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)

Two interleukin-2 receptor-dependent signaling pathways have thus far been identified: the c-fos/c-jun induction pathway mediated by src family protein-tyrosine kinases and the c-myc induction pathway. Here, we provide evidence for the existence of a third, rapamycin-sensitive pathway, which results in the induction of another proto-oncogene, bcl-2. In the hematopoietic cell line BAF-B03, the expression of any two of lckF505 (an active form of p56lck), Bcl-2, or c-Myc is sufficient to promote transit of the cell cycle, regardless of the activation state of the third pathway. We also provide evidence that epidermal growth factor receptor signaling may act through the same pathway that involves p56lck. These studies demonstrate a novel approach to dissecting signaling pathways regulating cellular proliferation.
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PMID:Three distinct IL-2 signaling pathways mediated by bcl-2, c-myc, and lck cooperate in hematopoietic cell proliferation. 773 74

The Wilms' tumor 1 gene (WT1) encodes a transcription factor of the zinc-finger family. As a result of alternative RNA splicing, the gene can be expressed as four polypeptides that differ in the presence or absence of a stretch of 17 amino acids just NH2 terminal of the four zinc fingers and a stretch of three amino acids (+/-KTS) between zinc fingers 3 and 4. In this study, cDNA constructs encoding the four human Wilms' tumor 1 splice variants were transiently transfected into the p53-negative Hep3B and the p53-positive HepG2 hepatoma cell lines. Morphological assessment of the WT1-expressing cells showed that the WT1(-KTS) splice variants induced apoptosis in both cell lines, whereas the WT1(+KTS) isoforms did not. The induction of apoptosis by the WT1(-KTS) isoforms appears to be p53 independent in the hepatoma cell lines. Furthermore, it was found that the WT1(-KTS)-induced apoptosis could not be suppressed by coexpression of either the Mr 21,000 E1B, the Bcl-2, or the BAG-1 protein. Coexpression of either the epidermal growth factor receptor or the insulin receptor, however, partially rescued the cells from apoptosis.
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PMID:Wilms' tumor 1-KTS isoforms induce p53-independent apoptosis that can be partially rescued by expression of the epidermal growth factor receptor or the insulin receptor. 910 24

Recently, attention has focused on the potential of oncogenes, tumour suppressor genes, and assessment of cell proliferation as biological response indicators in human cancer. In this study, immunocytochemical analysis was used to evaluate the usefulness of Ki67, epidermal growth factor receptor (EGFr), and the protein products of c-Myc and Bcl-2 as indicators of radiosensitivity in primary cultures of head and neck tumours. Primary cultures established from tumours taken at surgery were divided into two groups; the control group remained untreated, and the treatment group received a single dose of 2 Gy. The cultures were incubated for 14 days, after which time they were fixed and examined immunocytochemically. The response to treatment of the cultures was measured as the percentage of growth inhibition (%GI) in the treated cultures relative to the untreated controls. Expression of Ki67 measured after a single dose of 2 Gy significantly differentiated the radioresistant and radiosensitive groups (P = 0.045); high percentages of Ki67+ cells correlated with radioresistance. A significant difference was found between the expression of EGFr in the resistant and sensitive groups, as measured in control cultures and after a dose of 2 Gy (P = 0.002 and P = 0.03, respectively); high levels of expression of EGFr correlated with radioresistance. The level of expression c-Myc+ cells, as measured in control cultures, significantly distinguished the radiosensitive group from the radioresistant group (P = 0.05). These results indicate a potential role for these proteins as indicators of radioresistance.
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PMID:Potential indicators of radiosensitivity in squamous cell carcinoma of the head and neck. 932 97

Signaling through the epidermal growth factor receptor (EGFR) has been primarily implicated in the growth of epithelial cells including keratinocytes. However, the mechanism by which EGFR stimulation promotes keratinocyte cell growth is poorly understood. Here we report that human keratinocytes undergo apoptosis when incubated with the blocking EGFR monoclonal antibody 225 IgG, or PD153035, a highly specific EGFR tyrosine kinase inhibitor. Endogenous mRNA and protein levels of Bcl-XL, a member the Bcl-2 family which suppresses apoptosis, were specifically inhibited by EGFR blockade. Furthermore, stimulation of EGFR signaling through two natural ligands, transforming growth factor (TGF)-alpha and epidermal growth factor (EGF), increased the expression of Bcl-XL in quiescent keratinocytes and HaCaT cells. Finally, ectopic expression of Bcl-XL in HaCaT cells increased survival after EGFR blockade when compared to untransfected cells or HaCaT keratinocytes transfected with empty vector. These results suggest that the anti-apoptotic protein Bcl-XL plays an important role in the maintenance of keratinocyte survival in response to EGFR signaling.
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PMID:EGF receptor signaling inhibits keratinocyte apoptosis: evidence for mediation by Bcl-XL. 958 Jan 12

Detection of tumor-associated alterations in peritumoral normal mucosa may give insight into the molecular pathogenesis of oral cancer. In the present study, 100 archival oral squamous cell carcinomaswith adjacent nontumorous mucosa were immunohistochemically investigated with antibodies against p53, Mdm2, Bcl-2, WAF1, MIB1, epidermal growth factor receptor (EGF-R), and various CD44 isoforms. Additionally a standardized argyrophilic nucleolar organizer region (AgNOR)-associated proteins analysis was performed. No correlation was found between p53, Mdm2, Bcl-2, and WAF1 immunophenotypes of the respective tumors and adjacent mucosa. The proliferation-associated markers MIB1 and AgNORs showed a statistically significant sequential increase from normal to dysplastic mucosa to invasive carcinoma. Investigation of various CD44 adhesion molecules revealed a highly variable expression pattern in overt carcinomas with a significantly decreased expression of CD44 v4 and v9 variants and unaltered strong expression of v5 and v6 isoforms compared with normal oral epithelium. We conclude that proliferation markers (MIB1 and AgNORs), as well as selected CD44 isoforms, represent useful markers for the assessment of precancerous lesions. They may be utilized for screening patients at high risk for the development of oral cancer.
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PMID:Immunophenotypic analysis of normal mucosa and squamous cell carcinoma of the oral cavity. 989 90

Phenobarbital (PB) is a non-genotoxic liver tumor promoter used extensively in initiation-promotion protocols. To determine the mode of PB action, double transgenic mice overexpressing both the c-myc and transforming growth factor (TGF)-alpha genes were treated with PB in the food for 10 weeks, from 3 weeks of age. After 3-4 weeks on PB a peak in liver mass was noted, which subsequently leveled off at a value approximately 30% above untreated animals. The mitotic index in mice given PB peaked at 1 week of treatment and was significantly elevated compared with untreated animals. No significant difference between treated and untreated animals was seen thereafter, although a trend of PB-associated mitotic suppression was noticeable. The apoptotic index also showed a trend of suppression compared with untreated animals, significant after prolonged PB administration. Dysplastic hepatocytes were more prominent in PB-treated mice than untreated animals, particularly pericentrally. Removal of PB from the diet at 4 weeks of treatment led to a dramatic increase in apoptosis. This accompanied a drop in the liver mass to the level of untreated controls by 10 days. Throughout the study, PB-treated animals showed markedly lower levels of TGF-beta1 ligand, coincident with an elevated level of the anti-apoptotic protein Bcl-2. On withdrawal of PB, the levels of all these proteins rapidly changed to mirror those seen in untreated mice. In all treatment groups, no change in the levels of epidermal growth factor receptor, TGF-beta receptors I and II or Bcl-xS/L were seen. We conclude from our data that PB stimulates liver growth in double transgenic c-myc/TGF-alpha mice by induction of liver hypertrophy and inhibition of apoptosis, brought about by both a decrease in signaling through the TGF-beta pathway and an increase in Bcl-2. The data support the hypothesis that PB promotes neoplastic development through a reduction in the incidence of cell death.
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PMID:Phenobarbital promotes liver growth in c-myc/TGF-alpha transgenic mice by inducing hypertrophy and inhibiting apoptosis. 993 48

The epidermal growth factor receptor has multiple roles in epidermal biology relating to growth, migration, and, as shown recently, survival of keratinocytes. In cultured keratinocytes activation of the epidermal growth factor receptor upregulates expression of Bcl-x(L), an anti-apoptotic Bcl-2 homolog. The functional contribution of epidermal growth factor receptor-dependent Bcl-x(L) expression to keratinocyte survival is poorly understood. Here we demonstrate that inhibition of the epidermal growth factor receptor tyrosine kinase activity with either an epidermal growth factor receptor antagonistic monoclonal antibody (MoAb 425) or an epidermal growth factor receptor-selective tyrosine kinase inhibitor (AG 1478) downregulated Bcl-x(L) expression in normal human keratinocytes but had no effect on expression of the pro-apoptotic Bcl-2 homologs Bad, Bak, and Bax. Bovine pituitary extract and insulin partially alleviated both, downregulation of Bcl-x(L) expression and cell death upon epidermal growth factor receptor inhibition. Forced expression of Bcl-x(L) attenuated cell death of immortalized keratinocytes (HaCaT) induced by either forced suspension (anoikis) or by epidermal growth factor receptor blockade. These results demonstrate that epidermal growth factor receptor-dependent signaling pathways control the balance of pro-apoptotic and anti-apoptotic Bcl-2 family members expressed in normal keratinocytes. Inappropriate survival supported by aberrant signaling through the epidermal growth factor receptor may contribute to the pathogenesis of psoriasis and of squamous cell carcinomas.
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PMID:A central role of Bcl-X(L) in the regulation of keratinocyte survival by autocrine EGFR ligands. 1020 27

We examined effects of the anti-epidermal growth factor receptor monoclonal antibody C225 on proliferation, cell cycle phase distribution, apoptosis, and radiosensitivity in squamous cell carcinoma (SCC) cell lines derived from head and neck cancer patients. Exposure to C225 in culture inhibits SCC proliferation in a time-dependent manner, and the degree of growth inhibition, compared to controls, ranges from 20 to 75%. Flow cytometry analysis demonstrates that C225 treatment induces accumulation of cells in G1, which is accompanied by a 2-3-fold decrease in the percentage of cells in S phase. C225 exposure also induces apoptosis in SCC populations, as demonstrated by flow cytometry analysis using dual stainings of merocyanine 540 and Hoechst 33342. Western blot analysis indicates that C225 exposure induces accumulation of hypophosphorylated retinoblastoma protein and increases expression of p27KIP1. An increase in Bax expression and concurrent decrease in Bcl-2 expression are observed when SCC cells are exposed to C225. Examination of C225 effects on radiation response in SCCs demonstrates enhancement in radiosensitivity and amplification of radiation-induced apoptosis. These effects are observed in both single-dose and fractionated radiation experiments. C225 represents a promising growth-inhibitory agent that can influence cellular proliferation, apoptosis, and radiosensitivity in SCCs of the head and neck.
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PMID:Epidermal growth factor receptor blockade with C225 modulates proliferation, apoptosis, and radiosensitivity in squamous cell carcinomas of the head and neck. 1021 3

There is at present, much optimism about the possibility of finding selective anticancer drugs that will eliminate the cytotoxic side effects associated with conventional cancer chemotherapy. This hope is based on uncovering many novel molecular targets that are 'cancer-specific', which will allow the targeting of cancer cells while normal cells are spared. Thus far, encouraging results have been obtained with several of these novel agents at the preclinical level, and clinical trials have begun. These targets are involved at one level or more in tumor biology, including tumor cell proliferation, angiogenesis and metastasis. Novel targets for which advances are being made include the following: growth factor receptor tyrosine kinases such as the epidermal growth factor receptor and HER-2/neu (proliferation); the vascular endothelial growth factor receptor and the basic fibroblast growth factor receptor (angiogenesis); the oncogenic GTP-binding protein Ras (especially agents targeting Ras farnesylation, farnesyltransferase inhibitors) (proliferation); protein kinase C (proliferation and drug resistance); cyclin-dependent kinases (proliferation); and matrix metalloproteinases and angiogenin (angiogenesis and metastasis). Less explored, but potentially useful targets include the receptor tyrosine kinase platelet-derived growth factor receptor, mitogen-activated protein kinase cascade oncogenes such as Raf-1 and mitogen-activated protein kinase kinase, cell adhesion molecules such as integrins, anti-apoptosis proteins such as Bcl-2, MDM2 and survivin, and the cell life-span target telomerase.
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PMID:Novel anticancer drug discovery. 1041 54

Glioblastomas are the most frequent and most malignant astrocytic gliomas. The epidermal growth factor receptor (EGFR) gene is the most frequently amplified and overexpressed in glioblastomas. The expression of bcl-2 and Bax in EGFR-antisense transfected and un-transfected glioblastoma cell line, U87E and U87V was studied by immunohistochemistry and western blotting. Our results show that the expression of Bax was stronger and bcl-2 was weaker in EGFR-antisense transfected cell line than the untransfected control. Bcl-2 and Bax genes are probably involved in the reduction of malignancy of glioblastoma cell caused by the introduction of EGFR-antisense into these tumor cells.
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PMID:Expression of bcl-2 and Bax in EGFR-antisense transfected and untransfected glioblastoma cells. 1062 70


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