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)

A point mutation at codon 129 of the murine erythropoietin receptor (cEpoR) results in constitutive activation. We have generated a recombinant spleen focus-forming retrovirus in which the env gene is replaced by the cEpoR cDNA. Mice infected with this virus (but not by viruses expressing the wild-type EpoR) develop erythrocytosis and splenomegaly. From the spleen of infected animals we have isolated clonal, growth factor-independent, proerythroblast cell lines that express cEpoR, do not express the putative oncogene spi-1, and have rearranged and inactivated expression of the p53 suppressor oncogene. These cells induce erythroleukemia upon injection into mice. This demonstrates that oncogenic point mutations exist in a member of the cytokine receptor superfamily. The activated erythropoietin receptor does not transform cultured fibroblasts, suggesting why oncogenic mutations in other members of this receptor superfamily have not been detected.
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PMID:An activating mutation in the murine erythropoietin receptor induces erythroleukemia in mice: a cytokine receptor superfamily oncogene. 166 16

Granulocyte colony-stimulating factor (G-CSF) is a glycoprotein that critically regulates the viability, proliferation, and differentiation of granulocytic precursors and the function of neutrophils by signaling through its receptor. Cloning of the human G-CSF receptor (G-CSFR) cDNA has demonstrated sequence homology with other members of the hematopoietic/cytokine receptor superfamily. G-CSF stimulates the appearance of phosphotyrosine proteins in several types of human and murine myeloid cells. Since the receptor does not possess intrinsic tyrosine kinase activity, we hypothesized that G-CSFR interacts with and activates cytosolic protein-tyrosine kinases (PTKs). In vitro protein kinase assay of human G-CSFR immunoprecipitates demonstrated at least two tyrosine phosphoproteins, pp55 and pp70. We observed that G-CSF activated p53/p56lyn, a Src-related PTK, and p72syk, a non-Src-related PTK. Lyn and Syk were recovered in anti-G-CSFR immunoprecipitates; Lyn was detected in the absence of ligand. In addition, upon G-CSF stimulation, Lyn coimmunoprecipitated with Syk. Analysis of the G-CSFR amino acid sequence revealed a potential receptor activation motif for Syk. On the basis of immunoprecipitation and sequence analysis data, we propose that the human G-CSFR forms a three-component signaling complex with Lyn and Syk. Their sequential recruitment into the G-CSFR signaling complex demonstrates the coordinated involvement of two PTKs with a member of the hematopoietic/cytokine receptor superfamily.
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PMID:Granulocyte colony-stimulating factor receptor signaling involves the formation of a three-component complex with Lyn and Syk protein-tyrosine kinases. 819 19

Topical steroid treatment is a common therapy for psoriasis. Steroids are known to bind to specific cytoplasmic receptors and to influence gene expression. We investigated the effects of the novel steroid derivative mometasone furoate on the expression of putative target genes in normal human epidermal cells (KC). Gene expression was measured by semiquantitative mRNA-PCR. In addition, cytokine receptor characteristics were assessed by ligand binding studies. We found a dose-dependent downregulation of proinflammatory mediators (IL-8, TNF alpha). Genes involved in growth regulation (HER-2, p53) were also modulated. IL-8 binding to KC was inhibited. We conclude that modulation of the expression of cytokine, cytokine receptor and growth factor genes may contribute to the antipsoriatic action of steroids.
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PMID:Novel steroid derivative modulates gene expression of cytokines and growth regulators. 852 52

Cell death occurs by either apoptosis or necrosis. Apoptosis is a cellular event in which a sequence of biochemical and morphological changes conclude in the death of the cell. Apoptosis is an important mechanism to control the number of cells and maintain tissue architecture. Nitric oxide (NO) is a multifunctional molecule that is synthesized by a family of enzymes, namely nitric oxide synthases (NOS). NO is implicated in several physiological functions within the microvascular environment, i.e. regulation of vascular tone, antiplatelet and antileukocyte properties and modulation of cell growth. Several investigations have demonstrated effects of NO on gene transcription. In this regard, NO has been also implicated in the apoptotic processes. The goal of the present review is to summarize the current knowledge about the relationship between NO and different genes involved in the apoptotic phenomena with focus in the cells of the microvascular environment, i.e. monocytes/macrophages, endothelium and vascular smooth muscle cells. Different studies have revealed that stimulation and inhibition of different genes are required to stimulate apoptosis. NO modulates the expression of bcl-2 family members, p53, interleukin-1 beta-converting enzyme family proteases and the cytokine receptor Fas. Therefore, NO generated from NO donors or synthesized by NOS induces cell death via apoptosis in a variety of different cell types. On the other hand, in the endothelial cells NO seems to have a relevant role in the maintenance of the confluent endothelial monolayer inhibiting apoptotic-related mechanisms. Furthermore, the redox states of the cells play an important role in the effects of NO as promotor of apoptosis. There have been exciting advances in the understanding of the molecular relationship between apoptosis and NO. Therefore, NO could be an important mediator to consider in the context of future therapeutic applications particularly considering apoptosis as a mechanism to maintain vascular architecture.
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PMID:Role of nitric oxide in the control of apoptosis in the microvasculature. 978 75

The transcription factor p53 and the cytokine receptor FasL are two of the most famous regulators of cell life, and their alterations can cause a large number of pathologies, including cancer. In this review, we focused on how they can determine defective apoptosis, one of the causes of tumorigenesis and tumor progression. The importance of this knowledge lies in the new perspectives that gene therapy can offer to cure cancer.
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PMID:Defective apoptosis and tumorigenesis: role of p53 mutation and Fas/FasL system dysregulation. 1247 14

Multiple genetic and epigenetic alterations in oncogenes, tumour-suppressor genes, cell-cycle regulators, cell adhesion molecules, DNA repair genes and genetic instability as well as telomerase activation are implicated in the multistep process of human stomach carcinogenesis. However, particular combinations of these alterations differ in the two histological types of gastric cancer, indicating that well-differentiated or intestinal-type and poorly differentiated or diffuse-type carcinomas have distinct carcinogenetic pathways. In the multistep process of well-differentiated-type carcinogenesis, the genetic pathway can be divided into three subpathways: an intestinal metaplasia-->adenoma-->carcinoma sequence, an intestinal metaplasia-->carcinoma sequence and de novo. In the multistep process of well-differentiated-type or intestinal-type gastric carcinogenesis, infection with Helicobacter pylori may be a strong trigger for hyperplasia of hTERT-positive 'stem cells' in intestinal metaplasia. Genetic instability and hyperplasia of hTERT-positive stem cells precede replication error at the D1S191 locus, DNA hypermethylation at the D17S5 locus, pS2 loss, RARbeta loss, CD44 abnormal transcripts and p53 mutation, all of which accumulate in at least 30% of incomplete intestinal metaplasias. All of these epigenetic and genetic alterations are common events in intestinal-type gastric cancer. An adenoma-->carcinoma sequence is found in about 20% of gastric adenomas with APC mutations. In addition to these events, p53 mutation and loss of heterozygosity (LOH), reduced p27 expression, cyclin E expression and the presence of c-met 6.0-kb transcripts allow malignant transformation from the above precancerous lesions to intestinal-type gastric cancer. DCC loss, APC mutations, 1q LOH, p27 loss, reduced tumour growth factor (TGF)-beta type I receptor expression, reduced nm23 expression and c-erbB gene amplification are frequently associated with an advanced stage of intestinal-type gastric cancer. The de-novo pathway for carcinogenesis of well-differentiated gastric cancer involves LOH and abnormal expression of the p73 gene that is responsible for the development of foveolar-type gastric cancers with pS2 expression. On the other hand, LOH at chromosome 17p, mutation or LOH of p53 and mutation or loss of E-cadherin are preferentially involved in the development of poorly differentiated gastric cancers. In addition to these changes, gene amplification of K-sam, and c-met and p27 loss as well as reduced nm23 obviously confer progression, metastasis and diffusely productive fibrosis. Mixed gastric carcinomas composed of well-differentiated and poorly differentiated components exhibit some but not all of the molecular events described so far for each of the two types of gastric cancer. Besides these genetic and epigenetic events, well-differentiated and poorly differentiated gastric cancers also organize different patterns of interplay between cancer cells and stromal cells through the growth factor/cytokine receptor system, which plays an important role in cell growth, apoptosis, morphogenesis, angiogenesis, progression and metastasis. Meta-analysis of epidemiological studies and animal models show that both intestinal and diffuse types of gastric cancer are equally associated with H. pylori infection. However, H. pylori infection may play a role only in the initial steps of gastric carcinogenesis. Differences in H. pylori strain, patient age, exogenous or endogenous carcinogens and genetic factors such as DNA polymorphism and genetic instability may be implicated in two distinct major genetic pathways for gastric carcinogenesis.
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PMID:Genetic pathways of two types of gastric cancer. 1505 5

Interactions between proteins are at the heart of the cellular machinery. It is therefore not surprising that altered interaction profiles caused by aberrant protein expression patterns or by the presence of mutations can trigger cellular dysfunction, eventually leading to disease. Moreover, many viral and bacterial pathogens rely on protein-protein interactions to exert their damaging effects. Interfering with such interactions is an obvious pharmaceutical goal, but detailed insights into the protein binding properties as well as efficient screening platforms are needed. In this report, we describe a cytokine receptor-based assay with a positive readout to screen for disrupters of designated protein-protein interactions in intact mammalian cells and evaluate this concept using polypeptides as well as small organic molecules. These reverse mammalian protein-protein interaction trap (MAPPIT) screens were developed to monitor interactions between the erythropoietin receptor (EpoR) and suppressors of cytokine signaling (SOCS) proteins, between FKBP12 and ALK4, and between MDM2 and p53.
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PMID:Reverse MAPPIT: screening for protein-protein interaction modifiers in mammalian cells. 1590 18

We used microarray-based comparative genomic hybridization to explore genome-wide profiles of chromosomal aberrations in 26 samples of head and neck cancers compared to their pair-wise normal controls. The samples were obtained from Sudanese (n=11) and Norwegian (n=15) patients. The findings were correlated with clinicopathological variables. We identified the amplification of 41 common chromosomal regions (harboring 149 candidate genes) and the deletion of 22 (28 candidate genes). Predominant chromosomal alterations that were observed included high-level amplification at 1q21 (harboring the S100A gene family) and 11q22 (including several MMP family members). Regions of copy number increase was also identified at 6p21 (p21), 7p12 (EGFR), 17p13 (p53) and 19p13.2 (p19INK4d), while regions showing deletion included among others 3p25.2 (RAF1) and 9p21 (p15, p16). We found genes from four common biological pathways (MAPK signaling, cytokine-cytokine receptor interaction, ECM-receptor interaction and Jak-STAT signaling) to be predominantly over-represented in areas of gain and loss. The current study provides valuable information on chromosomal aberrations likely to be involved in the pathogenesis of head and neck cancers. An increased copy number of the S100A and MMP gene family members, known to be involved in invasion and metastasis, may play an important role in the development of the tumors. Hierarchical clustering of the chromosomal alterations with clinicopathological parameters showed little correlation, suggesting an occurrence of gains/losses regardless of ethnic differences and clinicopathological status between the patients from the two countries. Our findings indicate the existence of common gene-specific amplifications/deletions in these tumors, regardless of the source of the samples or attributed carcinogenic risk factors.
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PMID:Chromosomal aberrations in head and neck squamous cell carcinomas in Norwegian and Sudanese populations by array comparative genomic hybridization. 1881 24

Hyperpigmentation of the skin is characterized by increases in melanin synthesis and deposition. Although considered a significant psychosocial distress, little is known about the detailed mechanisms of hyperpigmentation. Recently, the tumor suppressor protein p53 has been demonstrated to promote ultraviolet B-induced skin pigmentation by stimulating the transcription of a melanogenic cytokine, POMC (pro-opiomelanocortin), in keratinocytes. Given that p53 can be activated by various kinds of diverse stresses, including sun exposure, inflammation, and aging, this finding led us to examine the involvement of p53 in cytokine receptor signaling, which might result in skin hyperpigmentation. Immunohistochemical and reverse transcription-PCR analyses revealed the increased expression and phosphorylation of p53 in the epidermis of hyperpigmented spots, accompanied by the higher expression of melanogenic cytokines, including stem cell factor, endothelin-1, and POMC. The involvement of p53 in hyperpigmentation was also indicated by the significantly higher expression of p53 transcriptional targets in the epidermis of hyperpigmented spots. Treatment of human keratinocytes and melanocytes with known p53 activators or inhibitors, including pifithrin-alpha (PFT), demonstrated significant increases or decreases, respectively, in the expression of melanogenic factors, including cytokines and their receptors. Additionally, PFT administration abolished stem cell factor-induced phosphorylation of mitogen-activated protein kinase in human melanocytes. Furthermore, when organ-cultured hyperpigmented spots, in vitro human skin substitutes, and mouse skin were treated with PFT or p53 small interfering RNA, the expression of melanogenic cytokines and their receptors was significantly decreased, as were levels of tyrosinase and melanogenesis. Taken together, these data reveal the essential role of p53 in hyperpigmentation of the skin via the regulation of paracrine-cytokine signaling, both in keratinocytes and in melanocytes.
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PMID:The essential role of p53 in hyperpigmentation of the skin via regulation of paracrine melanogenic cytokine receptor signaling. 1909 8

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.
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PMID:Polymorphisms in the BRCA1 and ABCB1 genes modulate menopausal hormone therapy associated breast cancer risk in postmenopausal women. 1967 6


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