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)

Tumor formation is in part driven by DNA copy number alterations (CNAs), which can be measured using microarray-based Comparative Genomic Hybridization (aCGH). Multiexperiment analysis of aCGH data from tumors allows discovery of recurrent CNAs that are potentially causal to cancer development. Until now, multiexperiment aCGH data analysis has been dependent on discretization of measurement data to a gain, loss or no-change state. Valuable biological information is lost when a heterogeneous system such as a solid tumor is reduced to these states. We have developed a new approach which inputs nondiscretized aCGH data to identify regions that are significantly aberrant across an entire tumor set. Our method is based on kernel regression and accounts for the strength of a probe's signal, its local genomic environment and the signal distribution across multiple tumors. In an analysis of 89 human breast tumors, our method showed enrichment for known cancer genes in the detected regions and identified aberrations that are strongly associated with breast cancer subtypes and clinical parameters. Furthermore, we identified 18 recurrent aberrant regions in a new dataset of 19 p53-deficient mouse mammary tumors. These regions, combined with gene expression microarray data, point to known cancer genes and novel candidate cancer genes.
 ...
PMID:Identification of cancer genes using a statistical framework for multiexperiment analysis of nondiscretized array CGH data. 1818 9

The phosphatase of regenerating liver (PRL) family, a unique class of oncogenic phosphatases, consists of three members: PRL-1, PRL-2, and PRL-3. Aberrant overexpression of PRL-3 has been found in multiple solid tumor types. Ectopic expression of PRLs in cells induces transformation, increases mobility and invasiveness, and forms experimental metastases in mice. We have now shown that small interfering RNA-mediated depletion of PRL expression in cancer cells results in the down-regulation of p130Cas phosphorylation and expression and prevents tumor cell anchorage-independent growth in soft agar. We have also identified a small molecule, 7-amino-2-phenyl-5H-thieno[3,2-c]pyridin-4-one (thienopyridone), which potently and selectively inhibits all three PRLs but not other phosphatases in vitro. The thienopyridone showed significant inhibition of tumor cell anchorage-independent growth in soft agar, induction of the p130Cas cleavage, and anoikis, a type of apoptosis that can be induced by anticancer agents via disruption of cell-matrix interaction. Unlike etoposide, thienopyridone-induced p130Cas cleavage and apoptosis were not associated with increased levels of p53 and phospho-p53 (Ser(15)), a hallmark of genotoxic drug-induced p53 pathway activation. This is the first report of a potent selective PRL inhibitor that suppresses tumor cell three-dimensional growth by a novel mechanism involving p130Cas cleavage. This study reveals a new insight into the role of PRL-3 in priming tumor progression and shows that PRL may represent an attractive target for therapeutic intervention in cancer.
 ...
PMID:A selective phosphatase of regenerating liver phosphatase inhibitor suppresses tumor cell anchorage-independent growth by a novel mechanism involving p130Cas cleavage. 1828 92

Biological effects of low-dose radiation (LDR) are distinguishable from those of high-dose radiation. Hormetic and adaptive responses are such two examples. However, whether adaptive response could be induced in tumor cells by LDR, especially under in vivo condition, remains elusive, and was systemically investigated in the present study. Four tumor cell lines: two human leukemia cell lines (erythroleukemia cell line K562, and acute promyelocytic leukemia cell line HL60), and two human solid tumor cell lines (lung carcinoma cell line NCI-H446 and glioma cell line U251), along with one normal cell line (human fibroblast cells, MRC-5), were irradiated with LDR at 75 mGy of X-rays as D1 and then 4 Gy of X-rays as D2 (i.e.: D1 + D2) or only 4 Gy of X-rays (D2 alone). Three tumor-bearing animal models were also used to further define whether LDR induces adaptive response in tumor cells in vivo. Adaptive response was observed only in normal cell line, but not in four tumor cell lines, in response to LDR, showing a resistance to subsequent D2-induced cell growth inhibition. Three tumor-bearing mouse models with U251, NCI-H446 or S180 tumor cells were used to confirm that pre-exposure of tumor-bearing mice to D1 did not induce the resistance of tumor cells in vivo to D2-induced tumor growth inhibition. Furthermore, a higher apoptotic effect, along with higher expression of apoptosis-related genes P53 and Bax and lower expression of anti-apoptosis gene Bcl-2, was found in tumor cells of the tumor-bearing mice exposed to D1 + D2 than those in the tumor cells of the tumor-bearing mice exposed to D2 alone. These results suggest that LDR does not induce adaptive response in the tumor cells under both in vitro and in vivo conditions, which is a very important, clinic-relevant phenomenon.
 ...
PMID:Low-dose radiation induces adaptive response in normal cells, but not in tumor cells: in vitro and in vivo studies. 1829 71

Mutational inactivation of the p53 tumor-suppressor gene, which regulates apoptosis mainly via the cell-intrinsic pathway, reduces the sensitivity of many cancers to conventional treatments. Targeting the cell-extrinsic pathway, which triggers p53-independent apoptosis, offers a unique therapeutic strategy to induce apoptosis in cancer cells. This article focuses on two proapoptotic receptor agonists, recombinant human Apo2-ligand/TNF-related apoptosis-inducing ligand (rhApo2L/TRAIL) and Apomab, which activate death receptor (DR) 4 and/or DR5, thus stimulating the cell-extrinsic pathway. These agents are under investigation for the treatment of solid tumor and hematologic malignancies. Preclinical data indicate that both molecules cause significant regression or growth inhibition of malignant tumors without significant toxicity. Initial data on rhApo2L/TRAIL and Apomab from phase 1 safety trials also confirm that these agents are suitable for further clinical investigation.
 ...
PMID:Targeting the extrinsic apoptosis pathway in cancer. 1849 20

The p53 tumor suppressor is a powerful growth suppressive and pro-apoptotic molecule frequently inactivated in human cancer. Many tumors overproduce its negative regulator MDM2, a specific p53 ubiquitin ligase and transcriptional inhibitor, to disable p53 function. Therefore, p53 activation by inhibiting MDM2 has been proposed as a novel strategy for cancer therapy in tumors expressing wild-type p53. Recently developed small-molecule p53-MDM2 binding inhibitors, the nutlins, selectively activate p53 function and induce cell cycle arrest and apoptosis in cancer cells. By stabilizing p53, nutlins also elevate the cellular level of its transcriptional target MDM2. Here, we present evidence that nutlin-induced MDM2 retains its ubiquitin ligase activity and contributes to the anti-tumor activity of p53-MDM2 binding inhibitors by facilitating the degradation of another p53 inhibitor, MDMX. MDM2 and MDMX levels were analyzed in a panel of 12 randomly selected solid tumor cell lines. In the presence of nutlin-3, MDM2 increased in all and MDMX decreased in most of the cell lines. MDMX was resistant to nutlin-induced degradation in 2/12 cell lines. In these cells, MDMX appears to be a major suppressor of the apoptotic response to p53 activation although this effect was only partially p53-dependent. Doxorubicin facilitated MDMX degradation through DNA damage response pathways and restored their sensitivity to nutlin, suggesting that combination therapy may be an effective way to overcome nutlin resistance in cancers with MDMX aberrations.
 ...
PMID:Elevated MDM2 boosts the apoptotic activity of p53-MDM2 binding inhibitors by facilitating MDMX degradation. 1852 Jan 79

Angiogenesis is a prerequisite for solid tumor growth, but there is relatively limited data regarding Hodgkin lymphoma. The purpose of this study was to examine the immunohistochemical expression of angiogenic and proliferation markers in Hodgkin biopsies in relation to clinical parameters. Immunostaining was performed on 65 Hodgkin biopsies with vascular endothelial growth factor (VEGF), hypoxia inducible factor-1 alpha (HIF-1alpha), platelet-derived growth factor receptor alpha (PDGFRalpha), Ki-67, and p53. Microvessel density (MVD) was determined by CD31 staining. In all cases, neoplastic cells and reactive background cells were evaluated. The neoplastic population expressed VEGF in 48% of the cases, HIF-1alpha in 54% of the cases, and PDGFRalpha in 95% of the cases. Both Ki-67 and p53 were positive in neoplastic cells in over 60% of the cases. The MVD had a median of 2.6/0.0625mm(2) which was not different from normal lymph nodes. VEGF in the non-neoplastic compartment showed increased staining in Ann Arbor stage I-II versus III-IV. In conclusion, VEGF, HIF-1alpha, and predominantly PDGFRalpha are expressed in neoplastic cells in the majority of Hodgkin lymphomas. As microvessel formation is not increased in Hodgkin, additional functions of these angiogenic molecules should be investigated.
 ...
PMID:Histological expression of angiogenic factors: VEGF, PDGFRalpha, and HIF-1alpha in Hodgkin lymphoma. 1895 Sep 58

Neuroblastoma (NB) is a primitive neuroectodermal tumor and the second most common solid tumor in children. NB exhibits heterogeneous behavior and spontaneous regression can occur in patients under 12 months of age. Response to treatment is both age- and stage-specific; however, patients over 1 year of age are generally considered high risk. NB tumors from these patients are often characterized by alterations in p53 expression and murine double minute (MDM2) activity with concomitant resistance to chemotherapy. We evaluated the ability of nutlin-3 to sensitize a p53-null and doxorubicin-resistant NB cell line, LA155N, to doxorubicin. Nutlin-3 treatment upregulated TAp73 and E2F1 protein levels. It potentiated the ability of doxorubicin to block cell proliferation and activate apoptosis and TAp73 knockdown resulted in a reduction of this sensitization. Additionally, PUMA expression was induced by the combination treatment, but reduced by knockdown of either TAp73 or E2F1. We conclude that, following nutlin-3 treatment, TAp73 and E2F1 are released from MDM2 and activated by doxorubicin to induce PUMA and apoptosis. This study addresses p53-independent mechanisms of nutlin-3 action in chemoresistant NB, especially in combination with chemotherapeutics. We believe that this model has strong clinical relevance for chemoresistant and p53 dysfunctional NB.
 ...
PMID:The MDM2 antagonist nutlin-3 sensitizes p53-null neuroblastoma cells to doxorubicin via E2F1 and TAp73. 1936 Mar 52

Neuroblastoma (NB) is the most common extracranial solid tumor in children below the age of 5 years. miR-34a, located in chromosome band 1p36, has been recently implicated as a tumor suppressor gene in NB. In addition, it has been shown that miR-34a is activated by TP53 by binding to a TP53 binding site upstream to the mature miR-34a. We studied NB tumors from 57 patients for miR-34a expression levels, 1p status, mutations in the TP53 coding region and mutations of the TP53 binding site. Reduced expression levels of miR-34a were identified in tumors harboring 1p36.3 Loss (P = 0.028). No mutations were identified in the coding region of TP53, or in the TP53 binding site. Thus, mutations in the binding site are not an additional mechanism for the inactivation of miR-34a in NB. Other regulatory mechanisms controlling miR-34a expression and its relationship to TP53 should be further explored.
 ...
PMID:Reduced levels of miR-34a in neuroblastoma are not caused by mutations in the TP53 binding site. 1937 81

Aurora kinases play a key role in regulating mitotic division and are attractive oncology targets. AT9283, a multi-targeted kinase inhibitor with potent activity against Aurora A and B kinases, inhibited growth and survival of multiple solid tumor cell lines and was efficacious in mouse xenograft models. AT9283-treatment resulted in endoreduplication and ablation of serine-10 histone H3 phosphorylation in both cells and tumor samples, confirming that in these models it acts as an Aurora B kinase inhibitor. In vitro studies demonstrated that exposure to AT9283 for one complete cell cycle committed an entire population of p53 checkpoint-compromised cells (HCT116) to multinucleation and death whereas treatment of p53 checkpoint-competent cells (HMEC, A549) for a similar length of time led to a reversible arrest of cells with 4N DNA. Further studies in synchronized cell populations suggested that exposure to AT9283 during mitosis was critical for optimal cytotoxicity. We therefore investigated ways in which these properties might be exploited to optimize the efficacy and therapeutic index of Aurora kinase inhibitors for p53 checkpoint compromised tumors in vivo. Combining Aurora B kinase inhibition with paclitaxel, which arrests cells in mitosis, in a xenograft model resulted in promising efficacy without additional toxicity. These findings have implications for optimizing the efficacy of Aurora kinase inhibitors in clinical practice.
 ...
PMID:Aurora B kinase inhibition in mitosis: strategies for optimising the use of aurora kinase inhibitors such as AT9283. 1944 47

We present a mathematical model for the formation of an avascular tumor based on the loss by gene mutation of the tumor suppressor function of p53. The wild type p53 protein regulates apoptosis, cell expression of growth factor and matrix metalloproteinase, which are regulatory functions that many mutant p53 proteins do not possess. The focus is on a description of cell movement as the transport of cell population density rather than as the movement of individual cells. In contrast to earlier works on solid tumor growth, a model is proposed for the initiation of tumor growth. The central idea, taken from the mathematical theory of dynamical systems, is to view the loss of p53 function in a few cells as a small instability in a rest state for an appropriate system of differential equations describing cell movement. This instability is shown (numerically) to lead to a second, spatially inhomogeneous, solution that can be thought of as a solid tumor whose growth is nutrient diffusion limited. In this formulation, one is led to a system of nine partial differential equations. We show computationally that there can be tumor states that coexist with benign states and that are highly unstable in the sense that a slight increase in tumor size results in the tumor occupying the sample region while a slight decrease in tumor size results in its ultimate disappearance.
 ...
PMID:A mathematical model for the onset of avascular tumor growth in response to the loss of p53 function. 1945 66


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