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 cooked meat mutagen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) produces tumors at multiple sites in the F344 rat, including adenocarcinomas of the colon. In the present study, the development of IQ-induced colorectal tumors was shown to be accompanied by the progressive inhibition of programmed cell death. This was associated with increased expression of the antiapoptosis protein Bcl-2 and decreased expression of bax, a known activator of apoptosis. Carcinomas bearing high levels of bcl-2 expression exhibited low levels of p53, the tumor suppressor protein that in some circumstances has been shown to down-regulate bcl-2. Because they lack mutations in the genes commonly associated with increased cell proliferation (APC, Ki-ras, and p53) and show no evidence of microsatellite instability, IQ-induced colon tumors might arise via the deregulation of bcl-2 expression, leading to inhibition of programmed cell death.
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PMID:Inhibition of apoptosis in colon tumors induced in the rat by 2-amino-3-methylimidazo[4,5-f]quinoline. 881 12

Epithelial cells are dependent upon adhesion to extracellular matrix for survival. We show that loss of beta1 integrin receptor contact with extracellular matrix signals the inhibition of G1 cyclin-dependent kinase activity. This loss of cyclin-dependent kinase activity leads to accumulation of the hypophosphorylated (active) form of the retinoblastoma tumor suppressor protein (Rb). We present evidence that in epithelial cells deprived of matrix contact, the growth suppression signal elicited by hypophosphorylated Rb opposes stimulatory signals from serum growth factors, leading to a cell cycle conflict that triggers apoptosis. This apoptotic pathway is modulated by Bcl-2 through a novel mechanism that regulates Rb phosphorylation. We present evidence that the Rb-dependent apoptotic pathway functions in vivo in the apoptosis of the prostate glandular epithelium following castration.
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PMID:Cell anchorage regulates apoptosis through the retinoblastoma tumor suppressor/E2F pathway. 907 23

In order to clarify the role of p53, known as a tumor suppressor protein and also as a key molecule of apoptotic cell death, we have studied p53 expression in relation to localization, time course, cell type, and TUNEL reaction in a rat model of transectional spinal cord injury. Other apoptosis related molecules, p21, Bcl-2 and Bax, that are in the cascade of p53 pathway, were also examined. p53 was expressed in cells residing in the vicinity of transection as early as 30 min. For the next 2 days, the positive cells spread in distribution, increased in number, and thereafter decreased. p53 immunoreactivity was localized primarily to the nucleus but not to cytoplasm. Double-staining with glial cell markers revealed that p53 immunoreactivity was often co-localized in microglia, oligodendrocytes and astrocytes, but not in neurons. In view of the results of the double-staining of p53 and Bcl-2, Bax or TUNEL, a variety of apoptosis-related molecules are expressed with p53, all within the first three days of injury. Further, the process of apoptosis via the p53, pathway appears complex even in this simple model of CNS injury. Our study suggests that the manipulation of these apoptosis-related molecules may prove useful in modifying the cell and tissue damage in traumatic CNS injury.
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PMID:Implications of p53 protein expression in experimental spinal cord injury. 1070 75

Mitochondria have been recently recognized to play a major role in the control of apoptosis or programmed cell death. Permeabilization of mitochondrial membranes, a decisive feature of early cell death, is regulated by members of the Bcl-2 family which interact with the permeability transition pore complex (PTPC). Thus, the cytoprotective oncoprotein Bcl-2 stabilizes the mitochondrial membrane barrier function, whereas the tumor suppressor protein Bax permeabilizes mitochondrial membranes. The regulation of membrane permeabilization is intertwined with that of the bioenergetic and redox functions of mitochondria. The implications of alterations in the composition of the PTPC and in mitochondrial function for the pathophysiology of cancer (reduced apoptosis) and neurodegeneration (enhanced apoptosis) are discussed.
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PMID:Pathophysiology of mitochondrial cell death control. 1121 28

Galectin-3 is a carbohydrate binding protein involved in multiple processes including cell-cycle regulation and apoptosis. The ability of galectin-3 to protect cells from apoptosis is dependent upon a region of the protein known as a BH-1 domain for its homology to the anti-apoptotic protein Bcl-2. Here, we show that a monoclonal antibody (MAb) to the human tumor suppressor protein p16INK4A recognizes a post-translationally modified form of human galectin-3. The modified form is detectable in only a subset of cell types expressing galectin-3, indicating that the modification is cell-type-specific. Although there is little amino acid sequence homology between p16INK4a and galectin-3, we show by epitope mapping that the modification directly affects the structure of galectin-3's BH-1 domain. Elucidation of the nature of this modification might provide further insight into galectin-3 function.
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PMID:An antibody to p16INK4A recognizes a modified form of galectin-3. 1146 65

The mechanism underlying the chemopreventive effects of the non-steroidal anti-inflammatory drug sulindac remains unclear. Its active metabolite, sulindac sulfide, induces cell cycle arrest as well as apoptosis in mammalian cell lines. We now show that in murine thymocytes, sulindac sulfide-induced cell death is p53, bax, Fas, and FasL independent. In contrast, bcl2 transgenic thymocytes are resistant to sulindac sulfide-induced apoptosis. In addition, we demonstrate that sulindac sulfide-induced cell cycle arrest in mouse embryonic fibroblasts (MEFs) is partly mediated by the retinoblastoma tumor suppressor protein (Rb) and the cyclin kinase inhibitor p21waf1/cip1. Furthermore, MEFs deficient in p21 or Rb are more susceptible to sulindac sulfide-induced cell death. These results suggest that sulindac may selectively target premalignant cells with cell cycle checkpoint deficits.
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PMID:Mechanisms of sulindac-induced apoptosis and cell cycle arrest. 1569 60

Silymarin, a plant flavonoid, has been shown to inhibit skin carcinogenesis in mice. However, the mechanism responsible for the anti-skin carcinogenic effects of silymarin is not clearly understood. Here, we report that treatment of JB6 C141 cells (preneoplastic epidermal keratinocytes) and p53+/+ fibroblasts with silymarin and silibinin (a major constituent of silymarin) resulted in a dose-dependent inhibition of cell viability and induction of apoptosis in an identical manner. Silymarin-induced apoptosis was determined by fluorescence staining (8-64% apoptosis) and flow cytometry (12-76% apoptosis). The silymarin-induced apoptosis was primarily p53 dependent because apoptosis occurred to a much greater extent in the cells expressing wild-type p53 (p53+/+, 9-61%) than in p53-deficient cells (p53-/-, 6-20%). The induction of apoptosis in JB6 C141 cells was associated with increased expression of the tumor suppressor protein, p53, and its phosphorylation at Ser15. The constitutive expression of antiapoptotic proteins Bcl-2 and Bcl-xl were decreased after silymarin treatment, whereas the expression of the proapoptotic protein Bax was increased. There was a shift in Bax/Bcl-2 ratio in favor of apoptotic signal in silymarin-treated cells, which resulted in increased levels of cytochrome c release, apoptotic protease-activating factor-1, and cleaved caspase-3 and poly(ADP-ribose) polymerase in JB6 C141 cells. The shift in Bax/Bcl-2 ratio was more prominent in p53+/+ fibroblasts than in p53-/- cells. Silymarin-induced apoptosis was blocked by the caspase inhibitor (Z-VAD-FMK) in JB6 C141 cells which suggested the role of caspase activation in the induction of apoptosis. These observations show that silymarin-induced apoptosis is primarily p53 dependent and mediated through the activation of caspase-3.
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PMID:Silymarin induces apoptosis primarily through a p53-dependent pathway involving Bcl-2/Bax, cytochrome c release, and caspase activation. 1571 92

P53 is a well-characterized tumor suppressor protein, which can induce apoptosis, either by inducing transcription of pro-apoptotic genes or by direct effects on mitochondrial membranes. Roughly 50% of human cancers are affected by the genetic or epigenetic inactivation of p53. Recently, p53 has been incriminated to play a cardinal role in the destruction of the immune system by human immunodeficiency virus (HIV-1) infection. This suspicion is based on several lines of evidence: (i) p53 exhibits activating phosphorylations in a subset of peripheral blood mononuclear cells and lymph node cells from HIV-1 carriers; (ii) some p53 target genes (e.g., PUMA, a pro-apoptotic member of the Bcl-2 family) are overexpressed in HIV-1 carriers; (iii) in vitro, p53 and/or PUMA are rate-limiting for the induction of cell death by HIV-1 infection or, in particular, by the HIV-1 Envelope (Env), in a variety of model systems, including the apoptosis of syncytia elicited by Env or cell death induced by the Env constituent gp120. Thus, p53 may constitute a novel therapeutic target for the treatment of AIDS.
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PMID:p53-A pro-apoptotic signal transducer involved in AIDS. 1586 25

Maternal diabetes affects the development of the offspring by altering the uterine environment. We aimed to investigate the extent to which the blood flow (measured as Tissue Perfusion Units; TPU) to implantation sites and the expression of developmentally important genes in the offspring are affected by maternal diabetes. We measured mRNA levels of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), Bcl-2 associated X protein (Bax), B-cell lymphoma protein (Bcl-2), tumor suppressor protein-53 (p53), paired box protein-3 (Pax-3) and vascular endothelial growth factor-A (Vegf-A). Moreover, we studied the effect on uterine blood flow (TPU) and the expression of the genes exerted by embryonic maldevelopment (malformation or resorption). Streptozotocin induced diabetic (D) and non-diabetic (N) pregnant rats were used in the study. Blood flow (TPU) to implantation sites was measured by a laser Doppler flow meter, and gene expression was analyzed by RT-PCR. Maternal diabetes caused increased blood flow (TPU) to implantation sites compared with normal pregnancy. Furthermore, implantation sites of D rats containing malformed offspring showed impaired growth and decreased blood flow (TPU) compared with their littermates at all gestational days. Resorbed offspring from both N and D rats displayed increased blood flow (TPU) compared with their non-resorbed littermates. Moreover, we found that maternal diabetes causes decreased expression of genes involved in the oxidative stress defense system (CuZnSOD in non-malformed D11 embryos, MnSOD at all gestational time points, ECSOD and Gpx-1 at GD11-GD15, CAT and Gpx-2 at GD15), decreased expression of Pax-3 at GD11, and increased expression of Vegf-A at all gestational time points. We conclude that both maternal metabolism and embryonic developmental state affect the blood flow (TPU) to the implantation site. Maternal diabetes causes decreased expression of anti-oxidative enzymes and enhanced angiogenesis in the offspring in rats.
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PMID:Altered uterine perfusion is involved in fetal outcome of diabetic rats. 1838 70

Multiple oncogenes (in particular phosphatidylinositol 3-kinase, PI3K; activated Akt1; antiapoptotic proteins from the Bcl-2 family) inhibit autophagy. Similarly, several tumor suppressor proteins (such as BH3-only proteins; death-associated protein kinase-1, DAPK1; the phosphatase that antagonizes PI3K, PTEN; tuberous sclerosic complex 1 and 2, TSC1 and TSC2; as well as LKB1/STK11) induce autophagy, meaning that their loss reduces autophagy. Beclin-1, which is required for autophagy induction acts as a haploinsufficient tumor suppressor protein, and other essential autophagy mediators (such as Atg4c, UVRAG and Bif-1) are bona fide oncosuppressors. One of the central tumor suppressor proteins, p53 exerts an ambiguous function in the regulation of autophagy. Within the nucleus, p53 can act as an autophagy-inducing transcription factor. Within the cytoplasm, p53 exerts a tonic autophagy-inhibitory function, and its degradation is actually required for the induction of autophagy. The role of autophagy in oncogenesis and anticancer therapy is contradictory. Chronic suppression of autophagy may stimulate oncogenesis. However, once a tumor is formed, autophagy inhibition may be a therapeutic goal for radiosensitization and chemosensitization. Altogether, the current state-of-the art suggests a complex relationship between cancer and deregulated autophagy that must be disentangled by further in-depth investigation.
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PMID:Control of autophagy by oncogenes and tumor suppressor genes. 1880 60


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