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)

Gene therapy for a variety of human cancers containing the mutant p53 (mt-p53) gene has been performed by direct injection of a retroviral or adenoviral vector containing the wild-type p53 (wt-p53) gene. Because many individuals with skin squamous cell carcinoma (SCC) have been shown to carry the p53 gene mutation, these patients are candidates for p53 gene therapy. For this reason, we established ponasterone A-inducible the wild-type p53 (wt-p53) protein-expressing clones by transfecting a ponasterone-inducible vector containing the wt-p53 gene into HSC-1 cells, which harbor the mutated p53 (m/w) at codon 173 (GTG --> TTG in one allele). Upon the induction of the wt-p53 protein, severe growth suppression was observed. Based on the results of the expression patterns of the p21, p16, RB, BAX and Bcl-2 proteins, as well as on the results of senescence-associated beta-galactosidase staining, the suppression was caused by senescence-like growth arrest of the cells. Although it is generally accepted that the suppression of tumor cell growth is caused by p53-induced apoptosis, permanent G1 arrest induced by p53 is also an important part of the growth-suppression mechanism in p53 gene therapy. The present results should expand the possibilities for p53 gene therapy for human skin SCCs containing the mutant p53 gene.
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PMID:Establishment of ponasterone A-inducible the wild-type p53 protein-expressing clones from HSC-1 cells, cell growth suppression by p53 expression and the suppression mechanism. 1900 4

We established a myeloma cell line (RPMI8226) with cyclin D1 overexpression in which the transfected cyclin D1 gene was stably expressed. D1 transfectants showed down-regulation of cyclin D2. Cell proliferation analysis did not show any differences among RPMI8226, mock control, and D1 transfectants. The number of S-phase cells increased while the number of G0/G1- and G2/M-phase cells decreased in D1 transfectants, which indicates a prolonged S-phase caused by cyclin D1 transfection. A decreased number of G2/M-phase cells was also detected in myeloma cells of patients with translocation t(11;14)(q13;q32). Western blot analysis revealed an increase in the hyperphosphorylated form of retinoblastoma (Rb) protein in D1 transfectants; however, the expression of p53, p16, Bax, Bad, Bcl-2, and Mcl-1 did not significantly change. Treatment with anti-myeloma drugs (melphalan, dexamethasone, bortezomib and immunomodulatory compounds) induced apoptosis earlier in D1 transfectants compared with RPMI8226 and mock control via the activation of both caspase-8 and -9. However, we could not detect a relationship between cyclin D1 expression and the response to treatment with VAD and bortezomib. Therefore, we assume that high sensitivity to anti-myeloma drugs depends on the duration of the S-phase, but a clinical response might depend on the number of myeloma cells with cyclin D1 overexpression.
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PMID:Ectopic cyclin D1 overexpression increases chemosensitivity but not cell proliferation in multiple myeloma. 1902 Jul 53

Vulvar carcinoma is a rare female genital neoplasia. Radical surgery, which has been the standard treatment approach, is often accompanied by considerable morbidity. To reduce the incidence of complications there has been a movement toward individualised therapy and less radical surgery. Associated with this, new tumour markers that could serve as prognostic indicators would be of considerable value to guide treatment decision. In this review, a brief update of molecular pathological markers of vulvar carcinomas is provided, and their impact as prognostic markers is addressed. p16, p21, p14, p27, cyclin A, cyclin D1, p53, vascular endothelial growth factor (VEGF), transforming growth factor alpha, HER-2 and epidermal growth factor receptor (EGFR) have been found to be important in the pathogenesis and/or progression of vulvar carcinomas. Furthermore, human papillomavirus, p16, p21, p14, p53, VEGF, CD44v3, CD44v6, CD44v4, CD44v9, CD44v10, HER-2, EGFR, matrix metalloproteinase-12, caspase 3, Bcl-2 and nm23-H1 have been correlated to clinical outcome of patients with vulvar carcinomas. However, due to the relative small number of studies reported for each molecular pathological marker, and the relative small number of vulvar carcinomas included and the lack of multivariate analysis in the majority of these studies, no conclusion regarding the prognostic value of these markers can be drawn. Therefore, the investigated markers have not yet earned a place in standard clinical diagnostics or treatment, and further studies are needed to clarify the clinical value of these markers.
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PMID:A review of molecular pathological markers in vulvar carcinoma: lack of application in clinical practice. 1925 52

Abnormalities in the signal transducer and activator of transcription (STAT) pathway are involved in the oncogenesis of several cancers. However, the mechanism by which dysregulated STAT5 signaling contributes to the progression of human colorectal cancer (CRC) has not been elucidated. To investigate the role of STAT5 in CRC progression, we depleted STAT5 with a small interfering RNA (siRNA). Our results demonstrate that STAT5 is involved in CRC cell growth, cell cycle progression, invasion and migration through regulation of gene expression, such as Bcl-2, p16(ink4a), p21(waf1/cip1), p27(kip1), E-cadherin, the focal adhesion kinase (FAK), vascular endothelial growth factor (VEGF) and matrix metalloproteinases. In addition, immunohistochemical staining reveals upregulation of STAT5 during CRC tumorigenesis. Moreover, phospho-STAT5 (pSTAT5) is predominantly localized in the cytoplasm of adenomas cells and colon adenocarcinoma cells, but primarily presented in the nucleus of normal colonic epithelium cells. Thus, pSTAT5 protein is shuttled from the nucleus to the cytoplasm in the oncogenesis of CRC, suggesting that activated STAT5 may also have cytoplasmic functions. In support of this hypothesis, we found that STAT5 formed a complex with p44/42 MAPK and SAPK/JNK in CRC cells, suggesting cross talk between STAT5 signaling and the MAPK pathway in the development of human CRC. Our findings illustrate the biological significance of STAT5 signaling in CRC progression, and provide novel evidence that intervention in STAT5 signaling may have potential therapeutic value in the prevention of human colorectal cancer.
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PMID:Inhibition of STAT5 induces G1 cell cycle arrest and reduces tumor cell invasion in human colorectal cancer cells. 1929 7

Large primary tumor and clinical nodal involvement in patients with anal carcinoma treated with chemoradiation are associated with poor disease-free survival (DFS). However, the outcome in individual patient is unpredictable. We hypothesized that biomarkers related to chemotherapy and/or radiation resistance would be associated with DFS. We analyzed clinical and biomarker data in 30 patients with anal carcinoma who had chemoradiation. Patient selection was based on the availability of untreated cancer for biomarkers, completion of prescribed chemoradiation, and patient outcomes (~50% disease-free) nonrepresentative of published cohorts but conducive to biomarker discovery. Ten biomarkers, Ki67, human telomerase (hTERT), epidermal growth factor receptor (EGFR), p53, p16, Bcl-2, vascular endothelial growth factor (VEGF), nuclear factor kappa-B (NF-kappaB), SHH, and Gli-1, were studied. Raw data as continuous variable (only EGFR was trichotomized) were analyzed. Univariate and multivariate Cox models were utilized to assess relationship between DFS and biomarkers. Twenty-three of 30 patients were women, tumor diameter was >5 cm in 30, and 37% had clinically positive nodes. Fourteen (30%) patients had a DFS event after chemoradiation. In univariate analysis, NF-kappaB (P = 0.01), SHH (P = 0.02), Gli-1 (P = 0.02), and tumor diameter (P = 0.03) were significantly associated with DFS, and Ki67 (P = 0.07) was marginally significant. In multivariate analysis, tumor diameter (P = 0.003), Ki67 (P = 0.005), NF-kappaB (P = 0.002), SHH (P = 0.02), and Gli-1 (P = 0.02) were significantly associated with DFS. Our data, albeit preliminary, suggest that several biomarkers (Ki67, NF-kappaB, SHH, and Gli-1) are associated with DFS. Upon further expansion and validation, these results may provide a biomarker-based understanding of heterogeneous clinical biology of patients with anal carcinoma.
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PMID:Molecular biomarkers correlate with disease-free survival in patients with anal canal carcinoma treated with chemoradiation. 1939 14

Many tumors are resistant to drug-induced cell-cycle arrest and apoptosis. We have reported that apoptosis can be restored in human multidrug-resistant (MDR) hepatocellular carcinoma cell lines by celecoxib. Here we show that P-glycoprotein (P-gp) mediates cell-cycle arrest and autophagy induced by celecoxib in human MDR overexpressing hepatocellular carcinoma cell line by down-regulation of the HGF/MET autocrine loop and Bcl-2 expression. Exposure of cells to a low concentration of celecoxib down-regulated the expression of mTOR and caused G1 arrest and autophagy, while higher concentration triggered apoptosis. Cell growth inhibition and autophagy were associated with up-regulation of the expression of TGFbeta1, p16(INK4b), p21(Cip1) and p27(Kip1) and down-regulation of cyclin D1, cyclin E, pRb and E2F. The role of P-glycoprotein expression in resistance of MDR cell clone to cell-cycle arrest, autophagy and apoptosis was shown in cells transfected with MDR1 small interfering RNA. These findings demonstrate that the constitutive expression of P-gp is involved in the HGF/MET autocrine loop that leads to increased expression of Bcl-2 and mTor, inhibition of eIF2alpha expression, resistance to autophagy/apoptosis and progression in the cell-cycle. Since mTor inhibitors have been proposed in treatment of "drug resistant" cancer, these data may help explain the reversing effect of mTor inhibitors.
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PMID:Down-regulation of the HGF/MET autocrine loop induced by celecoxib and mediated by P-gp in MDR-positive human hepatocellular carcinoma cell line. 1944 20

2-Methoxyestradiol (2-ME2) induces leukemia cells to undergo apoptosis in association with Bcl-2 inactivation but the mechanisms whereby Bcl-2 contributes to protection against programmed cell death in this context remain unclear. Here we showed that 2-ME2 inhibited the proliferation of Jurkat leukemia cells by markedly suppressing the levels of cyclins D3 and E, E2F1 and p21(Cip1/Waf1) and up-regulating p16(INK4A). Further, 2-ME2 induced apoptosis of Jurkat cells in association with down-regulation and phosphorylation of Bcl-2 (as mediated by JNK), up-regulation of Bak, activation of caspases-9 and -3 and PARP-1 cleavage. To determine the importance and mechanistic role of Bcl-2 in this process, we enforced its expression in Jurkat cells by retroviral transduction. Enforcing Bcl-2 expression in Jurkat cells abolished 2-ME2-induced apoptosis and instead produced a G1/S phase cell cycle arrest in association with markedly increased levels of p27(Kip1). Bcl-2 and p27(Kip1) were localized mainly in the nucleus in these apoptotic resistant cells. Interestingly, NF-kappaB activity and p50 levels were increased by 2-ME2 and suppression of NF-kappaB signaling reduced p27(Kip1) expression and sensitized cells to 2-ME2-induced apoptosis. Importantly, knocking-down p27(Kip1) in Jurkat Bcl-2 cells sensitized them to spontaneous and 2-ME2-induced apoptosis. Thus, Bcl-2 prevented the 2-ME2-induced apoptotic response by orchestrating a p27(Kip1)-dependent G1/S phase arrest in conjunction with activating NF-kappaB. Thus, we achieved a much better understanding of the penetrance and mechanistic complexity of Bcl-2 dependent anti-apoptotic pathways in cancer cells and why Bcl-2 inactivation is so critical for the efficacy of apoptosis and anti-proliferative inducing drugs like 2-ME2.
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PMID:Bcl-2 blocks 2-methoxyestradiol induced leukemia cell apoptosis by a p27(Kip1)-dependent G1/S cell cycle arrest in conjunction with NF-kappaB activation. 1944 21

Regulator of Cullins-1 (ROC1) or Ring Box Protein-1 (RBX1) is a RING component of SCF (Skp-1, cullins, F-box proteins) E3 ubiquitin ligases, which regulate diverse cellular processes by targeting a variety of substrates for degradation. However, little is known about the role of ROC1 in human cancer. Here, we report that ROC1 is ubiquitously overexpressed in primary human tumor tissues and human cancer cell lines. ROC1 silencing by siRNA significantly inhibited the growth of multiple human cancer cell lines via induction of senescence and apoptosis as well as G(2)-M arrest. Senescence induction is coupled with DNA damage in p53/p21- and p16/pRB-independent manners. Apoptosis is associated with accumulation of Puma and reduction of Bcl-2, Mcl-1, and survivin; and G(2)-M arrest is associated with accumulation of 14-3-3sigma and elimination of cyclin B1 and Cdc2. In U87 glioblastoma cells, these phenotypic changes occur sequentially upon ROC1 silencing, starting with G(2)-M arrest, followed by apoptosis and senescence. Thus, ROC1 silencing triggers multiple death and growth arrest pathways to effectively suppress tumor cell growth, suggesting that ROC1 may serve as a potential anticancer target.
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PMID:ROC1/RBX1 E3 ubiquitin ligase silencing suppresses tumor cell growth via sequential induction of G2-M arrest, apoptosis, and senescence. 1950 29

Porphyromonas gingivalis is an oral pathogen that is also associated with serious systemic conditions such as preterm delivery. Here we investigated the interaction between P. gingivalis and a cell line of extravillous trophoblasts (HTR-8) derived from the human placenta. P. gingivalis internalized within HTR-8 cells and inhibited proliferation through induction of arrest in the G1 phase of the cell cycle. G1 arrest was associated with decreased expression of cyclin D and of CDKs 2, 4 and 6. In addition, levels of CDK inhibitors p15, p16, p18 and p21 were increased following P. gingivalis infection. The amount of Rb was diminished by P. gingivalis, and transient overexpression of Rb, with concomitant upregulation of phospho-Rb, relieved P. gingivalis-induced G1 arrest. HTR-8 cells halted in the G1 phase became apoptotic, and apoptosis was accompanied by an increase in the ratio of Bax/Bcl-2 and increased activity of caspases 3, 7 and 9. HTR-8 cells infected with P. gingivalis also exhibited a sustained activation of ERK1/2, and knock-down of ERK1/2 activity with siRNA abrogated both G1 arrest and apoptosis. Thus, P. gingivalis can invade placental trophoblasts and induce G1 arrest and apoptosis through pathways involving ERK1/2 and its downstream effectors, properties that provide a mechanistic basis for pathogenicity in complications of pregnancy.
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PMID:Porphyromonas gingivalis invades human trophoblasts and inhibits proliferation by inducing G1 arrest and apoptosis. 1952 55

Predictive models are being used increasingly in effort to allow physician and patient expectations to be aligned with outcomes that are based on available data. Most predictive models for men who receive external beam radiotherapy for clinically localized prostate cancer are based on Gleason score, clinical tumor classification, and prostate-specific antigen (PSA) levels. More sophisticated models also have been developed that incorporate treatment-related variables, such as the dose of radiation and the use of androgen-deprivation therapy. Most of the predictive models applied to prostate cancer were derived using PSA recurrence rates as the major endpoint, but clinical endpoints have been incorporated increasingly into predictive models. Biomarkers also are increasingly being added to predictive models in an effort to strengthen them. The Radiation Therapy Oncology Group (RTOG) has completed studies on a wide range of markers using tissue from 2 phase 3 trials (RTOG 8610 and 9202). To date, preliminary assessments of p53; DNA ploidy; p16/retinoblastoma 1 protein; Ki-67; mouse double-minute p53 binding protein homolog; Bcl-2/Bcl-2-associated X protein; cytosine, adenine, and guanine repeats; cyclooxygenase-2; signal transducer and activator of transcription 3; cytochrome P450 3A4; and protein kinase A have been completed. Although they are not ready for widespread, routine use, there are reasons to believe that future models will combine these markers with traditional pretreatment and treatment-related variables and will improve our ability to predict outcome and select the optimal treatment. Cancer 2009;115(13 suppl):3112-20. (c) 2009 American Cancer Society.
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PMID:Predictive models in external beam radiotherapy for clinically localized prostate cancer. 1954 39


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