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)

To understand the role of the Src homology 2 (SH2) domain protein Shb in the signal transduction of tyrosine kinase receptor, NIH3T3 cells were transfected with a DNA construct expressing the Shb cDNA (NIHSHB cells). The NIHSHB cells expressed elevated levels of proteins with the estimated molecular weights of 77, 66 and 55 kDa as determined by immunoblotting. In contrast to the control cells, the NIHSHB cells failed to increase in cell number in the presence of 1% serum. This effect was largely due to apoptosis, since staining of pyknotic nuclei was observed using the terminal transferase labeling method. The NIHSHB cells displayed similar levels of c-myc mRNA and decreased contents of the p53 protein after culture in 1% serum compared with control cells. The addition of platelet-derived growth factor (PDGF-BB) restored the growth of the NIHSHB cells, whereas insulin-like growth factor-1 (IGF-1) failed to affect the proliferation of Shb overexpressing cells in 1% serum. We conclude that Shb overexpression is associated with cell degeneration under certain conditions, and that Shb could transduce apoptotic signals from tyrosine kinase receptors.
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PMID:Apoptosis of NIH3T3 cells overexpressing the Src homology 2 domain protein Shb. 880 85

Recent studies have suggested that insulin-like growth factors (IGFs) and insulin-like growth factor binding proteins (IGFBPs) may be implicated in the development and progression of breast cancer. Prostate-specific antigen (PSA), a serine protease, may play a role in the regulation of IGFs' function through cleavage of IGFBP-3, resulting in release of active IGFs from IGFBP-3. As IGFs, IGFBPs and PSA are all present in breast cancer, possible associations among these proteins were speculated. In this study, we have measured PSA, IGF-I, IGF-II, IGFBP-1 and IGFBP-3 in tumour tissue cytosols from 200 women with primary breast cancer, and have examined relationships between IGFs or IGFBPs and PSA along with other markers, including p53 protein, steroid hormone receptors (oestrogen and progesterone), cathepsin-D, epidermal growth factor receptor, Her-2/neu protein, S-phase fraction and DNA ploidy. Correlations or associations between PSA and IGF-I, IGF-II, IGFBP-1 or IGFBP-3 were not observed. IGF-II was positively correlated with both IGFBP-3 and IGFBP-1. IGF-I was not associated with either of the two binding proteins, nor with IGF-II. Both IGF-II and IGFBP-3 were inversely associated with the oestrogen receptor, and IGFBP-3 was also positively associated with S-phase fraction. Our finding of IGF-II and IGFBP-3 in association with unfavourable prognostic indicators of breast cancer suggests that IGFs may be involved in the progression of breast cancer.
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PMID:Associations between insulin-like growth factors and their binding proteins and other prognostic indicators in breast cancer. 888 11

Human papillomavirus-16 E6 and E7 inactivate the tumor suppressors p53 and pRB, respectively, and cooperate during malignant transformation, but the downstream molecular events remain incompletely understood. Using fibroblast cell lines derived from mice with a homozygous disruption of the insulin-like growth factor-1 receptor (IGF-1R) gene (R- cells) and their wild-type (WT) littermates, we have stably transfected plasmids encoding E6 and E7 proteins and examined their transforming potential in these cells. Consistent with previous studies using NIH3T3 cells, pooled cultures of E7-transfected WT cells readily formed colonies after suspension in soft agar. In contrast, R- cells were not transformed by E7. E6 had little transforming activity in WT (WT/E6) or R- (R-/E6) cells. However, transfection of R- cells with E6 plus E7 resulted in extensive colony formation. Because IGF-1R and E6 appear to be functionally equivalent in this transformation assay and both have been implicated in antiapoptotic responses, we investigated the apoptotic responses of the cells after exposure to the potent protein kinase C inhibitor, staurosporine. Compared to WT cells, R- cells were relatively resistant to staurosporine-induced apoptosis, but susceptibility to staurosporine was decreased in both WT/E6 and R-/E6 cells relative to WT and R- cells transfected with mock vector, respectively. In fibroblast cells from p53 gene knockout mice, transfection with E6 also conferred relative resistance to staurosporine-induced apoptosis. Our data suggest that transformation by E7 requires the participation of the IGF-1R and that E6 may assist E7 in transforming R- cells by functionally substituting for the IGF-1R. Because IGF-1R activated by its ligands (IGF-1 and IGF-2) protects cells from apoptosis, the role of the IGF-1R and E6 in transformation by E7 is probably related to the recruitment of survival pathways. In addition, because E6 suppressed apoptosis in p53 knockout cells, our data also suggest that E6 may participate in a p53-independent process that protects cells from apoptosis.
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PMID:Transformation by human papillomavirus 16 E6 and E7: role of the insulin-like growth factor 1 receptor. 889 68

Estrogen-like chemicals are unique compared to nonestrogenic xenobiotics, because in addition to their chemical properties, the estrogenic property of these compounds allows them to act like sex hormones. Whether weak or strong, the estrogenic response of a chemical, if not overcome, will add extra estrogenic burden to the system. At elevated doses, natural estrogens and environmental estrogen-like chemicals are known to produce adverse effects. The source of extra or elevated concentration of estrogen could be either endogenous or exogenous. The potential of exposure for humans and animals to environmental estrogen-like chemicals is high. Only a limited number of estrogen-like compounds, such as diethylstilbestrol (DES), bisphenol A, nonylphenol, polychlorinated biphenyls (PCBs), and dichlorodiphenyltrichloroethane (DDT), have been used to assess the biochemical and molecular changes at the cellular level. Among them, DES is the most extensively studied estrogen-like chemical, and therefore this article is focused mainly on DES-related observations. In addition to estrogenic effects, environmental estrogen-like chemicals produce multiple and multitype genetic and/or nongenetic hits. Exposure of Syrian hamsters to stilbene estrogen (DES) produces several changes in the nuclei of target organ for carcinogenesis (kidney): (1) Products of nuclear redox reactions of DES modify transcription regulating proteins and DNA; (2) transcription is inhibited; (3) tyrosine phosphorylation of nuclear proteins, including RNA polymerase II, p53, and nuclear insulin-like growth factor-1 receptor, is altered; and (4) DNA repair gene DNA polymerase beta transcripts are decreased and mutated. Exposure of Noble rats to DES also produces several changes in the mammary gland: proliferative activity is drastically altered; the cell cycle of mammary epithelial cells is perturbed; telomeric length is attenuated; etc. It appears that some other estrogenic compounds, such as bisphenol A and nonylphenol, may also follow a similar pattern of effects to DES, because we have recently shown that these compounds alter cell cycle kinetics, produce telomeric associations, and produce chromosomal aberrations. Like DES, bisphenol A after metabolic activation is capable of binding to DNA. However, it should be noted that a particular or multitype hit(s) will depend upon the nature of the environmental estrogen-like chemical. The role of individual attack leading to a particular change is not clear at this stage. Consequences of these multitypes of attack on the nuclei of cells could be (1) nuclear toxicity/cell death; (2) repair of all the hits and then acting as normal cells; or (3) sustaining most of the hits and acting as unstable cells. Proliferation of the last type of cell is expected to result in transformed cells.
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PMID:Biochemical and molecular changes at the cellular level in response to exposure to environmental estrogen-like chemicals. 901 29

Prostate tumor initiation and progression to malignancy may involve upregulation of the androgen receptor known to stimulate prostate cell proliferation; other etiologic mechanisms may include dysfunction of the apoptotic pathway but also deregulation in signal transduction and control of the cell cycle in prostate tissue; such abnormalities could arise from overexpression or mutations in a number of oncogenes or down-regulation by inactivating mutations, allelic loss, or other epigenetic mechanisms in tumor suppressor genes. The advantages and drawbacks of various delivery systems (retroviral, adenoviral, liposomes) used for human gene therapy are being considered. Several ex vivo and in vivo as well as cell culture studies are suggested for the therapy of the human prostate cancer using transfer and expression of genes that might be implicated in prostate carcinogenesis especially of the tumor suppressor p53. Expression of suicidal genes in prostate cancer cells using prostate-specific promoter and enhancer elements as well as targeting of the androgen receptor or the insulin-like growth factor genes with triplex technology in prostate cancer cells and their metastases, is expected to be of therapeutic value.
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PMID:Gene therapy of prostate cancer: p53, suicidal genes, and other targets. 917 86

The product of the WT1 Wilms tumor suppressor gene controls the expression of genes encoding components of the insulin-like growth factor and transforming growth factor beta signaling systems. The role of these growth factors in breast tumor growth led us to investigate possible WT1 gene expression in normal and cancerous breast tissue. WT1 was detected by immunohistochemistry in the normal mammary duct and lobule, and the patterns of expression were consistent with developmental regulation. In a survey of 21 infiltrating tumors, 40% lacked immunodetectable WT1 altogether and an additional 28% were primarily WT1-negative. Cytoplasmic, but not nuclear, localization of WT1 was noted in some tumor cells and WT1 was detected, sometimes at high levels, in more-advanced estrogen-receptor-negative tumors. In this highly malignant subset, the tumor suppressor protein p53, which can physically interact with WT1, was also sometimes detected. WT1 mRNA was detected in normal and tumor tissue by reverse transcription-coupled PCR. Alternative splicing of the WT1 mRNA may regulate gene targeting of the WT1 protein through changes either in its regulatory or zinc-finger domains. The relative proportions of WT1 mRNA splice variants were altered in a random sample of breast tumors, providing evidence that different tumors may share a common WT1-related defect resulting in altered regulation of target genes.
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PMID:Altered expression of the WT1 wilms tumor suppressor gene in human breast cancer. 922 27

The mRNA expressions of various growth regulatory molecules in single human anagen hair follicles were analysed by reverse transcription and polymerase chain reaction. Approximately 370 hair follicles were isolated from 20 normal individuals, and 0.90 +/- 0.34 microgram (mean +/- SD) total RNA was extracted per whole hair follicle. The mRNAs of fibroblast growth factor (FGF)-1, FGF-2, FGF-5, FGF-7, transforming growth factor (TGF)-alpha, TGF-beta 1, hepatocyte growth factor, insulin-like growth factor (IGF)-I, tumour suppressor gene p53 and high sulphur protein were detected in most or all of the examined hair follicles per target gene. In contrast, none of the mRNAs of FGF-3, FGF-4, FGF-6, FGF-9 and IGF-II was detected, and those of TGF-beta 2 and TGF-beta 3 were detected in only a limited number of the examined hair follicles. Among cyclin-dependent kinase inhibitors, the mRNAs of p21waf1/cip1 and p27kip1 were expressed in almost all the hair follicles, while those of p15INK4B and p16INK4A were not detected. These results suggest that both positive and negative factors for the proliferation and differentiation of follicular epithelial cells coexist in a human anagen hair follicle.
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PMID:Genes for a range of growth factors and cyclin-dependent kinase inhibitors are expressed by isolated human hair follicles. 941 26

The loss or functional inactivation of tumor suppressor genes appears to be one of the most fundamental genetic mechanisms of tumorigenesis, and rational insights into the signaling pathways of tumor suppressor genes have emerged as a successful strategy of identifying novel drug discovery targets downstream of the tumor suppressor protein itself. Elucidation of novel pathways downstream of p53 have established a link between this important tumor suppressor gene and the insulin-like growth factor-1 receptor (IGF-1r), either via direct regulation of IGF-1 receptor levels, or modulation of IGFs via transactivation of the insulin-like growth factor-binding protein 3 (IGF-BP3) gene. Binding of IGF-BP3 to IGFs inhibits both their mitogenic and cell survival functions, highlighting a novel pathway whereby p53 may regulate apoptosis in tumor cells.
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PMID:The p53/IGF-1 receptor axis in the regulation of programmed cell death. 944 44

Suppression of tumor cell growth by p53 results from the activation of both apoptosis and cell cycle arrest, functions which have been shown to be separable activities of p53. We have characterized a series of p53 mutants with amino acid substitutions at residue 175 and show that these mutants fall into one of three classes: class I, which is essentially wild type for apoptotic and cell cycle arrest functions; class II, which retains cell cycle arrest activity but is impaired in the induction of apoptosis; and class III, which is defective in both activities. Several residue 175 mutants which retain cell cycle arrest function have been detected in cancers, and we show that these have lost apoptotic function. Furthermore, several class II mutants have been found to be temperature sensitive for apoptotic activity while showing constitutive cell cycle arrest function. Taken together, these mutants comprise an excellent system with which to investigate the biochemical nature of p53-mediated apoptosis, the function of principal importance in tumor suppression. All of the mutants that showed loss of apoptotic function also showed defects in the activation of promoters from the potential apoptotic targets Bax and the insulin-like growth factor-binding protein 3 gene (IGF-BP3), and a correlation between full apoptotic activity and activation of both of these promoters was also seen with the temperature-sensitive mutants. However, a role for additional apoptotic activities of p53 was suggested by the observation that some mutants retained significant apoptotic function despite being impaired in the activation of Bax- and IGF-BP3-derived promoters. In contrast to the case of transcriptional activation, a perfect correlation between transcriptional repression of the c-fos promoter and the ability to induce apoptosis was seen, although the observation that Bax expression induced a similar repression of transcription from this promoter suggests that this may be a consequence, rather than a cause, of apoptotic death.
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PMID:Characterization of structural p53 mutants which show selective defects in apoptosis but not cell cycle arrest. 963 51

Increased protein kinase C(alpha) (PKC(alpha)) expression in glioblastoma cells is associated with proliferation and resistance to drug-induced apoptosis by an undefined anti-apoptotic pathway. To clarify the role of PKC in apoptosis, we have investigated the effect of the selective PKC inhibitor Ro 31-8220 (3-[1-[3-(amidinothio)propyl]-3-indolyl]-4-(1-methyl-3-indolyl)-1H -pyrrole-2,5-dione methanesulfonate) in two glioblastoma cell lines whose proliferation is dependent on high levels of PKC(alpha). U-87 and A172 cells treated with an IC50 of Ro 31-8220 exhibited nucleosomal DNA fragmentation that coincided with an increase in the number of apoptotic cells. This effect was preceded by the rapid nuclear accumulation of wild-type p53 within 2 hr, and an increased level of the pro-apoptotic protein, insulin-like growth factor-1-binding protein-3, (IGFBP3) but not other p53-regulated proteins such as p21WAF1 or Bax. Accumulation of p53 was also associated with the hypophosphorylated and activated form of the retinoblastoma tumor suppressor protein (RB) at later times after treatment. These results suggest that PKC(alpha) suppresses apoptosis in glioblastoma cells primarily by restricting the accumulation of p53 and the expression of insulin-like growth factor-1-binding protein, as well as by maintaining RB in an inactive hyperphosphorylated state.
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PMID:Induction of apoptosis in glioblastoma cells by inhibition of protein kinase C and its association with the rapid accumulation of p53 and induction of the insulin-like growth factor-1-binding protein-3. 963 8


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