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)

Targeting "oncogene addiction" is a promising strategy for anticancer therapy. We report a potent inhibition of crucial oncogenes by p53 upon reactivation by small-molecule RITA in vitro and in vivo. RITA-activated p53 unleashes the transcriptional repression of antiapoptotic proteins Mcl-1, Bcl-2, MAP4, and survivin; blocks the Akt pathway on several levels; and downregulates c-Myc, cyclin E, and beta-catenin. p53 ablates c-Myc expression via several mechanisms at the transcriptional and posttranscriptional level. We show that the threshold for p53-mediated transrepression of survival genes is higher than for transactivation of proapoptotic targets. Inhibition of oncogenes by p53 reduces the cell's ability to buffer proapoptotic signals and elicits robust apoptosis. Our study highlights the role of transcriptional repression for p53-mediated tumor suppression.
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PMID:Ablation of key oncogenic pathways by RITA-reactivated p53 is required for efficient apoptosis. 2848 10

High [(18)F]-2-fluorodeoxyglucose (FDG)-uptake of oral squamous cell carcinoma (OSCC), assessed by pretreatment positron emission tomography (PET), has indicated poor survival of patients. In this study, we sought to elucidate the underlying pathological and biological mechanisms of the close correlation in OSCC between high FDG-uptake and poor survival. Twenty-three patients who underwent both pretreatment FDG-PET and radical surgery were evaluated. We calculated the maximum standardized uptake value (SUVmax) as FDG-uptake. Tumor thickness and depth of invasion were quantitatively measured. Pathological specimens were immunohistochemically stained with antibodies to glucose transporter-1, E-cadherin, beta-catenin, vascular endothelial growth factor (VEGF), VEGF-C and Bcl-2, and their expressions were densitometrically assessed. SUVmax was significantly correlated with both tumor thickness and depth of invasion in simple regression analysis. Patients with SUVmax12 exhibited significantly shorter 3-year overall survival than patients with SUVmax < 12. Tumors with SUVmax > or =12 showed significantly greater tumor thickness, depth of invasion and average Bcl-2 intensity than those with SUVmax<12. Furthermore, tumor thickness> or =11.4mm, depth of invasion> or =11.8mm and average Bcl-2 intensity > or =50% were significantly correlated with poor survival. These results suggest that SUVmax in OSCC is significantly correlated with pathological features, and that it is both a non-invasive and useful parameter for predicting patients' prognosis.
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PMID:Tumor thickness, depth of invasion, and Bcl-2 expression are correlated with FDG-uptake in oral squamous cell carcinomas. 1945 11

Self-renewing cell populations such as hematopoietic stem cells and memory B and T lymphocytes might be regulated by shared signaling pathways. The Wnt-beta-catenin pathway is an evolutionarily conserved pathway that promotes hematopoietic stem cell self-renewal and multipotency by limiting stem cell proliferation and differentiation, but its role in the generation and maintenance of memory T cells is unknown. We found that induction of Wnt-beta-catenin signaling by inhibitors of glycogen sythase kinase-3beta or the Wnt protein family member Wnt3a arrested CD8(+) T cell development into effector cells. By blocking T cell differentiation, Wnt signaling promoted the generation of CD44(low)CD62L(high)Sca-1(high)CD122(high)Bcl-2(high) self-renewing multipotent CD8(+) memory stem cells with proliferative and antitumor capacities exceeding those of central and effector memory T cell subsets. These findings reveal a key role for Wnt signaling in the maintenance of 'stemness' in mature memory CD8(+) T cells and have major implications for the design of new vaccination strategies and adoptive immunotherapies.
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PMID:Wnt signaling arrests effector T cell differentiation and generates CD8+ memory stem cells. 2044 67

Restraint stress induces permeability changes in the small intestine, but little is known about the role of endogenous peroxisome proliferator-activated receptor-alpha (PPAR-alpha) ligand in the defects of the tight junction function. In the present study, we used PPAR-alpha knockout mice to understand the roles of endogenous PPAR-alpha on ileum altered permeability function in models of immobilization stress. The absence of a functional PPAR-alpha gene in PPAR-alpha knockout mice resulted in a significant augmentation of the degree of 1) TNF-alpha production in ileum tissues; 2) the alteration of zonula occludens-1, occludin, and beta-catenin (immunohistochemistry); and 3) apoptosis (terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling staining, Bax, Bcl-2 expression). Taken together, our results demonstrate that endogenous PPAR-alpha ligands reduce the degree of tight junction permeability in the ileum tissues associated with immobilization stress, suggesting a possible role of endogenous PPAR-alpha ligands on ileum barrier dysfunction.
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PMID:Role of peroxisome proliferator-activated receptor-alpha in ileum tight junction alteration in mouse model of restraint stress. 1955 62

Immunohistochemical studies in cervical intraepithelial neoplasia and cervical carcinoma are evaluated in this review. A variety of proteins like p53, bcl2, C-Myc, Ki 67, Cyclines, P16 INK4a, p21, p27, beta-catenin, Wnt and MCM, have been related to the development of cervical neoplasia and human papilloma virus infection. It is described how transcriptional factors of genes induce loss of heterozygosity, numerical chromosome abnormality and inactivation of gene products or the partial loss of some membrane glycoproteins induced by oncogenic human papillomaviruses (HPV).
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PMID:[Importance of immunohistochemical studies in the diagnosis and the prognostic evaluation of cervical intraepithelial neoplasia and invasive squamous cell carcinoma of the uterine cervix. Review]. 1966 19

Leiomyosarcoma (LMS) is a relatively uncommon malignant tumour derived from smooth muscle cells that rapidly metastasizes to distant regions. It rarely reaches oral tissues in which smooth muscle tissues are absent. We report the case of a 56-year-old woman who presented with LMS in the maxilla that had metastasized from a primary tumour in her uterus, received a total hysterectomy with bilateral salpingo-oophorectomy 9 months earlier. To reveal the poor prognosis of metastatic LMS, a total of 26 antibodies against different factors related to the proliferation, apoptosis, necrosis, and angiogenesis were simultaneously applied on the immunohistochemistry and immuno-blot detection in order to screen for expression n of different proteins in the metastatic LMS. Compared with the immunoreactions of primary uterine LMS, the different antibodies for cellular proliferation, i.e., proliferating cell nuclear antigen (PCNA), multiple primary neoplasm-2 (MPN-2), Max, p21, CDK4, p53, Rb-1, Bad, Bcl-2, epidermal growth factor receptor (EGF-R), hepatocyte growth factor (HGF), C-erbb2, Maspin, and DMBT-1, and those for angiogenesis, i.e., vWF, CD31, and Angiogenin, were more intensely expressed, while Bax, p16, Wnt-1, E-cadherin, and APC were relatively weakly expressed. In particular, beta-catenin was densely localized to the nuclei of tumour cells. These data suggest that rapid proliferation of the tumour cells is related to over-expression of different oncogenes, and that the infiltrative growth and early distant metastasis of these tumour cells are related to over-expression of angiogenesis factors. A total of seven cases of metastatic LMS to the oral cavity that had been published in the English literature were reviewed, and the reason for the poor prognosis in the metastatic LMS is suggested in this case report.
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PMID:Metastatic leiomyosarcoma in the oral cavity: case report with protein expression profiles. 1966 33

Thymic maturation of T cells depends on the intracellular interpretation of alphabetaTCR signals by processes that are poorly understood. In this study, we report that beta-catenin/Tcf signaling was activated in double-positive thymocytes in response to alphabetaTCR engagement and impacted thymocyte selection. TCR engagement combined with activation of beta-catenin signaled thymocyte deletion, whereas Tcf-1 deficiency rescued from negative selection. Survival/apoptotis mediators including Bim, Bcl-2, and Bcl-x(L) were alternatively influenced by stabilization of beta-catenin or ablation of Tcf-1, and Bim-mediated beta-catenin induced thymocyte deletion. TCR activation in double-positive cells with stabilized beta-catenin triggered signaling associated with negative selection, including sustained overactivation of Lat and Jnk and a transient activation of Erk. These observations are consistent with beta-catenin/Tcf signaling acting as a switch that determines the outcome of thymic selection downstream the alphabetaTCR cascade.
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PMID:Beta-catenin/Tcf determines the outcome of thymic selection in response to alphabetaTCR signaling. 1971 19

Cyclin L2 (CCNL2) is a novel member of the cyclin gene family. In a previous study, we demonstrated that CCNL2 expression was upregulated in ventricular septum tissues from patients with ventricular septal defect compared to healthy controls. In the present study, we established a stable CCNL2-overexpressing P19 cell line that can differentiate to myocardial cells when treated with 1% dimethyl sulfoxide (DMSO). Our data showed that stable CCNL2-overexpressing P19 cells were less differentiated after treatment with 1% DMSO and that expression of myocardial cell differentiation-related genes (such as cardiac actin, GATA4, Mef2C, Nkx2.5, and BNP) were reduced compared to vector-only transfected P19. Moreover, P19 cells overexpressing the CCNL2 gene had a reduced growth rate and a remarkably decreased S phase. We also found that these cells underwent apoptosis, as detected by two different apoptosis assays. The anti-apoptotic Bcl-2 protein was also downregulated in these cells. In addition, real-time PCR analysis revealed that expression of Wnt and beta-catenin was suppressed and GSK3beta was induced in the CCNL2-overexpressing P19 cells. These data suggest that overexpression of CCNL2 inhibited proliferation and differentiation of mouse embryonic carcinoma P19 cells and induced them to undergo apoptosis, possibly through the Wnt signal transduction pathway.
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PMID:Inhibition of proliferation and differentiation and promotion of apoptosis by cyclin L2 in mouse embryonic carcinoma P19 cells. 1978 86

This study was undertaken to determine the in vitro effect of lentivirus-mediated siPin1 on cell cycle and apoptosis of vascular smooth muscle cells (VSMCs). Further we sought to provide insight into the mechanisms behind these processes. Human umbilical artery smooth muscle cells (HUASMCs) were transfected with lentiviral siPin1. Real-time RT-PCR and Western blotting were used to examine Pin1 mRNA and protein expression. MTT and [(3)H]thymidine incorporation assays were employed to observe cell proliferation status. The apoptotic rate and cell cycle were analyzed by Hoechst33258 staining and flow cytometry. Finally we measured the expression of cyclin D1, beta-catenin, CDK4, cytochrome c, procaspase-3, cleaved caspase-3, procaspase-9, cleaved caspase-9, Bcl-2, Bax, STAT3, phosphorylated STAT3 and VEGF in lentiviral siPin1 infected VSMCs. Lentivirus-mediated siPin1 effectively diminished endogenous Pin1 expression in VSMCs resulting in cell cycle arrest and enhancement of apoptosis. This was accompanied by downregulation of cyclin D1, beta-catenin, CDK4, increase of Bax/Bcl-2 ratio, release of cytochrome c, and activation of caspase-3 and -9. We concluded that this effect was mediated, at least in part, via the beta-catenin/cyclin D1/CDK4 cascade, and that the mitochondrial pathway was responsible for VSMC apoptosis in the absence of Pin1. Our observations raised the possibility that Pin1 might be a potential therapeutic target to prevent stenosis.
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PMID:Inhibition of peptidyl-prolyl cis/trans isomerase Pin1 induces cell cycle arrest and apoptosis in vascular smooth muscle cells. 1990 10

Medulloblastoma is an aggressive primary brain tumor that arises in the cerebellum of children and young adults. The Sonic Hedgehog (Shh) signaling pathway that plays important roles in the pathology of this aggressive disease is a promising therapeutic target. In the present report we have shown that curcumin has cytotoxic effects on medulloblastoma cells. Curcumin suppressed also cell proliferation and triggered cell-cycle arrest at G(2)/M phase. Moreover, curcumin inhibited the Shh-Gli1 signaling pathway by downregulating the Shh protein and its most important downstream targets GLI1 and PTCH1. Furthermore, curcumin reduced the levels of beta-catenin, the activate/phosphorylated form of Akt and NF-kappaB, which led to downregulating the three common key effectors, namely C-myc, N-myc, and Cyclin D1. Consequently, apoptosis was triggered by curcumin through the mitochondrial pathway via downregulation of Bcl-2, a downstream anti-apoptotic effector of the Shh signaling. Importantly, the resistant cells that exhibited no decrease in the levels of Shh and Bcl-2, were sensitized to curcumin by the addition of the Shh antagonist, cyclopamine. Furthermore, we have shown that curcumin enhances the killing efficiency of nontoxic doses of cisplatin and gamma-rays. In addition, we present clear evidence that piperine, an enhancer of curcumin bioavailability in humans, potentiates the apoptotic effect of curcumin against medulloblastoma cells. This effect was mediated through strong downregulation of Bcl-2. These results indicate that curcumin, a natural nontoxic compound, represents great promise as Shh-targeted therapy for medulloblastomas.
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PMID:Curcumin inhibits the Sonic Hedgehog signaling pathway and triggers apoptosis in medulloblastoma cells. 2002 76


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