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)

Fifty samples of lung tissue from patients with non-small cell lung cancer were analyzed for the expression and localization of biomarkers related to squamous differentiation and programmed cell death. These markers include tissue transglutaminase (tTG), keratinocyte transglutaminase (kTG), involucrin, loricrin, and Bcl-2. We found that all of these markers are overexpressed in tumors as compared with histologically normal lung epithelium, where expression is minimal. Expression of the oncoprotein, Bcl-2, increased starting in squamous metaplasia and remained elevated in all lesions, including frank carcinoma. In contrast, expression of the other markers was elevated in the histologically abnormal noninvasive lesions but was decreased somewhat in invasive malignancy. In addition, we found that tTG, kTG, and Bcl-2, when expressed, were detected in mutually exclusive areas. These findings suggest that (1) these markers may prove useful, with more extensive testing and clinical correlation, in predicting risk for the development of lung cancer; and (2) pulmonary carcinogenesis may result from the failure of differentiation and programmed cell death mechanisms in the presence of oncogene overexpression rather than through oncogene/tumor suppressor gene abnormalities alone.
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PMID:Differentiation and programmed cell death-related intermediate biomarkers for the development of non-small cell lung cancer: a pilot study. 974 13

The oncogenic ras mutation is a common and critical step in gastrointestinal carcinogenesis. In a previous study, we demonstrated that oncogenic ras activated the EGF-related peptide autocrine loop and that the apoptosis resistance observed in the oncogenic ras-stimulated cell (IEC-ras cell) was dependent on this activated EGF-related peptide autocrine loop. STATs (signal transducers and activators of transcription), first identified as intracellular signal transducers stimulated by cytokines, are known to also be activated by EGF. However, the role of STATs in the survival signal of IEC-ras cells is not clear. In the present study, we demonstrate that STAT3 is constitutively activated in ras-stimulated cells and that STAT3 activation is considerably suppressed by the EGF-specific receptor kinase inhibitor AG 1478. We also show that disruption of the STAT3 pathway by introduction of a dominant-negative STAT3 mutant abolishes the apoptosis resistance against UVC and MMC treatment observed in IEC-ras cells without affecting proliferation. Moreover, the expression of Bcl-2 and Bcl-xL, apoptosis-suppressive proteins, is reduced in dominant-negative STAT3-transfected cells. Thus, STAT3 appears to be an important mediator of the antiapoptotic signal in IEC-ras cells.
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PMID:STAT3 mediates the survival signal in oncogenic ras-transfected intestinal epithelial cells. 976 67

Bcl-2 expression is confined to the base of the colonic crypt, whereas transforming growth factor beta (TGFbeta) is expressed in the upper crypt, as are the apoptotic death promoters, Bak and Bax. In colonic adenoma cells, TGFbeta induces a growth arrest. In some adenoma cell lines, this is accompanied by apoptosis and in others it is not. In this study, we used two human colonic adenoma cell lines: RG/C2, in which TGFbeta induces a G1 arrest without apoptosis, and BH/C1, in which TGFbeta induces both a G1 arrest and apoptosis. TGFbeta does not induce apoptosis in RG/C2 cells even if hydrocortisone and insulin are removed from the culture medium. In BH/C1 cells, TGFbeta induces apoptosis in the presence of insulin and hydrocortisone. Apoptosis induced by TGFbeta is preceded by a reduction in p26-Bcl-2 protein levels. There was no change in the levels of the p30 phosphorylated form of Bcl-2 or in levels of the proapoptotic proteins Bax or Bak. RG/C2 cells did not show decreased Bcl-2 levels in response to TGFbeta-induced growth inhibition. Therefore, TGFbeta regulates Bcl-2 expression in colonic adenoma cells which undergo apoptosis in response to TGFbeta, but not in those which are growth inhibited, but resistant to TGFbeta-induced apoptosis. TGFbeta may play an important role in the colonic epithelium, not only in the inhibition of cell proliferation, but also in the regulation of apoptosis.
Carcinogenesis 1998 Sep
PMID:Decreased levels of p26-Bcl-2, but not p30 phosphorylated Bcl-2, precede TGFbeta1-induced apoptosis in colorectal adenoma cells. 977 43

To evaluate the relationship between cell proliferation and apoptosis in sporadic colorectal carcinogenesis, immunohistochemistry for proliferation-associated antigen Ki-67 and in situ end labelling for identifying apoptotic bodies were performed on paraffin sections from 59 adenomas and 22 carcinomas. These results were correlated with the expression of the proliferation and apoptosis modulators Bcl-2 and p53. Carcinomas showed increased proliferation and apoptosis compared with adenomas (P<0.0001, P<0.001, respectively). There were positive linear correlations between proliferation and apoptosis in adenomas and carcinomas (P<0.02, P<0.05, respectively). The proliferative rate increased significantly from mild to moderate, and from moderate to severe dysplasia (P<0.002, P<0.001, respectively). Apoptotic rate also increased in this sequence, but the increases did not reach statistical significance (both P>0.05). Expression of Bcl-2 was associated with lower apoptotic rate in adenomas (P<0.025) but not in carcinomas (P>0.25), whereas p53 expression was correlated with higher proliferative rate in both adenomas and carcinomas (P<0.01, P<0.05, respectively). An inverse relationship between Bcl-2 and p53 expression was seen in both adenomas and carcinomas (P<0.05, P<0.005, respectively). These data suggest that the normal balance between proliferation and apoptosis is disturbed in colorectal carcinogenesis, both being increased, but proliferation occurs in excess. Bcl-2 and p53 may each play a role in modulating cell apoptosis or proliferation during the development of colorectal carcinoma.
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PMID:Imbalance between proliferation and apoptosis in the development of colorectal carcinoma. 987 Jun 85

Expression of several members of the Bcl-2 family proteins was investigated by means of both immunohistochemical analysis in 30 invasive ductal adenocarcinomas and 23 intraductal papillary-mucinous tumors (IPMTs) and immunoblot analysis in 6 cancer tissues and 7 pancreatic cancer cell lines. We found that Bcl-2 was expressed in 23%, Bax in 53%, Bcl-X in 90%, and Mcl-1 in 90% of the invasive ductal adenocarcinomas. In intraductal papillary-mucinous adenocarcinomas, the expression rate of Bax was 44% and those of Bcl-XL and Mcl-1 were 88%; these values were higher than those for intraductal papillary-mucinous adenomas. Immunoblot analysis identified Bcl-XL as the predominant form of the Bcl-X protein in both pancreatic cancer tissues and cell lines, and demonstrated that both Bcl-XL and Mcl-1 protein levels were uniformly high in all cell lines. These results suggest that an imbalance between antiapoptosis proteins (such as Bcl-2, Bcl-XL, and Mcl-1) and proapoptotic proteins (such as Bax and Bcl-Xs) is involved in the distinctive biologic features of adenocarcinomas of the pancreas. Furthermore, predominantly high expressions of Bcl-XL and Mcl-1 in intraductal papillary-mucinous adenocarcinomas might be involved in the carcinogenesis in IPMT of the pancreas.
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PMID:Immunohistochemical analysis of Bcl-2, Bax, Bcl-X, and Mcl-1 expression in pancreatic cancers. 988 81

Previous models of cutaneous carcinogenesis have primarily focused on the regulation of keratinocyte (KC) proliferation and differentiation. However, it has become clear in many neoplastic systems that altered rates of cell death and/or inability to undergo growth arrest can also contribute to the development of cancer. Apoptosis-regulatory proteins include those that block apoptosis such as Bcl-2 and Bcl-x, whilst a related protein Bax promotes apoptosis. Cell cycle regulatory proteins include those associated with growth arrest, i.e. p21wafl, p53, and those associated with proliferation, i.e. Ki-67. Paraffin embedded samples from ten different lesions of squamous cell carcinoma (SCC), Bowen's disease (BD), keratoacanthomas (KA), and nine normal adult skin samples were stained by immunohistochemistry to detect expression of Bcl-2, Bcl-x, Bax, Ki-67, p21wafl, p53 and apoptosis (TUNEL assay). Compared to low levels of Bcl-x and Bcl-2 immunostaining in normal skin, all the squamoproliferative lesions had strong and diffuse KC expression of Bcl-x (>80%) but minimal to absent KC Bcl-2 expression (<15%). Bax immunopositivity was limited to the basal layer in normal skin and BD. In contrast, by examining serial sections both Bcl-x and Bax appeared to be coexpressed by the majority of malignant KCs in KA and SCC (>70%). These immunostaining profiles reveal that squamoproliferative lesions, including invasive transformed KCs, preferentially express Bcl-x over Bcl-2, in addition to upregulating their Bax levels. Even though there were numerous TUNEL positive cells in these squamoproliferative lesions, no other evidence of apoptosis was seen reinforcing the necessity to use caution when relying on TUNEL staining for identification of programmed cell death in skin biopsies. Normal sun-exposed skin had low but detectable p53 and rare p21wafl KC expression. Significantly higher numbers of p21wafl and p53 immunopositive KCs were noted throughout the lesions in BD and SCC in contrast to KA where p53 and rare p21wafl immunopositive KCs were primarily limited to the periphery of the tumor cell islands. In general, p53 KC expression was higher in all squamoproliferative lesions and sun-exposed normal skin compared to p21Wafl expression. Summary of the expression of cell cycle regulatory proteins for both p21wafl and p53 KC expression was: SCC > BD > KA, in marked contrast to Ki-67 KC expression which was: BD > KA > SCC. The relatively few malignant cells in SCC that were actively participating in the cell cycle (i.e. Ki-67 positive) suggests that these neoplasms may arise primarily by increased cell survival and resistance to apoptosis rather than by hyperproliferation. These studies emphasize the importance of examining multiple members of protein families that regulate apoptosis, proliferation, growth arrest, and differentiation. It is the overall balance between these cellular phenomena that determine whether a cell remains viable or undergoes programmed cell death and contributes to the appearance of a neoplasm. The overexpression of Bcl-x may confer a survival advantage to malignant KCs unable to growth arrest to repair damaged DNA (mutant p53) and/or undergo terminal differentiation (increased p21wafl). Thus, mutation or aberrant expression of such proteins may participate in the multistep process of carcinogenesis that gives rise to these squamoproliferative lesions.
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PMID:Differential expression of cell survival and cell cycle regulatory proteins in cutaneous squamoproliferative lesions. 989 Mar 76

Squamous cell carcinomas of the Head and Neck (SCCHN) are related to carcinogens and proceed through multiple genetic and morphological steps. The aim of this study was to establish the status of p53 gene and p53-regulated proteins (Bax, Bcl-2 and Waf-1) expression in head and neck simultaneous preneoplastic and invasive lesions from patients with chronic alcohol and tobacco exposure. PCR-SSCP analysis of p53 gene and immunohistochemical analysis of Waf-1, Bax and Bcl-2 proteins were performed in 30 representative microdissected samples of mucosa exposed to carcinogens and preneoplastic or invasive lesions from 8 patients. P53 mutations were detected in all steps of carcinogenesis, but not in normal mucosa without carcinogen exposure. P53 mutations were different and multiple in concomittant areas of mucosa exposed to carcinogens, preneoplastic and invasive lesions at distant locations. Waf-1 and Bax protein expression was found in 100% of biopsies. Bcl-2 presented as basal cell positive staining in 95% of normal and preinvasive lesions and was overexpressed in only 30% of tumors, independently of p53 gene status. Bax/Bcl-2 ratio was > 1 in all premalignant lesions and < 1 in tumor samples only. There is evidence for the early, polyclonal origin of synchronous multiple preneoplastic and neoplastic lesions in the cancerization field. A P53 independent pathway seems to be implicated in Waf-1, Bax and Bcl-2 expression with an inversion of the Bax/Bcl-2 ratio restricted to invasive carcinomas.
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PMID:p53 mutations and p53, Waf-1, Bax and Bcl-2 expression in field cancerization of the head and neck. 989 51

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.
Carcinogenesis 1999 Jan
PMID:Phenobarbital promotes liver growth in c-myc/TGF-alpha transgenic mice by inducing hypertrophy and inhibiting apoptosis. 993 48

Our previous studies indicate that cadmium in mice can inhibit the formation of chemically induced and spontaneously occurring tumors in the liver and lung. Cadmium is an effective anti-tumor agent when given at non-toxic doses and even when given well after tumor formation, implying a unique sensitivity in certain tumor cells. The present studies tested the ability of cadmium to inhibit growth and progression of transplanted human pulmonary tumor xenografts. Male athymic nude mice were inoculated with either H460 cells, originally derived from a non-small cell pulmonary carcinoma, or DMS 114 cells, originally derived from a small cell lung carcinoma, under the left renal capsule. Starting 1 week later mice received 0, 125 or 250 p.p.m. cadmium in the drinking water, levels without effect on host animal growth or survival, and were observed over the next 4 weeks (H460 cells) or 100 days (DMS 114 cells). An additional experiment gave cadmium as an i.v. loading dose (20 micromol/kg) 4 days after renal inoculation with H460 cells and 200 p.p.m. cadmium in the drinking water from 7 days onward, with an observation period of 28 days. Cadmium caused dose-related reductions in the growth of tumors resulting from the inoculation of either H460 or DMS 114 cells of up to 83%. Additionally, cadmium reduced the rate of tumor metastasis to the lung by up to 58%. Cadmium treatment had no effects on either Bcl-2 or Bax protein expression in tumor xenografts, indicating that apoptotic pathways probably do not contribute to this anti-neoplastic effect. These studies show cadmium can effectively reduce growth and progression of human lung carcinoma xenografts in a fashion that is probably independent of apoptosis.
Carcinogenesis 1999 Jan
PMID:Cadmium-induced inhibition of the growth and metastasis of human lung carcinoma xenografts: role of apoptosis. 993 51

Apoptosis is a programmed cell death process in which cells commit suicide under certain environmental conditions. Recent studies suggest that apoptosis is controlled by a variety of cellular genes, and dysregulation of these genes plays an important role in the pathogenesis of human diseases, including cancer. BAG-1 is a novel anti-apoptotic protein isolated by its interaction with another anti-apoptotic protein, Bcl-2. It binds to several hormone receptors and growth factor receptors and modulates their function in apoptosis. However, the role of BAG-1 in the oncogenesis of human cervical cancer has yet to be illustrated. In this study, we examined the expression of BAG-1 in cervical normal and carcinoma cultured cells and tissues. BAG-1 was overexpressed in human cervical carcinoma cell lines and tissues. Overexpression was regulated at the transcriptional level. The increased expression of BAG-1 was correlated with enhanced resistance of cervical carcinoma cells to apoptosis induced by a DNA-damaging reagent. In addition, overexpression of BAG-1 enhanced the resistance of cervical cells to apoptosis. This study provided the first evidence that BAG-1 is upregulated in human cervical cancer and may play an important role in apoptosis and human cervical carcinogenesis.
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PMID:Overexpression of anti-apoptotic gene BAG-1 in human cervical cancer. 1004 62


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