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)

In the medical literature there are frequently conflicting reports on the utility of biological tumour markers available in the clinical management of breast cancer. In this review we analyse current information on the relationships between the most widely investigated breast cancer biological markers including oestrogen and progesterone receptors, p53, Bcl-2, c-erbB-2, cyclin expression, proliferative activity, DNA ploidy and the urokinase plasminogen activation system, as well as their relevance to prognosis and response to clinical treatment. By biological prognostic indicator, we mean a marker that correlates with survival and disease-free survival; the term predictor marker indicates a marker that is capable of predicting tumour sensitivity or resistance to various therapies. Similarly to other authors' experiences, our analysis suggests that oestrogen receptors are weak prognostic indicators and good predictors of response to endocrine therapy. Furthermore, there are consistent data suggesting that proliferation indices are good indicators of prognosis, and that they are directly related to response to chemotherapy and closely related to response to hormonotherapy. On the contrary, there is no evidence or conflicting data for all of the other biological markers. These should be considered in the context of randomized trials in order to precisely define their prognostic and predictive roles. p53 and c-erbB-2 seem to be the most promising factors, but their use in routine practice still needs validation.
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PMID:Prognosis and prediction of response in breast cancer: the current role of the main biological markers. 985 25

Plasminogen activator inhibitor-1 (PAI-1) plays an important role in the processes of peripheral tissue remodeling and fibrinolysis through the regulation of plasminogen activation. We found that cultured human astrocytes efficiently released PAI-1, and that both mRNA expression and protein release of PAI-1 were suppressed by pretreatment of the cells with daunorubicin. To examine the role of PAI-1 in the nervous system, neuronally differentiated PC-12 cells (PC-12 neurons) were maintained in a PAI-1-deficient culture medium derived from daunorubicin-pretreated astrocytes. The deficiency of PAI-1 in the medium caused a significant reduction in Bcl-2 and Bcl-XL mRNAs and an increase in Bcl-XS and Bax mRNAs in PC-12 neurons at 3 h. The changes in balance between mRNA expressions of the anti- and pro-apoptotic Bcl-2 family proteins caused caspase-3 activation following the release of cytochrome c from mitochondria. Apoptotic morphological change and DNA fragmentation were also observed in the neuronal cells at 24 h. Addition of exogenous PAI-1 protein to the inhibitor-deficient medium blocked the apoptotic changes in PC-12 neurons. However, addition of PAI-1 antibodies to control medium caused similar apoptotic changes in PC-12 neurons. During the apoptotic processes, plasminogen activator (PA) activity in the PAI-1-deficient medium was as low as the control level. The present data suggest that PAI-1 has physiological functions other than its role as PA inhibitor for the survival of neurons.
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PMID:Deficient release of plasminogen activator inhibitor-1 from astrocytes triggers apoptosis in neuronal cells. 1145 96

Skeletal muscle has a remarkable capacity to regenerate after injury. To determine whether changes in the expression of proteinases, 73-kDa constitutive heat shock cognate protein (Hsc70) and stress-inducible 72-kDa heat shock protein (Hsp70) (Hsc/Hsp70), and Bcl-2-associated gene product-1 (BAG-1) contribute to the remodeling response of muscle tissue, tibialis anterior muscles of male Sprague-Dawley rats were injected with 0.75% bupivacaine and removed at 3, 5, 7, 10, 14, 21, or 35 days postinjection (n = 5-7/group). The immunohistochemical analysis of desmin, alpha-actin, and developmental/neonatal myosin heavy chain expressions indicated the presence of myoblasts (days 3-7), inflammatory cells (days 3-7), degenerating myofibers (days 3-7), regenerating myofibers (days 5-10), and growing mature myofibers (days 10-21) in regenerating muscles. Our biochemical analysis documented profound adaptations in proteolytic metabolism characterized by significant increases in the enzyme activities of matrix metalloproteinases 2 and 9 and plasminogen activators (days 3-14), calpains 1 and 2 (days 3-7), cathepsins B and L(days 3-10), and proteasome (days 3-14). Proteasome activity was strongly correlated with proliferating cell nuclear antigen protein level, suggesting that proteasome played a key role in myoblast proliferation. The expression pattern of BAG-1, a regulatory cofactor of Hsc/Hsp70 at the interface between protein folding and proteasomal proteolysis, did not corroborate the changes in proteasome enzyme activity, suggesting that BAG-1 may promote other functions, such as the folding capacity of Hsc/Hsp70. Altogether, the diversity of functions attributed to proteinases in the present study was strongly supported by the relative changes in the proportion of myogenic and nonmyogenic cells over the time course of regeneration.
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PMID:Myogenic and nonmyogenic cells differentially express proteinases, Hsc/Hsp70, and BAG-1 during skeletal muscle regeneration. 1279 5

The benefit of postoperative adjuvant chemotherapy in patients with Dukes' B colorectal cancer is still uncertain and its routine use is not recommended. Prognostic biomarkers may be useful for identifying high-risk patients with resected, node-negative disease, and this stratification may represent an innovative strategy for designing adjuvant chemotherapy trials. Featured prognostic molecular markers can be divided into the following categories: cell proliferation indices (Ki-67, Mib-1, proliferating cell nuclear antigen); oncogenes/tumor suppressor genes [p53, K-ras, Deleted in Colorectal Cancer (DCC), Bcl-2, c-erbB2]; DNA repair (microsatellite instability); markers of angiogenesis (vascular count, vascular endothelial growth factor); markers of invasion/metastasis (plasminogen-related molecules, matrix metalloproteinases); and biochemical markers (thymidylate synthase). Studies that have investigated their prognostic role in Dukes' B colorectal cancer patients are reviewed here. Current data do not provide sufficient evidence for the incorporation of available prognostic biomarkers into clinical practice. However, a biomarker-based approach could be an effective strategy for improving results of postoperative adjuvant treatments in high-risk Dukes' B colorectal cancer patients. Markers of altered DCC function have shown promising prognostic role and sufficient prevalence in retrospective investigations and they deserve further assessment in prospective studies.
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PMID:Prognostic molecular markers for planning adjuvant chemotherapy trials in Dukes' B colorectal cancer patients: how much evidence is enough? 1285 43

IGFBP-5 has been associated with cell death in a number of systems; recently, the first evidence that it is involved in apoptosis of the mammary gland has been provided by studies, both in vivo and in vitro, involving the addition of exogenous IGFBP-5 and from a transgenic mouse expressing IGFBP-5 on a mammary-specific promoter. These studies have indicated that the effects are mediated in part by inhibition of IGF-signalling and involving members of the Bcl-2 family, but a role for IGF-independent effects cannot be ruled out. These IGF-independent effects involve potential interactions with components of the extracellular matrix involved in tissue remodelling such as components of the plasminogen system. In addition, intracellular events involving nuclear localisation of IGFBP-5 have been shown to have potential to inhibit cell proliferation. IGFBP-5 binds to a considerable number of molecules in the extracellular matrix, but the specific roles of these interactions in modulating its biological effects are poorly understood. The development of IGFBP-5 mutants, with differential binding characteristics, will aid in elucidating the precise roles of IGFBP-5 and potentially offer new therapeutic approaches based on IGF-independent effects in addition to its classical role of modulating IGF actions.
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PMID:Modulation of the actions of IGFs by IGFBP-5 in the mammary gland. 1471 Mar 62

We have demonstrated that insulin-like growth factor binding protein-5 (IGFBP-5) production by mammary epithelial cells increases dramatically during forced involution of the mammary gland in rats, mice and pigs. We proposed that growth hormone (GH) increases the survival factor IGF-I, whilst prolactin (PRL) enhances the effects of GH by decreasing the concentration of IGFBP-5, which would otherwise inhibit the actions of IGFs. To demonstrate a causal relationship between IGFBP-5 and cell death, we created transgenic mice expressing IGFBP-5, specifically, in the mammary gland. DNA content in the mammary glands of transgenic mice was decreased as early as day 10 of pregnancy. Mammary cell number and milk synthesis were both decreased by approximately 50% during the first 10 days of lactation. The concentrations of the pro-apoptotic molecule caspase-3 was increased in transgenic animals whilst the concentrations of two pro-survival molecules Bcl-2 and Bcl-x were both decreased. In order to examine whether IGFBP-5 acts by inhibiting the survival effect of IGF-I, we examined IGF receptor- and Akt-phoshorylation and showed that both were inhibited. These studies also indicated that the effects of IGFBP-5 could be mediated in part by IGF-independent effects involving potential interactions with components of the extracellular matrix involved in tissue remodeling, such as components of the plasminogen system, and the matrix metallo-proteinases (MMPs). Mammary development was normalised in transgenic mice by R3-IGF-I, an analogue of IGF-I which binds weakly to IGFBPs, although milk production was only partially restored. In contrast, treatment with prolactin was able to inhibit early involutionary processes in normal mice but was unable to prevent this in mice over-expressing IGFBP-5, although it was able to inhibit activation of MMPs. Thus, IGFBP-5 can simultaneously inhibit IGF action and activate the plasminogen system thereby coordinating cell death and tissue remodeling processes. The ability to separate these properties, using mutant IGFBPs, is currently under investigation.
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PMID:Insulin-like growth factor binding proteins initiate cell death and extracellular matrix remodeling in the mammary gland. 1599 1

While significant advances in the treatment of cancer occured during the last half of the twentieth century, parallel decreases in overall cancer death rates were not observed. Cancer therapy remains an area of significant unmet medical need. Abbott's oncology research programs are focused on pioneering trageted, less toxic therapies, aimed at different aspects of tumor growth and development. Oncology drugs in development at Abbott target several mechanisms of cancer progression by interfering with multiple processes necessary for tumor growth: recruitment of a blood supply, cell proliferation, and the development of metastases. They include a selective endothelin A-receptor antagonist (atrasentan/Xinlay), 3 angiogenesis inhibitors (ABT 510, a thrombospondin mimetic: ABT-869, a multitargeted receptor tyrosine kinase inhibitor; and ABT 828, recombinant human plasminogen kringle 5), a cell proliferation inhibitor (ABT-751, an antimitotic agent), an apoptosis inducer (ABT 737, a Bcl-2 family inhibitor), and a poly(ADP-ribose)polymerase inhibitor.
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PMID:Targeting the unmet medical need: the Abbott Laboratories oncology approach. 1622 44

Inhibition of endothelial cell proliferation and angiogenesis is emerging as an important strategy in cancer therapeutics. Kringle 5 (K5) of human plasminogen is a potent angiogenesis inhibitor. Previous studies have shown K5 exposure promotes caspase activity and apoptosis in endothelial cells. Here we report that K5 treatment evokes an autophagic response in endothelial cells that is specific and initiated even in the absence of nutritional stress. Endothelial cells exposed to K5 up-regulated Beclin 1 levels within a few hours. Furthermore, progressively increasing amounts of antiapoptotic Bcl-2 were found to be complexed with Beclin 1, although total levels of Bcl-2 remained unchanged. Prolonged exposure to K5 ultimately led to apoptosis via mitochondrial membrane depolarization and caspase activation in endothelial cells. Knocking down Beclin 1 levels by RNA interference decreased K5 induced autophagy but accelerated K5-induced apoptosis. These studies suggest that interfering with the autophagic survival response can potentiate the antiangiogenic effects of Kringle 5 in endothelial cells.
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PMID:Kringle 5 of human plasminogen, an angiogenesis inhibitor, induces both autophagy and apoptotic death in endothelial cells. 1727 2

Angiogenesis, the process by which new blood vessels are formed is critical for embryonic development and physiological functioning of normal tissues. Angiogenesis also plays a critical role in the pathology of many diseases including cancer, wherein the supply and demand for blood vessels determines the rate of cancer growth. A number of therapeutic strategies are being developed to inhibit pathological angiogenesis. Kringle domains of plasminogen such as kringle 5 (K5) and a proteolytic fragment of collagen type XVIII (endostatin) are well-characterized, potent angiogenesis inhibitors. These inhibitors activate different intracellular signaling pathways to induce apoptosis and inhibit cell proliferation. Recent studies from our group have shown that K5 and endostatin can also induce autophagy in addition to apoptosis in endothelial cells. A common feature of the two treatments was the upregulation of Beclin 1 levels leading to alterations in the Beclin 1-Bcl-2 complex. Angiogenesis inhibitor-induced autophagy in endothelial cells was independent of nutritional or hypoxic stress and initiated even in the presence of endothelial-specific survival factors such as vascular endothelial growth factor (VEGF). Interfering with the autophagic response by knocking down Beclin 1 levels dramatically increased apoptosis of endothelial cells. These findings identify the autophagic response as a novel target for enhancing the therapeutic efficacy of angiogenesis inhibitors.
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PMID:Autophagy and angiogenesis inhibition. 1764 71

Plasminogen Kringle 5(K5) is a proteolytic fragment of plasminogen, which displays potent anti-angiogenic activities. K5 has been shown to induce apoptosis in proliferating endothelial cells; however the exact mechanism has not been well explored. The present study was designed to elucidate the possible molecular mechanism of K5-induced endothelial cell apoptosis. Our results showed that K5 inhibited basic fibroblast growth factors activated in human umbilical vein endothelial cells (HUVECs), indicating proliferation in a dose-dependent manner and induced endothelial cell death via apoptosis. K5 exposure activated caspase 7, 8 and 9. These results suggested that both the intrinsic mitochondrial apoptosis pathway and extrinsic pathway might be involved in K5-induced apoptosis. K5 reduced mitochondrial membrane potential (MMP) of HUVECs, demonstrating mitochondrial depolarization in HUVECs. K5 increased the ratio of Bak to Bcl-x(L) on mitochondria, decreased the ratio in cytosol, and had no effect on the total amounts of these proteins. K5 also did not effect on Bax/Bcl-2 distribution. K5 increased the ratio of Bak to Bcl-x(L) on mitochondrial that resulted in mitochondrial depolarization, cytochrome c release and consequently the cleavage of caspase 9. These results suggested that K5 induces endothelial cell apoptosis at least in part via activating mitochondrial apoptosis pathway. The regulation of K5 on Bak and Bcl-x(L) distribution may play an important role in endothelial cell apoptosis. These results provide further insight into the anti-angiogenesis roles of K5 in angiogenesis-related ocular diseases and solid tumors.
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PMID:Plasminogen K5 activates mitochondrial apoptosis pathway in endothelial cells by regulating Bak and Bcl-x(L) subcellular distribution. 2165 47


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