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)

Altered signaling pathways are key regulators of cellular functions in tumor cells. Constitutive activation of signal transducer and activator of transcription (STAT)3 and -5 may be involved in tumor formation and progression. We have investigated the role of STAT5 in cutaneous melanoma metastases using various RNA and protein techniques. In melanoma specimens, Stat5b transcripts were upregulated approximately 3.8-fold. In 13 of 21 (62%) human melanoma metastases, STAT5 was phosphorylated in comparison to normal human melanocytes and benign nevi. The STAT5 target gene Bcl-2 was frequently upregulated. The investigation of the underlying mechanism revealed specific STAT5 activation by recombinant human epidermal growth factor (rEGF). rEGF-induced activation of STAT5 occurred in vitro through the non-receptor tyrosine kinases transforming gene (src) of Rous Sarcoma virus and Janus kinase 1. Inhibition of Stat5b expression by small interfering RNA strongly reduced the expression of Bcl-2 and led to decreased cell viability and increased apoptosis in the melanoma cell lines A375 and BLM. Transfection with dominant-negative Stat5b caused enhanced cell death and G1 arrest in A375 cells. Our study identifies phosphorylated STAT5 in melanoma and shows regulation through rEGF; STAT5 may thus act as a survival factor for growth of human melanoma and may represent a potential target for molecular therapy.
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PMID:STAT5 phosphorylation in malignant melanoma is important for survival and is mediated through SRC and JAK1 kinases. 1674 10

Tumors of the central nervous system account for approximately 9% of all primary neoplasm in humans, while tumors of covering elements, the meninges, account for 13-19% and constitute the second largest group of brain tumors. These are known to exhibit a variety of chromosomal abnormalities besides change in the expression level of certain oncogenes. Among oncogenes, bcl2, an anti-apoptotic factor and ROS1 that encodes a protein with a structure similar to the epidermal growth factor (EGF) and insulin receptor and has a tyrosine kinase activity, have been shown to be associated with many malignant tumors. In the present study we have analysed the expression of bcl2 using immuno-histochemistry and ROS1 expression by reverse-transcription coupled with polymerase chain reaction (RT-PCR) of the transcript using primers specific for the intra-cellular domain and then tried to correlate the findings with the subtype of the meningioma defined on the basis of histology. Out of the six bcl2 positive cases in our study, there were three transitional tumors, two fibroblastic and one recurrent meningioma subtype. bcl2 seemed to be more consistently expressed in the cytoplasm of spindle cell component of meningiomas. Thirteen meningiothelial meningiomas did not show any staining for bcl2. ROS1 gene expression could be detected in 4 tumors all of those were Grade-I meningothelial meningiomas. One of the malignant meningioma included in the study was clearly negative for bcl2 as well as ROS1. Thus bcl2 and ROS1 oncogene expression in meningiomas are not concurrent and neither can be ascribed to any histologic subtype or grade of tumor.
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PMID:Bcl2 and ROS1 expression in human meningiomas: an analysis with respect to histological subtype. 1676 43

The adaptation response of the remnant gut to massive intestinal resection represents a mitogenic signal involving all bowel wall layers. In the mucosa, this response results in taller villi, deeper crypts, and enhanced enterocyte turnover as gauged by greater rates of both proliferation and apoptosis. Although the exact mechanisms and mediators of this important compensatory response remain incompletely understood, work from this laboratory over the past decade has illuminated a crucial role for intact receptor signaling for a robust response. Using a murine model for intestinal resection, transgenic, null and mutant mouse strains have provided unique experimental paradigms to dissect molecular mechanisms for epidermal growth factor (EGF) receptor-directed influence on adaptation. Stimulation of this receptor is linked with a magnified adaptation response, whereas attenuation of the activity of this receptor is associated with impaired adaptation. EGF receptor activation and expression are both elevated in enterocytes after resection, and salivary levels of EGF-the major ligand for the EGF receptor-are increased. In addition to stimulation of enterocyte proliferation, EGF receptor signaling prevents the typical increase in rates of enterocyte apoptosis, probably by affecting the ratio of expression of both pro- and anti-apoptotic Bcl-2 family members. The key to optimizing care for patients with short gut syndrome will necessarily follow a thorough understanding of intestinal adaptation responses.
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PMID:Critical roles for EGF receptor signaling during resection-induced intestinal adaptation. 1681 5

Unlike the tocopherols, the tocotrienols, also members of the vitamin E family, have an unsaturated isoprenoid side chain. In contrast to extensive studies on tocopherol, very little is known about tocotrienol. Because the nuclear factor-kappaB (NF-kappaB) pathway has a central role in tumorigenesis, we investigated the effect of gamma-tocotrienol on the NF-kappaB pathway. Although gamma-tocotrienol completely abolished tumor necrosis factor alpha (TNF)-induced NF-kappaB activation, a similar dose of gamma-tocopherol had no effect. Besides TNF, gamma-tocotrienol also abolished NF-kappaB activation induced by phorbol myristate acetate, okadaic acid, lipopolysaccharide, cigarette smoke, interleukin-1beta, and epidermal growth factor. Constitutive NF-kappaB activation expressed by certain tumor cells was also abrogated by gamma-tocotrienol. Reducing agent had no effect on the gamma-tocotrienol-induced down-regulation of NF-kappaB. Mevalonate reversed the NF-kappaB inhibitory effect of gamma-tocotrienol, indicating the role of hydroxymethylglutaryl-CoA reductase. Gamma-tocotrienol blocked TNF-induced phosphorylation and degradation of IkappaBalpha through the inhibition of IkappaBalpha kinase activation, thus leading to the suppression of the phosphorylation and nuclear translocation of p65. gamma-Tocotrienol also suppressed NF-kappaB-dependent reporter gene transcription induced by TNF, TNFR1, TRADD, TRAF2, TAK1, receptor-interacting protein, NIK, and IkappaBalpha kinase but not that activated by p65. Additionally, the expressions of NF-kappaB-regulated gene products associated with antiapoptosis (IAP1, IAP2, Bcl-xL, Bcl-2, cFLIP, XIAP, Bfl-1/A1, TRAF1, and Survivin), proliferation (cyclin D1, COX2, and c-Myc), invasion (MMP-9 and ICAM-1), and angiogenesis (vascular endothelial growth factor) were down-regulated by gamma-tocotrienol. This correlated with potentiation of apoptosis induced by TNF, paclitaxel, and doxorubicin. Overall, our results demonstrate that gamma-tocotrienol inhibited the NF-kappaB activation pathway, leading to down-regulation of various gene products and potentiation of apoptosis.
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PMID:Gamma-tocotrienol inhibits nuclear factor-kappaB signaling pathway through inhibition of receptor-interacting protein and TAK1 leading to suppression of antiapoptotic gene products and potentiation of apoptosis. 1711 79

Doxorubicin (DOX) selection of CCRF-CEM leukaemia cell line resulted in multidrug resistance (MDR) CEM/A7R cell line, which overexpresses MDR, 1 coded P-glycoprotein (Pgp). Here, we report for the first time that oncoprotein Cripto, a founding member of epidermal growth factor-Cripto-FRL, 1-Criptic family is overexpressed in the CEM/A7R cells, and anti-Cripto monoclonal antibodies (Mab) inhibited CEM/A7R cell growth both in vitro and in an established xenograft tumour in severe combined immunodeficiency mice. Cripto Mab synergistically enhanced sensitivity of the MDR cells to Pgp substrates epirubicin (EPI), daunorubicin (DAU) and non-Pgp substrates nucleoside analogue cytosine arabinoside (AraC). In particular, the combination of anti-Cripto Mab at less than 50% of inhibition concentrations with noncytotoxic concentrations of EPI or DAU inhibited more than 90% of CEM/A7R cell growth. Cripto Mab slightly inhibited Pgp expression, and had little effect on Pgp function, indicating that a mechanism independent of Pgp was involved in overcoming MDR. We demonstrated that anti-Cripto Mab-induced CEM/A7R cell apoptosis, which was associated with an enhanced activity of the c-Jun N-terminal kinase/stress-activated protein kinase and inhibition of Akt phosphorylation, resulting in an activation of mitochondrial apoptosis pathway as evidenced by dephosphorylation of Bad at Ser136, Bcl-2 at Ser70 and a cleaved caspase-9.
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PMID:Anti-Cripto Mab inhibit tumour growth and overcome MDR in a human leukaemia MDR cell line by inhibition of Akt and activation of JNK/SAPK and bad death pathways. 1734 96

Chronic renal disease is characterized by declining renal function, loss of intrinsic renal cells, and their replacement with fibrotic tissue. This study investigates apoptosis and its regulation in the context of chronic renal disease. RNA was extracted from renal biopsies from patients with various forms of chronic renal disease. Expression of genes of the Bcl-2 family, death receptor pathway, and growth factors were measured by reverse-transcription real-time polymerase chain reaction. Apoptosis was detected by the terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end-labeling technique. Tubulointerstitial apoptosis was positively associated with tubulointerstitial injury and renal dysfunction and increased 2.3-fold per unit (U) increase in transforming growth factor beta(1) (TGFbeta(1)) mRNA (P<0.05). Conversely, a 1 U increase in epidermal growth factor (EGF) mRNA was associated with a 47% decrease in tubulointerstitial apoptosis (P<0.05). Tubulointerstitial injury was correlated with increased TGFbeta(1) and tumour necrosis factor alpha (TNFalpha) mRNA (P<0.005) and decreased EGF mRNA (P<0.05). Additionally, for a 10 U decrease in the glomerular filtration rate there was an estimated increase of 5 and 10% in TGFbeta(1) and TNFalpha mRNA, respectively (P<0.05), whereas EGF mRNA decreased by an estimated 15% (P<0.005). Therefore dysregulation of cytokine/growth factor expression plays a central role in the progression of chronic renal disease through contribution to renal cell loss, tubulointerstitial injury, and renal dysfunction.
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PMID:Dysregulated growth factor gene expression is associated with tubulointerstitial apoptosis and renal dysfunction. 1736 Nov 17

Expression of Bcl-x(L) correlates with the clinical outcomes of patients with cancer. While the role of Bcl-2 in angiogenesis is becoming increasingly evident, the function of Bcl-x(L) in angiogenesis is unclear. Here, we showed that epidermal growth factor (EGF) induces in vitro capillary sprouting and Bcl-x(L) expression in primary endothelial cells. Bcl-x(L)-transduced human dermal microvascular endothelial cells (HDMEC-Bcl-x(L)), but not empty vector control cells, spontaneously organize into capillary-like sprouts. Searching for a mechanism to explain these responses, we observed that Bcl-x(L) induced expression of the pro-angiogenic chemokines CXC ligand-1 (CXCL1) and CXC ligand-8 (CXCL8), and that blockade of CXC receptor-2 (CXCR2) signaling inhibited spontaneous sprouting of HDMEC-Bcl-x(L). Bcl-x(L) led to Bcl-2 upregulation, but Bcl-2 did not upregulate Bcl-x(L), suggesting the existence of a unidirectional crosstalk from Bcl-x(L) to Bcl-2. EGF and Bcl-x(L) activate the mitogen-activated protein kinase/ERK pathway resulting in upregulation of vascular endothelial growth factor (VEGF), a known inducer of Bcl-2 in endothelial cells. Inhibition of VEGF receptor signaling in HDMEC-Bcl-x(L) prevented Bcl-2 upregulation and demonstrated the function of a VEGF-mediated autocrine loop. Bcl-2 downregulation by RNAi blocked CXCL1 and CXCL8 expression downstream of Bcl-x(L), and markedly decreased angiogenesis in vivo. We conclude that Bcl-x(L) functions as a pro-angiogenic signaling molecule controlling Bcl-2 and VEGF expression. These results emphasize a complex interplay between Bcl-2 family members beyond their classical roles in apoptosis.
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PMID:Unidirectional crosstalk between Bcl-xL and Bcl-2 enhances the angiogenic phenotype of endothelial cells. 1757 63

Long-term clinical observations and ongoing studies have shown antitumor effects of external Qi of Yan Xin Qigong (YXQG-EQ) that originated from traditional Chinese medicine (TCM). In order to understand the molecular mechanisms underlying the antitumor effects of YXQG-EQ, we investigate the effects of YXQG-EQ on growth and apoptosis in androgen-independent prostate cancer PC3 cells. We found that exposure to YXQG-EQ led to G2/M arrest associated with reduced cyclin B1 expression and apoptosis in PC3 cells. YXQG-EQ treatment inhibited constitutive and epidermal growth factor-induced Akt phosphorylation, basal and TNF-alpha-induced NF-kappaB activation, and downregulated anti-apoptotic Bcl-2 and Bcl-xL expression. In contrast, exposure to YXQG-EQ increased phosphorylation of Akt and Erk1/2 in human umbilical vein endothelial cells (HUVEC), and had no cytotoxic effect on either HUVEC or peripheral blood mononuclear cells (PBMC). These results indicate that YXQG-EQ has profound effects on growth and apoptosis of prostate cancer cells by targeting survival pathways including the Akt and NF-kappa B pathways.
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PMID:External Qi of Yan Xin Qigong induces G2/M arrest and apoptosis of androgen-independent prostate cancer cells by inhibiting Akt and NF-kappa B pathways. 1808 Aug 2

Progesterone plays a pivotal role in controlling uterine leiomyoma growth. The authors review studies they conducted to evaluate the comparative effects of asoprisnil on proliferation, apoptosis, and growth factor expression in cultured leiomyoma and normal myometrial cells. Treatment with asoprisnil decreased the proliferating cell nuclear antigen-positive rate and the number of viable cells and increased the terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate nick end labeling- positive rate in cultured leiomyoma cells in a dose-dependent manner ( P < .05). Similarly, asoprisnil decreased Bcl-2 expression and increased cleaved caspase-3 and cleaved poly(adenosine 5'-diphosphate-ribose) polymerase in leiomyoma cells but not in normal myometrial cells. Similarly, asoprisnil decreased epidermal growth factor (EGF), insulin-like growth factor-I (IGF-I), and transforming growth factor (TGF) beta mRNA and protein expression, as well as EGF receptor, IGF-IR alpha, and TGF RII protein expression in leiomyoma cells but not in cultured normal myometrial cells. These results suggest that asoprisnil selectively inhibits proliferation by downregulating the growth factors and their receptor expression and induces apoptosis in leiomyoma cells without affecting proliferation and apoptosis in normal myometrial cells.
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PMID:Comparative effects of SPRM asoprisnil (J867) on proliferation, apoptosis, and the expression of growth factors in cultured uterine leiomyoma cells and normal myometrial cells. 1808 6

We tested the hypothesis that epidermal growth factor (EGF) limits hypoxia-induced apoptosis in cultured human trophoblasts by phosphorylation of the proapoptotic protein Bcl-2-associated death promoter (BAD). Cytotrophoblasts were isolated from placentas of uncomplicated pregnancies at 38-40 wk gestation. Primary trophoblasts or transfected JEG3 trophoblast cells were cultured in less than 1 or 20% oxygen in the presence or absence of EGF and signaling pathway inhibitors. BAD, green fluorescent protein (GFP)-BAD, 14-3-3, Bcl-X(L), and neoepitopes formed during apoptotic cleavage of cytokeratin 18 intermediate filaments were quantified using immunoblotting. Cultures immunostained by fluorescent antibodies were analyzed by confocal microscopy for BAD and GFP. Fluorescence resonance energy transfer was used to detect molecular interaction between endogenous BAD and GFP-BAD. We found EGF increased the phosphorylation of BADser112 under standard culture conditions. Whereas hypoxia enhanced apoptosis and increased phosphorylation of both BADser136 and BADser155, hypoxia diminished phosphorylation of BADser112, and this effect was reversible by EGF. Transfected GFP-BAD, which directly interacted with endogenous BAD by colocalization and fluorescence resonance energy transfer, enhanced hypoxia-induced apoptosis in JEG3 cells. EGF reduced apoptosis in hypoxic JEG3 cells that overexpressed GFP-BAD but not in cells overexpressing GFP-BAD that harbored a serine-to-alanine mutation at the 112 site. Coimmunoprecipitation studies showed that EGF reduced the proapoptotic interaction of BAD with Bcl-X(L). The effect of EGF on phosphorylation of BADser112 was dependent on the action of p38 MAPK. We conclude that EGF signals via p38 MAPK to increase phosphorylation of BADser112 and thereby limit trophoblast apoptosis.
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PMID:Epidermal growth factor abrogates hypoxia-induced apoptosis in cultured human trophoblasts through phosphorylation of BAD Serine 112. 1827 61


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