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)

Detecting the presence and diversity of low-level mutations in human tumors undergoing genomic instability is desirable due to their potential prognostic value and their putative influence on the ability of tumors to resist drug treatment and/or metastasize. However, direct measurement of these genetic alterations in surgical samples has been elusive, because technical hurdles make mutation discovery impractical at low-mutation frequency levels (<10(-2)). Here, we describe inverse PCR-based amplified restriction fragment length polymorphism (iFLP), a new technology that combines inverse PCR, RFLP, and denaturing high-performance liquid chromatography to allow scanning of the genome at several thousand positions per experiment for low-level point mutations. Using iFLP, widespread, low-level mutations at mutation frequency 10(-2)-10(-4) were discovered in genes located on different chromosomes, e.g., OGG1, MSH2, PTEN, beta-catenin, Bcl-2, P21, ATK3, and Braf, in human colon cancer cells that harbor mismatch repair deficiency whereas mismatch repair-proficient cells were mutation free. Application of iFLP to the screening of sporadic colon cancer surgical specimens demonstrated widespread low-level mutations in seven out of 10 samples, but not in their normal tissue counterparts, and predicted the presence of millions of diverse, low-incidence mutations in tumors. Unique low-level mutational signatures were identified for each colon cancer cell line and tumor specimen. iFLP allows the high-throughput discovery and tracing of mutational signatures in human cells, precancerous lesions, and primary or metastatic tumors and the assessment of the number and heterogeneity of low-level mutations in surgical samples.
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PMID:Inverse PCR-based RFLP scanning identifies low-level mutation signatures in colon cells and tumors. 1505 10

The initial aim of this study was to examine the expression profiles of P53 and its upstream genes, downstream genes, and cell cycle regulators to determine whether these markers are useful for making a differential diagnosis among the benign, borderline, and malignant ovarian epithelial tumors. Between borderline and malignant tumors, the increased expression levels of P53, Bax, Cyclin E, and cyclin-dependent kinase-2 as well as the decreased expression levels of growth arrest and DNA damage (GADD45) and murine double minute-2 (MDM2) were significantly associated with malignancy (P < 0.01, each). Using the receiver operating curve (ROC), the most reliable cutoff value of the added-up staining scores of those markers was 4.5 with 79% sensitivity and 89% specificity for malignancy. Between benign and borderline tumors, the P21 and Bax expression levels were significantly higher in borderline tumors, whereas the Bcl-2 expression level was much higher in benign tumors (P < 0.01, each). Using the ROC, the cutoff value of the added-up staining scores used to discriminate between the two groups was 2.5 with 70% sensitivity and 74% specificity for borderline tumors. Thus, for the differential diagnosis between borderline and malignant tumors, the cutoff value 4.5 of the cumulative staining scores can be used. However, the cutoff value 2.5 for discrimination between benign and borderline tumors may not be useful because of its relatively low sensitivity and specificity. In addition, the P53, GADD45, Cyclin E, and MDM2 expression levels in malignant ovarian tumors might be useful for determining the histologic grade and type.
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PMID:Diagnostic approach using the expression profiling of the P53 tumor suppressor gene and its related proteins in ovarian epithelial tumors. 1588 69

Endometriosis is defined as the presence of endometrial glands and stroma outside the uterus. Apoptosis, a physiological process by which multicellular organisms eliminate superfluous cells, is altered in tumor tissue. Here we studied the expression of the apoptosis-related proteins p53, bcl-2, bax, p21 and fas in proliferative (n=9) and secretory (n=9) endometrium, and in peritoneal (n=11), ovarian (n=20) and colorectal (n=20) endometriosis, by qualitative and semi-quantitative immunohistochemical methods using the percentage of positive cells and HSCORE analysis. In endometrium, p53, p21 and fas expression was low, whereas bax and bcl-2 expression was elevated. Using HSCORE analysis, only bcl-2 expression varied during the menstrual cycle (48.9+/-34.2% in the proliferative phase, 11.5+/-24.7% in the secretory phase, p=0.01). Using HSCORE analysis, p53 expression was higher in ovarian endometriosis than in peritoneal (p<0.0001) and colorectal endometriosis (p=0.03). P21 expression was higher in ovarian endometriosis than in peritoneal (p=0.01) and colorectal endometriosis (p=0.01). Bcl-2 expression was lower in ovarian endometriosis than in peritoneal (p=0.0002) and colorectal endometriosis (p<0.0001). Fas expression was higher in peritoneal endometriosis than in ovarian (p=0.02) and colorectal endometriosis (p=0.008). In conclusion, these results confirm the involvement of apoptosis in the pathogenesis of endometriosis. Moreover, expression of apoptosis-related proteins varies according to the location of endometriosis suggesting the involvement of different apoptotic pathways.
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PMID:Expression of apoptosis-related proteins in peritoneal, ovarian and colorectal endometriosis. 1637 43

Polybrominated diphenyl ethers (PBDEs) are hydrophobic and persistent additive flame retardants that seemingly transfer into environmental compartments where they bioaccumulate i.e. in human biota. We examined the micronucleus-forming activities of low-dose PBDEs (congeners 47, 99, 153, 183 or 209) in MCF-7 cells along with their ability to modulate growth, cell biochemistry [by infrared (IR) microspectroscopy], clonogenic survival or quantitative expression of cytochrome P450 isoenzymes (CYP1A1, CYP1A2 and CYP1B1), cyclin-dependent kinase inhibitor 1A [CDKN1A (P21(WAF1/CIP1))], B-cell leukaemia/lymphoma-2 (BCL-2) and Bcl-2-associated X (BAX). Elevations in micronucleus formation were observed following treatment with 10(-12) to 10(-9) M PBDE concentrations despite the fact that less than one-fourth of the concentration of each test agent administered partitioned out of the media and into the incubating cells. However, low-dose treatment levels remained within the range of reported concentrations measured in UK serum samples collected in 2003. Clonogenic survival and gene expression was unaltered following 10(-12) to 10(-9) M PBDE treatment but significant (P < 0.05) elevations in growth kinetics were observed. Significant alterations in IR cell spectra were associated with treatments, and plotted clusters following principal component analysis highlighted these changes. Whether such in vitro effects point to an underlying ability of PBDEs to initiate and drive target-cell alterations in vivo now needs to be addressed.
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PMID:Low-dose treatment with polybrominated diphenyl ethers (PBDEs) induce altered characteristics in MCF-7 cells. 1698 Jul 5

Pro-carcinogens, such as benzo[a]pyrene (B[a]P), that are exogenous ligands of the aromatic hydrocarbon receptor may influence the susceptibility of target-cell populations through the up-regulation of cytochrome P450 (CYP) mixed function oxidases. We examined whether the growth kinetics of MCF-7 cells might determine the level of up-regulation of CYP1A1, CYP1A2 or CYP1B1 by B[a]P, and whether this could then influence subsequent levels of DNA damage. Cell cultures manipulated to be G(0)/G(1)-phase concentrated, S-phase concentrated or G(2)/M-phase concentrated were treated with B[a]P and the expression levels of CYP1A1, CYP1A2, CYP1B1, cyclin-dependent kinase inhibitor 1A [CDKN1A (P21(WAF1/CIP1))], B-cell leukaemia/lymphoma-2 (BCL-2), and Bcl-2-associated X levels were determined. Levels of DNA damage were measured as DNA single-strand breaks (SSBs) by the alkaline single-cell gel electrophoresis (comet) assay or as DNA adducts by (32)P-postlabelling analysis. B[a]P-induced up-regulation of CYP1A1 was >100-fold in S-phase-concentrated cells, but in G(0)/G(1)-phase- or G(2)/M-phase-concentrated cultures up-regulation occurred to a significantly lower extent. Consistent with this, B[a]P-treated S-phase-concentrated cultures exhibited markedly up-regulated P21(WAF1/CIP1), higher levels of dose-related increases in DNA SSBs, and increased DNA adduct levels presumably as a result of CYP1A1-mediated activation of B[a]P to B[a]P-diol-epoxide compared with the cultures enriched for the other cell cycle phases. Growth kinetics in vitro may be an important predeterminant of susceptibility to an exogenous pro-carcinogen in short-term test systems and these findings have important implications when extrapolating such results to a particular target-cell population in vivo.
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PMID:Growth kinetics in MCF-7 cells modulate benzo[a]pyrene-induced CYP1A1 up-regulation. 1723 83

Minoxidil induces hair growth in male pattern baldness and prolongs the anagen phase. All-trans retinoic acid (ATRA) has been reported to act synergistically with minoxidil in vivo: they can enhance more dense hair regrowth than either compound alone. We evaluated the effect of minoxidil combined with ATRA on hair growth in vitro. The effect of co-treatment of minoxidil and ATRA on hair growth was studied in hair follicle organ culture. In cultured human dermal papilla cells (DPCs) and normal human epidermal keratinocytes, the expressions of Erk, Akt, Bcl-2, Bax, P53 and P21 were evaluated by immunoblot analysis. Minoxidil plus ATRA additively promoted hair growth in vitro, compared with minoxidil alone. In addition, minoxidil plus ATRA elevated phosphorylated Erk, phosphorylated Akt and the ratio of Bcl-2/Bax, but decreased the expressions of P53 and P21 more effectively than by minoxidil alone. Our results suggest that minoxidil plus ATRA would additively enhance hair growth by mediating dual functions: 1) the prolongation of cell survival by activating the Erk and Akt signaling pathways, and 2) the prevention of apoptosis of DPCs and epithelial cells by increasing the ratio of Bcl-2/Bax and downregulating the expressions of P53 and P21.
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PMID:Promotive effect of minoxidil combined with all-trans retinoic acid (tretinoin) on human hair growth in vitro. 1744 38

PTEN is a tumor suppressor gene mutated in many human cancers. We generated a bronchioalveolar epithelium-specific null mutation of Pten in mice [SP-C-rtTA/(tetO)(7)-Cre/Pten(flox/flox) (SOPten(flox/flox)) mice] that was under the control of doxycycline. Ninety percent of SOPten(flox/flox) mice that received doxycycline in utero [SOPten(flox/flox)(E10-16) mice] died of hypoxia soon after birth. Surviving SOPten(flox/flox)(E10-16) mice and mice that received doxycycline postnatally [SOPten(flox/flox)(P21-27) mice] developed spontaneous lung adenocarcinomas. Urethane treatment accelerated number and size of lung tumors developing in SOPten(flox/flox) mice of both ages. Histological and biochemical examinations of the lungs of SOPten(flox/flox)(E10-16) mice revealed hyperplasia of bronchioalveolar epithelial cells and myofibroblast precursors, enlarged alveolar epithelial cells, and impaired production of surfactant proteins. Numbers of bronchioalveolar stem cells (BASCs), putative initiators of lung adenocarcinomas, were increased. Lungs of SOPten(flox/flox)(E10-16) mice showed increased expression of Spry2, which inhibits the maturation of alveolar epithelial cells. Levels of Akt, c-Myc, Bcl-2, and Shh were also elevated in SOPten(flox/flox)(E10-16) and SOPten(flox/flox)(P21-27) lungs. Furthermore, K-ras was frequently mutated in adenocarcinomas observed in SOPten(flox/flox)(P21-27) lungs. These results indicate that Pten is essential for both normal lung morphogenesis and the prevention of lung carcinogenesis, possibly because this tumor suppressor is required for BASC homeostasis.
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PMID:Pten controls lung morphogenesis, bronchioalveolar stem cells, and onset of lung adenocarcinomas in mice. 1790 29

This study addressed the influence of propylthiouracil (PTU)-induced hypothyroidism on postnatal and adult neurogenesis. PTU was administered from birth to postnatal day 10 (P10) or P21, leading to decreased neural stem cell/progenitor proliferation in the dentate gyrus, as well as significantly fewer granule cells and reduced hippocampal volume. Upon P22 PTU withdrawal, plasma thyroid hormone levels were normal by P90, there was no difference in the number of dentate gyrus or subventricular proliferating cells, but brain weight was smaller. In addition, dentate gyrus density of surviving BrdU-labeled cells increased, with no changes to the olfactory bulb. Quantitative PCR revealed decreased FGF-2, NGF, Wnt3a, and VEGF-A hippocampal expression during PTU treatment, with recovery in adulthood. Pro-apoptotic Bax was up-regulated, and anti-apoptotic Bcl-2 was down-regulated, during PTU treatment, both of which were normalized in the adult brain. In contrast, apoptosis-inducing factor (AIF) was down-regulated in the adult. These results suggest that mechanisms in the adult brain attempt to compensate for decreased neurogenesis due to postnatal hypothyroidism.
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PMID:Effects of postnatal thyroid hormone deficiency on neurogenesis in the juvenile and adult rat. 1923 74

Our goals were to examine the dual-directional regulation effects of resveratrol (1) in vitro by using MCF-7 cells (estradiol receptor-positive cells), study its mechanism of action, and give a systematical analysis of the regulatory networks of each related factor. An MTT test and growth curve showed that the proliferation of MCF-7 cells was inhibited by a high concentration of 1, and that its IC(50) was 8.70 x 10(-5) +/- 0.23 mol/l. However, 1 induced the proliferation of MCF-7 cells at 10(-7)-10(-5) mol/l, and resulted in a peak proliferation at 1.0 x 10(-7) mol/l. A high concentration of 1 arrested cell cycle progression at the G(1) phase, and a typical "sub-G(1) peak" of apoptotic cells was also observed by flow cytometry. The proliferation index of MCF-7 cells increased significantly with a low concentration of 1 (p < 0.05). 1 in high concentrations induced Bax, caspase-3, and cyclin-dependent kinase (CDK) inhibitor P21 expression, whereas the expressions of cyclin CDK2, Bcl-2, and proliferating cell nuclear antigen (PCNA) were decreased by 1 treatment. Conversely, treatment with low concentrations of 1 decreased the expression of P21 and Bax, while the expressions of cyclin CDK2, Bcl-2, and PCNA were increased. These results suggest that 1 had a dual-regulatory effect on MCF-7 cells. CDK-associated protein was a key factor at both the high and low concentrations used in this study.
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PMID:Effect of proliferation, cell cycle, and Bcl-2s of MCF-7 cells by resveratrol. 1943 Oct 20

The optimal administration time for applying epidermal growth factor receptor inhibitors combined with radiotherapy has been unclear. We investigated the efficacy of combining gefitinib with radiation in different treatment schedules. We demonstrated that gefitinib was administered to A549 lung cancer cells in three ways (administration before irradiation, administration upon irradiation, administration after irradiation) to establish the radiosensitizing effect. Cell-survival rates were evaluated by colony-forming assays. Cell apoptosis and cell-cycle distribution were investigated using flow cytometry; meanwhile, the expression of P21, Cdc25c, Bcl-2, Bax, Rad51 and phosphorylated DNA-PKcs (phospho-DNA-PK) after 6 Gy irradiation and/or gefitinib were determined by Western blot analysis. The sensitizer enhancement ratios of the gefitinib administration before irradiation, administration upon irradiation, and administration after irradiation groups were 2.23, 1.51 and 1.30, respectively. A higher apoptosis rate and G(2)/M phase arrest were observed in cells at 48 h after exposure to 6 Gy irradiation when gefitinib was administrated before irradiation. Increased cell apoptosis and cell cycle arrest were further supported by the expression changes of Bcl-2, Bax, P21, Cdc25c, Rad51 and phospho-DNA-PK at the same time. The best radiosensitizing effect was obtained when gefitinib was delivered before irradiation. Apoptosis might be an important way of cell killing and G(2)/M phase arrest might be an important mechanism of apoptosis. The expression proportion changes of P21/Cdc25c proteins may play an important role in G(2)/M cell cycle arrest. Moreover, the pro-apoptotic/antiapoptotic and DNA repair factors may be important modulators taking part in the molecular events of the radiosensitizing effect of gefitinib combined with irradiation.
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PMID:Radiosensitizing effects of gefitinib at different administration times in vitro. 1943 83


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