Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Loss of heterozygosity and chromosomal rearrangement of the WWOX gene, which is located at 16q23.3-24.1, have been detected in ovarian, breast, hepatocellular, and prostate carcinomas and in other neoplasias. This gene, which spans the common chromosomal fragile site 16D, contains 9 exons and encodes a 46 kDa WWOX protein that contains 414 amino acids. The evidence from cancer cell lines and primary tumor tissues suggests that WWOX is a tumor suppressor gene and that its inactivation contributes to cancer development. The results from studies of WWOX gene knockout cancer cells and a WWOX knockout mouse model partly confirm this hypothesis. The nature of the various proteins that the WWOX protein can interact with, such as c-Jun, TNF, p53, p73, AP-2 gamma, and E2F-1, suggests that WWOX plays a central role in tumor suppression through transcriptional repression and apoptosis, with its apoptotic function the more prominent of the two. However, there is not universal agreement that WWOX is a tumor suppressor gene. Further analysis is needed to reveal the true nature of WWOX.
 ...
PMID:WWOX tumor suppressor gene. 1843 86

TNF plays diverse and contrasting roles in cancer, promoting skin carcinogenesis and metastasis, but also possessing potent antitumor effects in mice. TNF via TNFR1 axis induces NFkappaB, and may contribute to inflammation-facilitated neoplasia. On the other hand, lymphomas are cited as rare complications of anti-TNF therapy in humans. In order to address possible modulating role of TNF and of a related cytokine, LTalpha, in spontaneous tumorigenesis, we compared mice with p53-TNF, p53-LTalpha, p53-TNFR1 and p53-TNF-LT combined deficiencies. Unexpectedly, neither of these mice showed significant modulation of their survival or shift in the spectrum of emerging tumors, as compared to p53-deficient mice, arguing against direct link between TNF blockade and lymphoma development.
 ...
PMID:Ablation of TNF or lymphotoxin signaling and the frequency of spontaneous tumors in p53-deficient mice. 1844 81

Increasing studies suggest that SALL4 may play vital roles in leukemogenesis and stem cell phenotypes. We have mapped the global gene targets of SALL4 using chromatin immunoprecipitation followed by microarray hybridization and identified more than 2000 high-confidence, SALL4-binding genes in the human acute promyelocytic leukemic cell line, NB4. Analysis of SALL4-binding sites reveals that genes involved in cell death, cancer, DNA replication/repair, and cell cycle were highly enriched (P < .05). These genes include 38 important apoptosis-inducing genes (TNF, TP53, PTEN, CARD9, CARD11, CYCS, LTA) and apoptosis-inhibiting genes (Bmi-1, BCL2, XIAP, DAD1, TEGT). Real-time polymerase chain reaction has shown that expression levels of these genes changed significantly after SALL4 knockdown, which ubiquitously led to cell apoptosis. Flow cytometry revealed that reduction of SALL4 expression in NB4 and other leukemia cell lines dramatically increased caspase-3, annexin V, and DNA fragmentation activity. Bromodeoxyuridine-incorporation assays showed decreased numbers of S-phase cells and increased numbers of G1- and G2-phase cells indicating reduced DNA synthesis, consistent with results from cell proliferation assays. In addition, NB4 cells that express low levels of SALL4 have significantly decreased tumorigenecity in immunodeficient mice. Our studies provide a foundation in the development of leukemia stem cell-specific therapy by targeting SALL4.
 ...
PMID:SALL4 is a key regulator of survival and apoptosis in human leukemic cells. 1848 8

Many genes implicated in schizophrenia can be related to glutamatergic transmission and neuroplasticity, oligodendrocyte function, and other families clearly related to neurobiology and schizophrenia phenotypes. Others appear rather to be involved in the life cycles of the pathogens implicated in the disease. For example, aspartylglucosaminidase (AGA), PLA2, SIAT8B, GALNT7, or B3GAT1 metabolize chemical ligands to which the influenza virus, herpes simplex, cytomegalovirus (CMV), rubella, or Toxoplasma gondii bind. The epidermal growth factor receptor (EGR/EGFR) is used by the CMV to gain entry to cells, and a CMV gene codes for an interleukin (IL-10) mimic that binds the host cognate receptor, IL10R. The fibroblast growth factor receptor (FGFR1) is used by herpes simplex. KPNA3 and RANBP5 control the nuclear import of the influenza virus. Disrupted in schizophrenia 1 (DISC1) controls the microtubule network that is used by viruses as a route to the nucleus, while DTNBP1, MUTED, and BLOC1S3 regulate endosomal to lysosomal routing that is also important in viral traffic. Neuregulin 1 activates ERBB receptors releasing a factor, EBP1, known to inhibit the influenza virus transcriptase. Other viral or bacterial components bind to genes or proteins encoded by CALR, FEZ1, FYN, HSPA1B, IL2, HTR2A, KPNA3, MED12, MED15, MICB, NQO2, PAX6, PIK3C3, RANBP5, or TP53, while the cerebral infectivity of the herpes simplex virus is modified by Apolipoprotein E (APOE). Genes encoding for proteins related to the innate immune response, including cytokine related (CCR5, CSF2RA, CSF2RB, IL1B, IL1RN, IL2, IL3, IL3RA, IL4, IL10, IL10RA, IL18RAP, lymphotoxin-alpha, tumor necrosis factor alpha [TNF]), human leukocyte antigen (HLA) antigens (HLA-A10, HLA-B, HLA-DRB1), and genes involved in antigen processing (angiotensin-converting enzyme and tripeptidyl peptidase 2) are all concerned with defense against invading pathogens. Human microRNAs (Hsa-mir-198 and Hsa-mir-206) are predicted to bind to influenza, rubella, or poliovirus genes. Certain genes associated with schizophrenia, including those also concerned with neurophysiology, are intimately related to the life cycles of the pathogens implicated in the disease. Several genes may affect pathogen virulence, while the pathogens in turn may affect genes and processes relevant to the neurophysiology of schizophrenia. For such genes, the strength of association in genetic studies is likely to be conditioned by the presence of the pathogen, which varies in different populations at different times, a factor that may explain the heterogeneity that plagues such studies. This scenario also suggests that drugs or vaccines designed to eliminate the pathogens that so clearly interact with schizophrenia susceptibility genes could have a dramatic effect on the incidence of the disease.
 ...
PMID:Schizophrenia susceptibility genes directly implicated in the life cycles of pathogens: cytomegalovirus, influenza, herpes simplex, rubella, and Toxoplasma gondii. 1855 48

Numerous effective anticancer drugs have been developed from botanical sources, and there remains a significant untapped resource in herbal medicines. In this study, we evaluated the chemical composition of extracts from American ginseng after steaming, the antiproliferative effects of the ginsenosides in the extracts on SW-480 human colorectal cancer cells, and their apoptotic mechanisms. American ginseng roots were steamed at 120 degrees C for 2 or 4 h. Representative ginsenosides in the unsteamed and steamed extracts were determined using HPLC. The antiproliferative effects of the ginsenosides Rb1, Rg3 and Rh2 on SW-480 cells were determined by the MTS method. The effect of extract steamed for 4 h on apoptosis of SW-480 cell was assayed by flow cytometry after staining with annexin V/PI. The expression of 84 apoptotic-related genes, including TNF, mitochondria and p53 pathways, was determined using real-time quantitative PCR array analysis. The mitochondrial membrane potential (Deltapsim) was analyzed after staining with FC-1. Steaming of American ginseng increased Rg3 and Rh2 content and antiproliferative activity significantly. The quantitative PCR array data demonstrated that multiple genes in mitochondrial pathway are involved in American ginseng-induced apoptosis of SW-480 cells and the expression profiling was validated by the cellular functional assay. The mitochondrial pathway may play a key role in American ginseng-mediated cancer cell apoptosis.
 ...
PMID:The mitochondrial pathway is involved in American ginseng-induced apoptosis of SW-480 colon cancer cells. 1921 14

Inflammatory bowel disease (IBD) includes two similar yet distinct conditions called ulcerative colitis (UC) and Crohn's disease (CD). These diseases affect the digestive system and cause the inflammation of intestinal tissue, form sores and bleed easily. Most children with IBD are diagnosed in late childhood and adolescence. However, both UC and CD have been reported as early as in infancy. Most information pertaining to the epidemiology of IBD is based upon adult studies. Symptoms include abdominal pain, cramping, fatigue and diarrhea. Genetic factors play a significant role in determining IBD susceptibility. Epidemiological data support a genetic contribution to the pathogenesis of IBD. Recently, numerous new genes have been identified as being involved in the genetic susceptibility to IBD: TNF-308A, CARD15 (NOD2), MIF-173, N-acetyltransferase 2 (NAT2), NKG2D (natural killer cell 2D), STAT6 (signal transducer and activator of transcription 6), CTLA-4 (cytotoxic T lymphocyte antigen-4), MICA-MICB (major histocompatibility complex A and B), HLA-DRB1, HLA class-II, IL-18, IL-4, MICA-A5, CD14, TLR4, Fas-670, p53 and NF-kappaB. The characterization of these novel genes has the potential to identify therapeutic agents and aid clinical assessment of phenotype and prognosis in patients with IBD (UC and CD).
 ...
PMID:Epidemiology and gene markers of ulcerative colitis in the Chinese. 1923 40

Mechanisms that may allow circulating monocytes to persist as CD4 T cells diminish in HIV-1 infection have not been investigated. We have characterized steady-state gene expression signatures in circulating monocytes from HIV-infected subjects and have identified a stable antiapoptosis gene signature comprised of 38 genes associated with p53, CD40L, TNF, and MAPK signaling networks. The significance of this gene signature is indicated by our demonstration of cadmium chloride- or Fas ligand-induced apoptosis resistance in circulating monocytes in contrast to increasing apoptosis in CD4 T cells from the same infected subjects. As potential mechanisms in vivo, we show that monocyte CCR5 binding by HIV-1 virus or agonist chemokines serves as independent viral and host modulators resulting in increased monocyte apoptosis resistance in vitro. We also show evidence for concordance between circulating monocyte apoptosis-related gene expression in HIV-1 infection in vivo and available datasets following viral infection or envelope exposure in monocyte-derived macrophages in vitro. The identification of in vivo gene expression associated with monocyte resistance to apoptosis is of relevance to AIDS pathogenesis since it would contribute to: 1) maintaining viability of infection targets and long-term reservoirs of HIV-1 infection in the monocyte/macrophage populations, and 2) protecting a cell subset critical to host survival despite sustained high viral replication.
 ...
PMID:Circulating monocytes in HIV-1-infected viremic subjects exhibit an antiapoptosis gene signature and virus- and host-mediated apoptosis resistance. 1929 47

The esophageal squamous cell carcinoma is multifactorial disease involving genetic and environmental factors. The paper presents most important human data on the polymorphisms of selected genes that have been linked with higher risk of the neoplasm. The most widely studied group were genes encoded molecules engaged in biotransformations of xenobiotics, in particular potential carcinogens, like alcohol (ADH2) and aldehyde (ALDH2) dehydrogenases, various isoenzymes of cytochrome P450 (CYP1A1, CYP2E1) and glutathione S-transferase (GSTM1, GSTT1, GSTP1). High interest was also put for polymorphism in DNA repair genes, i.e., OGG1, XRCC1, XPD, XPG and MGMT as well as genes associated with nucleotide biosyntesis like methylenotetrahydrofolate reductase and thymidylate synthase and in control of cell cycle and apoptosis e.g., p53, Fas, FasL or TNF. Furthermore, it was revealed that predisposition to cancer in certain individual could be determined by coexistence of unprofitable allele of a few genes. Introduction of genetic screening test allows effective, purpose-oriented methods of prevention and in patients suffered from the cancer--application of optimal therapy and minimization of side-effects.
 ...
PMID:[Genetic base of esophageal squamous cell carcinoma susceptibility]. 1938 10

To understand the design principles of the molecular interaction network associated with the irreversibility of cell apoptosis and the stability of cell surviving, we constructed a Boolean network integrating both the intrinsic and extrinsic pro-apoptotic pathways with pro-survival signal transduction pathways. We performed statistical analyses of the dependences of cell fate on initial states and on input signals. The analyses reproduced the well-known pro- and anti-apoptotic effects of key external signals and network components. We found that the external GF signal by itself did not change the apoptotic ratio from randomly chosen initial states when there is no external TNF signal, but can significantly offset apoptosis induced by the TNF signal. While a complete model produces the expected irreversibility of the apoptosis process, alternative models missing one or more of four selected inter-component connections indicate that the feedback loops directly involving the caspase 3 are essential for maintaining irreversibility of apoptosis. The feedback loops involving P53 showed compensating effects when those involving caspase 3 have been removed. The GF signal significantly increases the stability of the surviving states of the network. The apoptosis network seems to use different modules by design to control the irreversibility of the apoptosis process and the stability of the surviving states. Such a design may accommodate the needed plasticity for the network to adapt to different cellular environments: depending on the strength of external pro-surviving signals, apoptosis can be induced either easily or difficultly by pro-apoptotic signal of varying strengths, but proceed with invariable irreversibility.
 ...
PMID:Boolean network-based analysis of the apoptosis network: irreversible apoptosis and stable surviving. 1942 37

Menopausal hormone therapy (HT) is associated with an increased breast cancer risk among postmenopausal women. In this study, we investigated genetic effect modification of HT associated breast cancer risk in 3,149 postmenopausal breast cancer patients and 5,489 controls from the two German population-based case-control studies MARIE and GENICA. Twenty-eight polymorphisms of 14 candidate genes including two drug and hormone transporter genes (ABCB1/MDR1 and SHBG), four genes involved in cell cycle regulation (BRCA1, P21/CDKN1A, STK15/AURKA and TP53), six cytokine genes (IGFBP3, IL6, TGFB1, TNF, LTA and IGF1), and two cytokine receptor genes (EGFR and ERBB2) were genotyped using validated methods. Conditional logistic regression was used to assess multiplicative statistical interaction between polymorphisms and duration of estrogen-progestagen therapy and estrogen monotherapy use with regard to breast cancer risk assuming log-additive and co-dominant modes of inheritance. Women homozygous for the major ABCB1_rs2214102_G allele were found to be at a significantly increased breast cancer risk associated with combined estrogen-progestagen therapy [odds ratio (OR) = 1.17, 95% confidence interval (CI) = 1.12-1.23, P (interaction) = 0.022]. Additionally, risk associated with estrogen monotherapy was modified by BRCA1_rs799917. We observed a trend with increasing minor T alleles leading to the highest risk in homozygous carriers of the minor allele [OR (95% CI) = 1.17 (0.98-1.39), 1.06 (0.98-1.14), and 1.02 (0.94-1.11) for homozygous minor, heterozygous, and homozygous major allele carriers, respectively; P (interaction) = 0.032]. Our results suggest that genetic variants in ABCB1 and BRCA1 may modify the effect of HT on postmenopausal breast cancer risk.
 ...
PMID:Polymorphisms in the BRCA1 and ABCB1 genes modulate menopausal hormone therapy associated breast cancer risk in postmenopausal women. 1967 6


<< Previous 1 2 3 4 5 6 7 8 9 10