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)

Whereas butyrate is well known to induce apoptosis in transformed colon cells in vitro, evidence exists that it inhibits apoptosis of colon crypt cells in vivo. In this study, pigs were fed with resistant potato starch to increase microbial butyrate formation in the colon and to investigate its effects on mitosis and apoptosis. In addition, apoptosis regulating proteins were determined by immunocytochemistry, such as proapoptotic Bak, antiapoptotic Bcl-2, and the epidermal growth factor (EGF), which is synthesized by goblet cells and functions as a survival factor. Two groups of 6 barrows were both supplied with 381 g crude protein and 31 MJ metabolizable energy (ME) daily over a 19-day experimental period. The rations differed in the carbohydrate composition. The controls received gelatinized starch as the main carbohydrate, whereas the experimental group (butyrate group) received a ration with raw potato starch (low ileal digestibility). In the feces, butyrate concentration and pH were monitored daily. After killing the pigs, colon tissue was obtained for histologic and immunocytochemical evaluation, which was performed separately in the luminal, middle, and stem cell compartment of the crypts. In the butyrate group, the total number of apoptotic cells was reduced by 34% (P< or =.001) compared with controls, whereas the mitotic rate was not altered. The crypt depth was only moderately increased by 15%. Apoptosis in the luminal compartment of the butyrate group was reduced by 18.8%, but was increased by 21.7% in the stem cell compartment. The effect of butyrate on apoptosis was paralleled by an increased number of Bcl-2 positive cells mainly in the luminal compartment (butyrate: 2.6 cells; controls: 1.2 cells, P< or =.001), which was more pronounced compared with the number of Bak positive cells in the same compartment. Bak activity in the stem cell compartment was 3.4-fold increased compared with controls (P< or =.001). The size of EGF-positive stained mucus-droplets from the goblet cells was increased in the butyrate group (P< or =.001). We conclude that butyrate inhibits apoptosis of colonocytes in vivo. An excessive proliferation of crypts is counteracted by a shift of the remaining apoptosis towards the stem cell compartment.
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PMID:Increased butyrate formation in the pig colon by feeding raw potato starch leads to a reduction of colonocyte apoptosis and a shift to the stem cell compartment. 1462 97

It is now evident that the use of levonorgestrel-releasing intrauterine system (LNg-IUS) is effective for long-term management of menorrhagic women with uterine myomas because of a striking reduction in menorrhagia. This prompted us to characterize the effects of progesterone (P4) on the growth and apoptosis of uterine leiomyoma cells. On the other hand, we have recently noted that epidermal growth factor (EGF) and IGF-I play a crucial role in prompting uterine leiomyoma growth through stimulating the proliferative potential and inhibiting apoptosis of cultured human leiomyoma cells. In the present review, attention was paid to evaluate the effects of P4 on the expression of growth factors (EGF, IGF-I) and apoptosis-related factors (TNFalpha, Bcl-2 protein) in cultured uterine leiomyoma cells. Treatment with P4 augmented EGF and Bcl-2 protein expression, but inhibited IGF-I and TNFalpha expression in cultured leiomyoma cells. It is known that TNFalpha induces apoptosis in a variety of cell types and Bcl-2 protein is an apoptosis-inhibiting gene product. Thus, the results obtained suggest that P4 has dual actions on uterine leiomyoma growth: one is to stimulate leiomyoma cell growth and survival through up-regulating EGF and Bcl-2 protein expression as well as down-regulating TNFalpha expression in those cells, and the other is to inhibit leiomyoma cell growth through down-regulating IGF-I expression in those cells. This may explain why the size of uterine myomas during use of LNg-IUS increases in some but decreases in other instances. This may also explain why the size of uterine myomas during pregnancy does not increase despite the overwhelming increase in circulating concentrations of sex steroid hormones.
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PMID:Effects of progesterone on growth factor expression in human uterine leiomyoma. 1466 73

Uterine leiomyomas develop during the reproductive years and regress after menopause, indicating ovarian steroid-dependent growth potential. Although the clinical and biochemical observations have traditionally supported an important role for estrogen in the promotion of leiomyoma growth, there is also increasing evidence to suggest the involvement of progesterone in the pathogenesis of leiomyoma. In this review, much attention has been paid to characterizing the molecular mechanisms of sex steroidal regulation of leiomyoma growth and apoptosis by evaluating the effects of sex steroids on the expression of growth factors and apoptosis-related factors. The effects of GnRH agonist on the expression of these factors in leiomyoma are also described. 17beta-Estradiol up-regulates epidermal growth factor (EGF) receptor, but down-regulates p53 protein in leiomyoma cells, whereas progesterone augments EGF and Bcl-2 protein, but inhibits insulin-like growth factor (IGF-I) and tumour necrosis factor (TNFalpha). Since it is now evident that EGF and IGF-I act as local factors which stimulate leiomyoma growth, these findings suggest that progesterone may have dual actions, stimulatory and inhibitory, on leiomyoma cell growth and survival, depending on the local growth factor conditions around each leiomyoma. This may explain why the size of uterine leiomyomas during the use of levonorgestrel-releasing intrauterine system (LNG-IUS) increases in some but decreases in other instances. This may also explain why the size of leiomyomas during pregnancy does not increase despite the overwhelming increase in circulating concentrations of sex steroid hormones. Moreover, there is further evidence to suggest that the interactions between estrogen receptors and progesterone receptors may be involved in the modulation of gene transcription activity in leiomyoma. This review demonstrates that leiomyoma growth is integrally regulated by the complex cross-talk between sex steroid hormones and growth factors.
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PMID:Sex steroidal regulation of uterine leiomyoma growth and apoptosis. 1514 Aug 68

Anoikis is a rapid apoptosis response that is initiated within a few minutes after inhibition of integrin signaling. In mammary epithelia, anoikis is mediated by subcellular translocation of Bax from the cytosol to mitochondria where it activates the intrinsic apoptosis pathway. The Bcl-2 homology 3 domain-only protein, Bim, has been proposed to have a key role in the apoptosis response of an epithelial cell line with reduced sensitivity to loss of integrin signaling, which undergoes apoptosis over a period of several days in suspension culture. Here we tested the involvement of Bim in the rapid anoikis response of mouse mammary epithelial cells and discovered that Bim does not have a role in detecting integrin-mediated signals. Instead Bim senses the loss of survival cues mediated by epidermal growth factor. Cell lines selected over many passages in culture have lost much of their sensitivity to anoikis signals arising from an altered cellular microenvironment and may undergo apoptosis through acquired mechanisms.
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PMID:Bim is an apoptosis sensor that responds to loss of survival signals delivered by epidermal growth factor but not those provided by integrins. 1529 7

Transcription factor NGFI-B (neuronal growth factor-induced clone B), also called Nur77 or TR3, is an immediate early gene and an orphan member of the nuclear receptor family. The NGFI-B protein also has a function distinct from that of a transcription factor; it translocates to mitochondria to initiate apoptosis. Recently, it was demonstrated that NGFI-B interacts with Bcl-2 by inducing a conformational change in Bcl-2, converting it from protector to a killer. After exposing rat cerebellar granule neurons to glutamate (100 mum, 15 min), NGFI-B translocated to the mitochondria. Growth factors such as the epidermal growth factor activate the MAP kinase ERK, the activity of which may determine whether a cell survives or undergoes apoptosis. In the present study we found that the epidermal growth factor activated ERK2 in cerebellar granule neurons and that this activation prohibited glutamate-induced subcellular translocation of NGFI-B. Likewise, overexpressed active ERK2 resulted in a predominant nuclear localization of green fluorescent protein-tagged NGFI-B. Thus, activation of ERK2 may overcome apoptosis-induced subcellular translocation of NGFI-B. This finding represents a novel and rapid growth factor survival pathway that is independent of gene regulation.
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PMID:ERK2 prohibits apoptosis-induced subcellular translocation of orphan nuclear receptor NGFI-B/TR3. 1544 59

Necrotizing enterocolitis (NEC) is a devastating intestinal disease of premature infants. Although end-stage NEC is characterized histopathologically as extensive necrosis, apoptosis may account for the initial loss of epithelium before full development of disease. We have previously shown that epidermal growth factor (EGF) reduces the incidence of NEC in a rat model. Although EGF has been shown to protect intestinal enterocytes from apoptosis, the mechanism of EGF-mediated protection against NEC is not known. The aim of this study was to investigate if EGF treatment elicits changes in expression of apoptotic markers in the ileum during the development of NEC. With the use of a well-established neonatal rat model of NEC, rats were divided into the following three experimental groups: dam fed (DF), milk formula fed (NEC), or fed with formula supplemented with 500 ng/ml EGF (NEC+EGF). Changes in ileal morphology, gene and protein expression, and histological localization of apoptotic regulators were evaluated. Anti-apoptotic Bcl-2 mRNA levels were markedly reduced and pro-apoptotic Bax mRNA levels were markedly elevated in the NEC group compared with DF controls. Supplementation of EGF into formula significantly increased anti-apoptotic Bcl-2 mRNA, whereas pro-apoptotic Bax was significantly decreased. The Bax-to-Bcl-2 ratio for mRNA and protein was markedly decreased in NEC+EGF animals compared with the NEC group. The presence of caspase-3-positive epithelial cells was markedly reduced in EGF-treated rats. These data suggest that alteration of the balance between pro-and anti-apoptotic proteins in the site of injury is a possible mechanism by which EGF maintains intestinal integrity and protects intestinal epithelium against NEC injury.
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PMID:Epidermal growth factor reduces intestinal apoptosis in an experimental model of necrotizing enterocolitis. 1552 52

Overexpression of anti-apoptotic Bcl-2 family members and deregulation of the pathways that regulate pro-apoptotic family members have been observed in non-small cell lung cancers (NSCLC). Previous reports have identified both Bcl-2 and Bcl-x(L) proteins as survival factors in lung cancer cells since reductions in these proteins can induce apoptosis and sensitize lung cancer cells to apoptosis induced by chemotherapy agents. Myeloid cell leukemia-1 (Mcl-1), another member of the Bcl-2 family, has been found to be a critical survival factor in hematopoietic cells, yet little data exists for a role of Mcl-1 in human lung cancers. We used NSCLC cell lines to explore how Mcl-1 levels affect lung cancer cell survival and studied tumors from patients to determine expression patterns of Mcl-1. NSCLC cells express abundant Mcl-1 protein and depletion of Mcl-1 levels by antisense Mcl-1 oligonucleotides induces apoptosis in A549 and H1299 lung cancer cells. Reduction in Mcl-1 levels can sensitize lung cancer cells to apoptosis induced by cytotoxic agents as well as by ionizing radiation. Lung cancer cells overexpressing Mcl-1 are less sensitive to apoptosis induced by chemotherapeutic agents, ZD1839 (an inhibitor of EGFR tyrosine kinase) and Bcl-2 or Bcl-x(L) antisense oligonucleotides. We find that epidermal growth factor (EGF) can enhance Mcl-1 protein levels in an ERK-dependent manner. Signal transduction agents that reduce Mcl-1 levels correlated with their individual ability to induce apoptosis in lung cancer cells. Finally, NSCLC tumors taken directly from patients have elevated levels of Mcl-1 protein compared with normal adjacent lung tissue. Therefore, agents that target Mcl-1 can induce apoptosis and sensitize cells to apoptosis induced by cytotoxic agents. Mcl-1 protein is overexpressed in a subset of human NSCLC and enhanced levels of Mcl-1 may protect lung cancer cells from death induced by a variety of pro-apoptotic stimuli.
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PMID:Mcl-1 regulates survival and sensitivity to diverse apoptotic stimuli in human non-small cell lung cancer cells. 1575 61

Primary chemotherapy represents an ideal model to evaluate the relationships between treatments and the prognostic and predictive parameters provided by the new technologies. First- and second-generation trials have shown that primary chemotherapy significantly improves the rate of breast conservation without increasing the risk of ipsilateral recurrence and while assuring survival rates comparable with those achieved with postoperative chemotherapy. Moreover, patients who exhibited a pathologic complete response (pCR) showed better progression-free survival and overall survival. The third-generation trials were aimed at improving the percentage of pCR, identifying and validating gene and protein biomarkers of chemotherapy sensitivity, and better defining the individual risk of relapse. Several parameters, such as index of proliferation and apoptosis, expression of proteins (eg, p53 and Bcl-2), and hormone receptor and epidermal growth factor family receptors, have been related to response to primary chemotherapy. Negative hormone receptors and greater proliferative activity seem to be the only parameters more consistently associated with greater chemotherapy sensitivity. However, the strength of this association is not sufficient to differentiate patients at different degrees of risk and does not allow for an individualized therapeutic choice. Newer technologies offer the possibility of evaluating thousands of genes and identifying clusters of gene expression associated with significantly different risks of relapse and patterns of sensitivity/resistance to specific drugs. The primary chemotherapy model is the ideal clinical setting in which to validate the relationship between tumor molecular profiling and treatment outcomes and to design tailored therapies based on observed effects on individual tumors.
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PMID:Predictive value of biologic parameters for primary chemotherapy in operable breast cancer. 1627 81

Defects in apoptosis signaling in hepatocytes contribute to tumorigenesis in hepatocellular carcinoma (HCC). In addition, treatment with chemotherapeutic drugs is often ineffective in HCC patients due to the apoptosis resistance of cancer cells. Anti-apoptotic members of the Bcl-2 family, including myeloid cell leukemia-1 (Mcl-1), which regulate intrinsic apoptosis induction at the mito-chondrial level, are often overexpressed in human cancer, and are implicated with disease grade and prognosis. Yet, little is known about the role of Mcl-1 in HCC. In this study, we analyzed the relevance of Mcl-1 expression for the apop-tosis resistance of human HCC. Mcl-1 protein expression was considerably enhanced in human HCC tissue compared to adjacent non-tumor tissue. In addition, Mcl-1 was prominently expressed in various HCC cell lines. Mcl-1 basal expression is dependent on a functional phosphatidylinositol-3 kinase (PI3K)/Akt signaling pathway; treatment of the cells with a specific PI3 kinase inhibitor led to both decreased Mcl-1 expression and a sensitization towards chemotherapeutic drug-induced apoptosis. Furthermore, the hepatocyte growth factor and epidermal growth factor induced Mcl-1 expression in an Akt- and ERK-dependent manner. Finally, specific upregulation of Mcl-1 in HCC cells inhibited chemotherapeutic drug-induced apoptosis. Our data suggest that Mcl-1 is an important factor for the apoptosis resistance of human HCC, and constitutes an interesting target for HCC therapy.
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PMID:Mcl-1 is an anti-apoptotic factor for human hepatocellular carcinoma. 1632 76

Airway mucus hypersecretion is now recognized as a key pathophysiological feature in many patients with asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis. Consequently, it is important to develop drugs that inhibit mucus hypersecretion in these susceptible patients. Conventional therapies, including anticholinergics, ss2-adrenoceptor agonists, corticosteroids, mucolytics and macrolide antibiotics, have variable efficacy in inhibiting airway mucus hypersecretion, and are less effective in COPD than in asthma. Novel pharmacotherapeutic targets are being investigated, including inhibitors of nerve activity (e.g. large conductance calcium-activated potassium, BKCa, channel activators), tachykinin receptor antagonists, epoxygenase inducers (e.g. benzafibrate), inhibitors of mucin exocytosis (e.g. anti-myristoylated alanine-rich C kinase substrate (MARCKS), peptide and Munc-18B blockers), inhibitors of mucin synthesis and goblet cell hyperplasia (e.g. epidermal growth factor (EGF), receptor tyrosine kinase inhibitors, p38 mitogen-activated protein (MAP), kinase inhibitors, MAP kinase kinase/extracellular signal-regulated kinase (MEK/ERK), inhibitors, human calcium-activated chloride (hCACL2), channel blockers and retinoic acid receptor-a antagonists), inducers of goblet cell apoptosis (e.g. Bax inducers or Bcl-2 inhibitors), and purinoceptor P(2Y2) antagonists to inhibit mucin secretion or P(2Y2) agonists to hydrate secretions. However, real and theoretical differences delineate the mucus hypersecretory phenotype in asthma from that in COPD. More information is required on these differences to identify specific therapeutic targets which, in turn, should lead to rational design of anti-hypersecretory drugs for treatment of airway mucus hypersecretion in asthma and COPD.
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PMID:Treatment of airway mucus hypersecretion. 1658 97


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