dependent protein kinase that is involved in DNA double-stranded break repair. These correlations were not detected in normal B cells. The sensitivity of leukemic cells to FLUD but not to ADM, CPM or to DEX was reduced in pre-treated patients. These data support the hypothesis that in B-CLL cells death-modulators and molecules modulating cell cycle and DNA repair are regulated in a coordinated manner. Leukemia (2000) 14, 40-46.
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PMID:Chemosensitivity of B cell chronic lymphocytic leukemia and correlated expression of proteins regulating apoptosis, cell cycle and DNA repair. 1063 75

The apoptosis-resistant phenotype of cloned high-metastatic A11 and low-metastatic P29 cells isolated from Lewis lung carcinoma was compared. The results showed that A11 cells were more resistant to apoptosis induced by microenvironmental stresses such as serum starvation, glucose deprivation and hypoxia than P29 cells as judged by viability, DNA laddering, and chromatin condensation and fragmentation. Both cell lines were insensitive to tumor necrosis factor-alpha-mediated apoptosis. P29 cells expressed a much higher level of Fas antigen on the cell surface than A11 cells. However, both cell lines were also insensitive to Fas-mediated apoptosis. The apoptosis resistant phenotype of A11 cells was associated with the expression level of caspase-3, but not with those of Bcl-2, Bcl-X(L) Bax, p27Kip1 and DAP kinase. There was no difference between A11 and P29 cells in the expression of E-cadherin, the adhesiveness to the extracellular matrix components or the expression levels of metastasis-associated genes such as c-Ha-ras, c-jun, p53 and nm23. Furthermore, A11 cells exhibited lower motile and invasive abilities than P29 cells. These results suggest that the apoptosis-resistant phenotype is an important factor for determining the metastatic ability of A11 cells. Supporting this, P29 cells became more apoptosis-resistant after treatment of the cells with dimethylsulfoxide which is reported to enhance the experimental metastatic potential of the cells.
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PMID:Resistance to apoptosis induced by microenvironmental stresses is correlated with metastatic potential in Lewis lung carcinoma. 1065 7

Ubiquitin-mediated proteolysis controls intracellular levels of various cell cycle regulatory proteins, and its inhibition has been shown to induce apoptosis in proliferating cells. In the present study, we examined induction of apoptosis in oral squamous cell carcinoma (OSCC) cells by treatment with specific proteasome inhibitors, carbobenzoxy-L-leucyl-L-leucyl-L-norvalinal and lactacystin. In all three OSCC cell lines examined, apoptotic changes such as apoptotic body formation and DNA fragmentation were observed at various degrees after 24 h of the carbobenzoxy-L-leucyl-L-leucyl-L-norvalinal or lactacystin treatment. HSC2 cells showed the most prominent apoptotic changes among the cell lines examined and demonstrated the highest level of accumulation of p27Kip1 protein after the treatment with proteasome inhibitor. Reduced expressions of cyclin D1 and phospho pRb were also observed after the treatment with proteasome inhibitor. Moreover, 12 h of treatment with the proteasome inhibitor inhibited cdk2/cyclin E kinase activity and increased the ratio of the cell cycle population at the G1 phase. The proteasome inhibitor led to inhibition of cell cycle progression. In addition, activation of CPP32 and reduced expression of Bcl-2 were observed. Because apoptosis induced by the proteasome inhibitor was inhibited by treatment with antisense p27Kip1 oligonucleotide, accumulation of the p27Kip1 protein might play an important role in the apoptosis induced by proteasome inhibitor. The present results suggest that inhibition of proteasome function may be used as a possible target of novel therapy for OSCC.
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PMID:p27Kip1 accumulation by inhibition of proteasome function induces apoptosis in oral squamous cell carcinoma cells. 1074 16


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