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

Caspase-8, also known as MACH/FLICE/Mch5, is the most upstream-located cysteine-aspartyl-protease (caspase) in a caspase cascade involved in apoptosis triggered by members of the tumor necrosis factor receptor superfamily or other stimuli such as chemotherapeutic agents. Regulation of caspase-8 expression on a post-translational level has been studied in detail, whereas only little information is available on its control by gene transcription. We identified and cloned the human caspase-8 promoter, determined the transcriptional start site of the caspase-8 gene, and examined the regulatory mechanisms of the promoter with respect to its basal activity as well as to its inducibility upon apoptotic stimuli in human hepatoma cells. We identified two minimal sequences essential for basal transcription of caspase-8 and demonstrate that a single SP1 and an ETS-like binding motif mediate this effect. We further show that the caspase-8 promoter is inducible and demonstrate that adenoviral infection increases caspase-8 mRNA levels. However, the increase in caspase-8 gene transcription after adenoviral infection absolutely depends on the p53 status of the hepatoma cell line, implying that caspase-8 is a target gene of p53. We show that delivery of exogenous p53 alone is sufficient to induce the caspase-8 promoter even in p53-deficient Hep3B hepatoma cells. Subsequent promoter deletion analysis in combination with luciferase reporter assays identified a p53-responsive element downstream of the transcriptional start site. We demonstrate that this p53-responsive sequence overlaps with the ETS-like binding site and suggest that an additional p53-inducible, yet unknown factor interacts with this region of the caspase-8 promoter. In summary, our study contributes to the understanding of the transcriptional regulation of the caspase-8 gene by basal (SP1- and ETS-dependent) and inducible (p53-dependent) mechanisms.
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PMID:The human caspase-8 promoter sustains basal activity through SP1 and ETS-like transcription factors and can be up-regulated by a p53-dependent mechanism. 1274 79

Over the past 15 years, a wealth of information has been published on transcripts and proteins 'induced' (requiring new protein synthesis) in mammalian cells after ionizing radiation (IR) exposure. Many of these studies have also attempted to elucidate the transcription factors that are 'activated' (i.e., not requiring de novo synthesis) in specific cells by IR. Unfortunately, all too often this information has been obtained using supralethal doses of IR, with investigators assuming that induction of these proteins, or activation of corresponding transcription factors, can be 'extrapolated' to low-dose IR exposures. This review focuses on what is known at the molecular level about transcription factors induced at clinically relevant (< or =2 Gy) doses of IR. A review of the literature demonstrates that extrapolation from high doses of IR to low doses of IR is inaccurate for most transcription factors and most IR-inducible transcripts/proteins, and that induction of transactivating proteins at low doses must be empirically derived. The signal transduction pathways stimulated after high versus low doses of IR, which act to transactivate certain transcription factors in the cell, will be discussed. To date, only three transcription factors appear to be responsive (i.e. activated) after physiological doses (doses wherein cells survive or recover) of IR. These are p53, nuclear factor kappa B(NF-kappaB), and the SP1-related retinoblastoma control proteins (RCPs). Clearly, more information on transcription factors and proteins induced in mammalian cells at clinically or environmentally relevant doses of IR is needed to understand the role of these stress responses in cancer susceptibility/resistance and radio-sensitivity/resistance mechanisms.
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PMID:Transcription factors activated in mammalian cells after clinically relevant doses of ionizing radiation. 1294 88

RECQ4 is a member of the RecQ helicase family, which has been implicated in the regulation of DNA replication, recombination and repair. p53 modulates the functions of RecQ helicases including BLM and WRN. In this study, we demonstrate that p53 can regulate the transcription of RECQ4. Using nontransformed, immortalized normal human fibroblasts, we show that p53-dependent downregulation of RECQ4 expression occurred in G1-arrested cells, both in the absence or presence of exogenous DNA damage. Wild-type p53 (but not the tumor-derived mutant forms) repressed RECQ4 promoter activity. The camptothecin or etoposide-dependent p53-mediated repression was attenuated by trichostatin A (TSA), an inhibitor of histone deacetylases (HDACs). Repression of the RECQ4 promoter was accompanied with an increased accumulation of HDAC1, and the loss of SP1 and p53 binding to the promoter. The simultaneous formation of a camptothecin-dependent p53-SP1 complex indicated its occurrence outside of the RECQ4 promoter. These data suggest that p53-mediated repression of RECQ4 transcription during DNA damage results from the modulation of the promoter occupancy of transcription activators and repressors.
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PMID:Tumor suppressor p53 represses transcription of RECQ4 helicase. 1567 34

mtCLIC/CLIC4 is a p53 and tumor necrosis factor alpha (TNFalpha) regulated intracellular chloride channel protein that localizes to cytoplasm and organelles and induces apoptosis when overexpressed in several cell types of mouse and human origin. CLIC4 is elevated during TNFalpha-induced apoptosis in human osteosarcoma cell lines. In contrast, inhibition of NFkappaB results in an increase in TNFalpha-mediated apoptosis with a decrease in CLIC4 protein levels. Cell lines expressing an inducible CLIC4-antisense construct that also reduces the expression of several other chloride intracellular channel (CLIC) family proteins were established in the human osteosarcoma lines SaOS and U2OS cells and a malignant derivative of the mouse squamous papilloma line SP1. Reduction of CLIC family proteins by antisense expression caused apoptosis in these cells. Moreover, CLIC4-antisense induction increased TNFalpha-mediated apoptosis in both the SaOS and U2OS derivative cell lines without altering TNFalpha-induced NFkappaB activity. Reducing CLIC proteins in tumor grafts of SP1 cells expressing a tetracycline-regulated CLIC4-antisense substantially inhibited tumor growth and induced tumor apoptosis. Administration of TNFalpha i.p. modestly enhanced the antitumor effect of CLIC reduction in vivo. These results suggest that CLIC proteins could serve as drug targets for cancer therapy, and reduction of CLIC proteins could enhance the activity of other anticancer drugs.
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PMID:Antisense suppression of the chloride intracellular channel family induces apoptosis, enhances tumor necrosis factor {alpha}-induced apoptosis, and inhibits tumor growth. 1569

Human PCAN1 (prostate cancer gene 1) is a prostate-specific gene that is highly expressed in prostate epithelial tissue, and frequently mutated in prostate tumors. To better understand the regulation of the PCAN1 gene, a 2.6-kb fragment of its 5' flanking region was obtained by PCR. Its promoter activity was examined via the dual-luciferase reporter assay after it had been cloned into a pGL(3)-basic vector generating pGL(3)-p2.6 kb and transfected into LNCaP cells. pGL(3)-basic and pGL(3)-control were respectively used as the negative and positive controls. Sequence analysis with the MatInspector database showed that some possible binding sites for the transcriptional factors, NKX3.1, P53, SP1, cEBP and the PPAR/RXR heterodimers may locate on a 2.6-kb region upstream of the PCAN1 gene. To examine the relevant regulation of PCAN1, pGL(3)-p2.6 kb was transfected into the prostate cancer cell line LNCaP, which was treated with R1881 (10(-7) approximately 10(-9) mol/l), 17beta-estradiol (17beta-E(2), 10(-7) approximately 10(-9) mol/l), all-trans-retinoic acid (all-trans-RA, 10(-5) approximately 10(-7) mol/l) or 9-cis-retinoic acid (9-cis-RA, 10(-5) approximately 10(-7) mol/l), and eukaryotic expression plasmids of NKX3.1, p53, Sp1, Pten, PPARgamma or cEBPalpha were cotransfected with pGL(3)-p2.6 kb into LNCaP cells. pRL-TK, a Renilla luciferase reporter vector, was cotransfected into all the transfection lines as an internal control. The activities of pGL(3)-p2.6 kb (PCAN1 promoter) were analyzed via the dual-luciferase reporter assay 48 h after transfection. The results showed that 9-cis-RA enhanced the PCAN1 promoter activity in a dose-dependent manner, while R1881, 17beta-E(2) and all-trans-RA had no significant effect on PCAN1 promoter activities. Cotransfection with pGL(3)-p2.6kb and the expression plasmids of NKX3.1, p53, Sp1 or Pten respectively resulted in 1.66-, 2.48-, 2.00-and 1.72-fold 2.6 kb PCAN1 promoter activity increases relative to the controls, which were cotransfected with pcDNA3.1(+), while cotransfection of PPARgamma and cEBPalpha yielded no significant effect on PCAN1 promoter activities. These results could be applied for further study of the function and transcription regulation of the PCAN1 gene in prostate development and carcinogenesis.
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PMID:Molecular cloning and analysis of the human PCAN1 (GDEP) promoter. 1746 39

Multidrug resistance (MDR) is associated with the overproduction of the 170-kDa transmembrane protein P-glycoprotein (MDR1) caused by transcriptional activation. However, the activity of the MDR1 promoter in response to different doses of ionizing radiation has not been investigated. In this study, two squamous cell carcinoma oral cavity cell lines, T-167 and T-409, were exposed to either a standard clinical dose of 2 Gy or low-dose fractionated radiation therapy (LDFRT), delivered as 0.5 Gy in four fractions. MDR1 gene expression and degree of cell death were assessed. Clinically relevant 2-Gy dose of radiation resulted in increased expression of MDR1 by reverse transcription-PCR and luciferase reporter assays in both cell lines (T-167 and T-409), whereas LDFRT did not. LDFRT caused enhanced apoptosis when compared with the 2-Gy dose in T-167 and T-409 cells as assessed by terminal nucleotidyl transferase-mediated nick end labeling (TUNEL) assays. Transcription of the MDR1 gene is regulated by numerous transcription factors, which include nuclear factor-kappaB (NF-kappaB), NF-Y, SP1, YB1, MEF1 (MDR1 promoter-enhancing factor 1), p53, and NF-R1. Interestingly, 2 Gy robustly induced both NF-kappaB and NF-Y in T-167 and T-409 cells, but did not show induction when exposed to LDFRT. Silencing the expression of the DNA binding subunit of NF-kappaB, p50, by small interfering RNA vector resulted in a decrease of MDR1 function by rhodamine 123 efflux assay in T167 cells exposed to 2 Gy. Together, these results provide evidence for the lack of induction of P-glycoprotein expression by LDFRT, which has important implications in combinatorial cancer therapy, including the use of LDFRT as an adjuvant for chemotherapy.
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PMID:Lack of P-glycoprotein expression by low-dose fractionated radiation results from loss of nuclear factor-kappaB and NF-Y activation in oral carcinoma cells. 1823 65

Deregulation of cell cycle leads to cell transformation and cancer development. Here we present profiling the proteome dynamics using 2-DE and constructing the associated functional networks during the cell cycle of human hepatoma cells, Mahlavu. The protein dynamics was validated by hierarchical clustering analysis on the proteome, and by Northern blot assays on the selected 14-3-3 proteins. Of the 2665 protein spots, 201 with variation coefficient of expression dynamics >20% throughout the cell cycle were subjected to analysis. Degree of the global protein dynamics was phase dependent with the greatest in transitional phases of S/G2, G2/M, and G1/S. Concurrence of pathways coordinating cell-cycle progression versus arrest, and/or pathways regulating apoptosis versus antiapoptosis was always identified during the cell cycle, suggesting the existence of counteracting mechanisms for intracellular homeostasis. Data mining of the results suggested that the key transcription factors in G0/G1, G1/S, S, and G2/M were p53 and SP1, c-Myc, c-Myc and p53, and YY1 and c-Jun, respectively. Our findings for the first time provide insights into the regulation of mammalian cell-cycle progression at the proteome level, and grant a model to study disease mechanisms and to discover therapeutic targets for anticancer therapy.
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PMID:Profiling the proteome dynamics during the cell cycle of human hepatoma cells. 1865 25

Recent evidence suggests tumor-initating cells (TICs), also called cancer stem cells, are responsible for tumor initiation and progression; therefore, they represent an important cell population for development of future anti-cancer therapies. In this study, we show that the sesquiterpene lactone parthenolide (PTL) is cytotoxic to prostate TICs isolated from prostate cancer cell lines: DU145, PC3, VCAP, and LAPC4, as well as primary prostate TICs. Furthermore, PTL inhibited TIC-driven tumor formation in mouse xenografts. Using an integrated molecular profiling approach encompassing proteomics, profiles of activated transcription factors and genomics we ascertained the effects of PTL on prostate cancer cells. In addition to the previously described effects of PTL, we determined that the non-receptor tyrosine kinase src, and many src signaling components, including: Csk, FAK, beta1-arrestin, FGFR2, PKC, MEK/MAPK, CaMK, ELK-1, and ELK-1-dependent genes are novel targets of PTL action. Furthermore, PTL altered the binding of transcription factors important in prostate cancer including: C/EBP-alpha, fos related antigen-1 (FRA-1), HOXA-4, c-MYB, SNAIL, SP1, serum response factor (SRF), STAT3, X-box binding protein-1 (XBP1), and p53. In summary, we show PTL is cytotoxic to prostate TICs and describe the molecular events of PTL-mediated cytotoxicity. Therefore, PTL represents a promising therapeutic for prostate cancer treatment.
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PMID:Effects of the sesquiterpene lactone parthenolide on prostate tumor-initiating cells: An integrated molecular profiling approach. 1920 13

Epigenetic gene inactivation in mammalian cells involves many silencing mechanisms. One of these mechanisms is the transcriptional repression by targeted promoter hypermethylation. However, the molecular mechanisms involved in the site-specific DNA (hyper)methylation are not fully elucidate. By using the Dnmt3a/c-myc interaction as an example, we here showed that this interaction promotes the site-specific methylation of CG dinucleotides localized in c-myc boxes of promoter regions of CDKN2a, CCND1 and TIMP2 genes. Indeed, the invalidation of c-myc reveals that c-myc allows the Dnmt3a recruitment on c-myc box of c-myc-regulated genes. Acellular experiments corroborated and complemented these results by revealing that the specificity of consensus sequence for DNA methylation of Dnmt3a is increased in presence of c-myc. Indeed, our work indicates that Dnmt3a and Dnmt3b have consensus sequences to methylate DNA (T/A/C)(A/T)(T/G/A)CG(T/G/C)G(G/C/A) and (A/C)(C/G/A)(A/G)CGT(C/G)(A/G). Thus, the low specificity of these sequences (consensual for 162 and 48 possibilities, respectively) does not support the idea of targeted DNA methylation. By monitoring transcription factor arrays spotted with 103 transcription factors, we next identified 42 transcription factors interacting with Dnmt3a and Dnmt3b (such as CREB and FOS), 27 transcription factors interacting with Dnmt3a (such as AP2alpha and p53), 10 transcription factors interacting with Dnmt3b (such as SP1 and SP4) and 24 transcription factors devoid of direct interaction with Dnm3a and Dnmt3b (such as C/EBPalpha and NFkappaB-p65). Thus, The description of direct interaction between Dnmt3a and/or Dnmt3b and transcription factors provides rational molecular explanation to the mechanisms of targeted DNA (hyper)methylation, and to the mechanisms by which transcription factors repress genes expression.
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PMID:Dnmt3/transcription factor interactions as crucial players in targeted DNA methylation. 1978 33

Colon cancer is the third and fourth most prevalent cancer among Iranian men and women, respectively. Suicide gene therapy is one of the alternative therapeutic modalities for cancer. The application of specific promoters for therapeutic genes should decrease the adverse effects of this modality. The combined aims of this study were to design a specific suicide gene therapy construct for colon cancer and study its effect in distinct representatives of transformed and nontransformed cells. The KRAS oncogene signaling pathway is one of the most important signaling pathways activated in colon cancer; therefore, we inserted the urokinase plasminogen activator receptor (uPAR; PLAUR gene) promoter as one of the upregulated promoters by this pathway upstream of a suicide gene (thymidine kinase [TK]) and a reporter gene (beta-galactosidase, beta-gal [LacZ]). This promoter is a natural combination of different motifs responsive to the RAS signaling pathway, such as the transcription factors AP1 (FOS/JUN), SP1, SP3, and AP2alpha, and nuclear factor kappa B (NFkappaB). The reporter plasmid under the control of the uPAR promoter (PUCUPARLacZ) had the ability to express beta-gal in colon cancer cells (human colon adenocarcinoma [SW480] and human colorectal carcinoma [HCT116] cell lines), while it could not express beta-gal in nontransformed human umbilical vein endothelial cells (HUVEC) and normal colon cells. After confirming the ability of pUCUPARTK (suicide plasmid) to express TK in SW480 and HCT116 cells by real-time PCR, cytotoxicity assays showed that pUCUPARTK decreased the viability of these cells in the presence of ganciclovir 20 and 40 microg/mL (and higher), respectively. Although M30 CytoDEATH antibody could not detect a significant rate of apoptosis induced by ganciclovir in pUCUPARTK-transfected HCT116 cells, the percentage of stained cells was marked in comparison with untreated cells. While this antibody could detect apoptosis in HCT116 cell line transfected with positive control plasmid, it could not detect apoptosis in SW480 cells transfected with the same positive control. This discrepancy could be attributed to the different mechanisms of TK/ganciclovir-induced apoptosis in tumor protein p53 (TP53)-expressing (HCT116) and -deficient (SW480) cells. Annexin-propidium iodide staining could detect apoptosis in treated, pUCUPARTK-transfected SW480 and HCT116 cells. This study showed that the uPAR promoter can be considered as a suitable candidate for specific suicide gene therapy of colon cancer and probably other cancers in which the RAS signaling pathway is involved in their carcinogenesis process.
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PMID:Selective suicide gene therapy of colon cancer exploiting the urokinase plasminogen activator receptor promoter. 2019 27


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