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)

Distinct patterns of cell proliferation and apoptosis have been recognized for tubular, interstitial, and glomerular cells in chronic obstructive uropathy (OU). In many experimental models of OU, tubular cell apoptosis develops quickly after ureter ligation, peaks between 7 and 24 days postobtruction (about 30-fold of control), and tapers thereafter. Apoptosis initially involves the dilated collecting ducts, but subsequently spreads to other tubules. Tubular cell apoptosis probably accounts for renal tissue loss in OU because a direct correlation between its degree and the decline in dry kidney weight is well-documented. Pronounced tubular cell proliferation occurs shortly after ureter ligation, peaks at about day 6 (60-fold above control), and quickly subsides to baseline. Because the peak of tubular cell proliferation immediately precedes the onset of tubular cell apoptosis, a pathogenetic link may exist between these two processes. Interstitial cell apoptosis occurs with an increasing frequency throughout the course of OU (up to 35-fold above control). Interstitial cell proliferation appears in a bimodal pattern with the early peak coinciding with that of tubular cell proliferation and consisting mostly of fibroblasts, whereas the later peak consists mostly of inflammatory cells. Glomerular cell apoptosis and proliferation are not different from control, which explains, in part, the structural integrity of the glomeruli throughout the disease course. Although the general pathways of cell apoptosis and proliferation are well known, the molecular control of these processes in OU is poorly understood. In addition, whether apoptosis or proliferation of tubular and interstitial cells is differentially regulated remains to be studied. However, several molecules known to be activated or overexpressed in kidney with OU may modulate cell apoptosis and proliferation. The relevant functions of these molecules include induction of apoptosis (angiotensin II, reactive oxygen species, jun-N-terminal kinase, p53), inhibition of the cell cycle (transforming growth factor-beta, p21), inhibition of apoptosis (clusterin, epidermal growth factor, insulin-like growth factor, bcl-2, osteopontin), or promotion of interstitial fibroblast proliferation (platelet-derived growth factor).
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PMID:Cell apoptosis and proliferation in obstructive uropathy. 981 55

This recent symposium featured speakers from several clinical and research disciplines. Among the findings: peptic ulcer disease is a significant predisposing risk factor (odds ratio = 3.9) for pancreatic cancer; as many as 50% of all intraductal papillary mucinous neoplasms are associated with invasive adenocarcinomas; alteration of gene expression via methylation of a gene promotor region constitutes a potentially reversible method of tumor suppressor gene inactivation; > 400 transcriptional alterations of gene expression have been identified for pancreatic cancer; some common molecular markers such as p53 and HER-2/neu may be related to morphologic alterations of in situ neoplasia and to transcriptional alterations of gene expression rather than mutational events; epidermal growth factor (EGF), transforming growth factor beta (TGF-beta), and related molecules may modulate gene transcription via "autocrine" or "paracrine" mechanisms; several cytokines, amylin (islet amyloid polypeptide), and other cachexia factors are responsible for paraneoplastic peripheral insulin resistance, ineffective utilization of glucose, and profound cachexia. In the clinical diagnostic arena: the World Health Organization established a standard nomenclature for intraductal papillary mucinous neoplasms, mucinous cystic tumors, intraductal mucinous hyperplasias, and solid pseudopapillary tumors; focal glandular differentiation may be commonly identified within pancreatic endocrine neoplasms (islet cell tumors) while not necessarily implying an unfavorable prognosis typical of ductal adenocarcinomas; positron emission tomography scanning may be used for evaluation of early tumor response to novel chemotherapeutic regimens; helical computed tomography (CT) is the state of the art in preoperative imaging for pancreatic cancer; neoadjuvant 5-fluorouracil (5-FU)-based chemoradiation in 39 "resectable" patients provided a median survival of 19 months, actuarial 4-year survival of 19%, and improved local tumor control; gemcitabine has shown promise in alleviating tumor-related symptoms with a significantly better "clinical benefit response" than single agent 5-FU (23.8 vs. 4.8%, p = 0.0022) based on change in pain intensity, daily analgesic consumption, performance status, and weight; a significant survival advantage was demonstrated in patients treated with conventional therapies whose tumors expressed p21WAF-1, an important inhibitor of cell cycle progression and downstream molecule of p53 and TGF-beta; a p21-adenovirus (rAD-p21) gene therapy resulted in significant growth inhibition of pancreatic cancer cell lines in tissue culture, and development of a successful SCID mouse-human pancreatic adenocarcinoma xenograft model provided an animal model for preclinical trials of rAD-p21.
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PMID:Current concepts in pancreatic cancer: symposium summary. 982 Nov 73

The authors examined the growth response of cardinal ligamental fibroblasts derived from patients with prolapsus uteri (HPLiF) and compared it with the response of those from control subjects (HCLiF). The growth rate during the logarithmic growth phase was not different between HPLiF and HCLiF, while the cell density at confluence (saturation density) was significantly higher in HPLiF than in HCLiF. When added alone, platelet-derived growth factor (PDGF), insulin-like growth factor-I (IGF-I), and epidermal growth factor (EGF) produced minimal effects on DNA synthesis in HCLiF. The simultaneous addition of PDGF, IGF-I and EGF synergistically stimulated the DNA synthesis. In contrast, PDGF alone was able to initiate DNA synthesis in HPLiF. The combination of PDGF, IGF-I, and EGF significantly stimulated the DNA synthesis of HPLiF compared with HCLiF. p53 protein and p53 gene transcripts decreased by 50% in HPLiF. The anti-WAF1 antibody reacted intensely with a 21-kDa protein in the homogenates of control fibroblasts, while the immunoreactive band in prolapsus fibroblasts was clearly reduced. These results indicate that the higher proliferative activity at near confluency in prolapsus fibroblasts may result from the decreased expression of p53 protein and p53 mRNA followed by the decrease in p21 protein. Furthermore, the failure of cells to enter quiescence may lead to a decrease in the synthesis and deposition of elastin and thus may contribute to the loss of supportive function in uterine connective tissues.
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PMID:Decrease in p53 protein in cultured cardinal ligament fibroblasts from patients with prolapsus uteri. 982 80

DNA synthesis was inhibited in A431 cells by epidermal growth factor (EGF) in a p21/CIP1-dependent manner [where CIP1 is cyclin-dependent kinase (CDK)-interacting protein 1]. When 1 or 10 nM EGF was added, the level of p21/CIP1 was increased to the same extent, and the protein level peaked after approx. 5 h of incubation. The increase in p21/CIP1 mRNA upon addition of EGF was rapid, and was enhanced in the presence of cycloheximide. The half-life of p21/CIP1 mRNA in EGF-treated A431 cells was increased approx. 2-fold; this is in contrast with the case in MCF-7 cells with normal p53, in which the half-life of p21/CIP1 mRNA was not increased upon addition of EGF. This increased stability accounts for most of the increase in mRNA levels observed in A431 cells during short incubation periods. Additionally, upon prolonged incubation of A431 cells with EGF, the half-life of the protein was also increased compared with that in untreated cells and in cells treated with EGF for short time periods. Nuclear run-on assays demonstrated only marginal stimulation of transcription by 10 or 1 nM EGF, or by 10 ng/ml tumour necrosis factor alpha. Our results indicate that the most important mechanisms by which EGF increases p21/CIP1 protein levels in A431 cells are post-transcriptional and post-translational stabilization.
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PMID:Epidermal growth factor increases the level of the cyclin-dependent kinase (CDK) inhibitor p21/CIP1 (CDK-interacting protein 1) in A431 cells by increasing the half-lives of the p21/CIP1 transcript and the p21/CIP1 protein. 989 7

2-Acetylaminofluorene (AAF) is a potent tumor promoter in rat liver carcinogenesis models. In the resistant hepatocyte model, AAF is combined with a growth stimulus for efficient promotion of preneoplastic lesions. The promoting property of AAF in this model is closely associated with mito-inhibition of normal hepatocytes, an effect to which initiated cells are resistant. How AAF induces growth arrest is not known, but genotoxic as well as non-genotoxic effects have been implicated. To elucidate the mechanisms of AAF-induced mito-inhibition, we studied the expression of the tumor suppressor protein p53 and the cyclin-dependent kinase (cdk) complexes mediating G1 progression and S-phase entry. Hepatocytes were isolated from male Fisher 344 rats fed either a control diet or a diet supplemented with 0.02% AAF for 1 wk and cultured in a defined serum-free medium containing epidermal growth factor, insulin, and dexamethasone. Thymidine labeling revealed a profound inhibition of DNA synthesis in AAF-exposed cells compared with control cells. The retinoblastoma protein did not become hyperphosphorylated in AAF-exposed cells. Thus, inhibition of G1 cyclin-cdk activity was implied as a cause of growth arrest. Indeed, G1 cell-cycle arrest was accompanied by reduced induction and nuclear accumulation of the cyclin D1-cdk4 complex and inhibited nuclear translocation of cdk2. Furthermore, the growth arrest was not mediated through p21/waf1 upregulation, although nuclear levels of p53 were increased. Thus, carcinogen-induced mito-inhibition may be effected by altered levels and localization of G1 cyclin-cdk complexes, independent of the upregulation of cdk inhibitory proteins.
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PMID:Alteration of G1 cell-cycle protein expression and induction of p53 but not p21/waf1 by the DNA-modifying carcinogen 2-acetylaminofluorene in growth-stimulated hepatocytes in vitro. 1002 9

The incidence of adenocarcinoma of the esophagus has been increasing in developing countries over the last three decades and probably reflects a genuine increase in the incidence of its recognized precursor lesion, Barrett's metaplasia. Despite advances in multimodality therapy, the prognosis for invasive esophageal adenocarcinoma is poor. An improved understanding of the molecular biology of this disease may allow improved diagnosis, therapy, and prognosis. We focus on recent developments in the molecular and cell biology of Barrett's metaplasia, a heterogeneous lesion affecting the transitional zone of the gastro-esophageal junction whose associated molecular alterations may vary both in nature and temporally. Early premalignant clones produce biological and genetic heterogeneity as seen by multiple p53 mutations, p16 mutations, aneuploidy, and abnormal methylation resulting in stepwise changes in differentiation, proliferation, and apoptosis, allowing disease progression under selective pressure. Abnormalities in expression of growth factors of the epidermal growth factor family and cell adhesion molecules, especially cadherin/catenin complexes, may occur early in invasion. Exploitation of these molecular events may lead to a more appropriate diagnosis and understanding of these lesions in the future.
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PMID:Molecular evolution of the metaplasia-dysplasia-adenocarcinoma sequence in the esophagus. 1023 32

Here we report the characterization of an SV40 large-T antigen-immortalized stromal cell line, WPMY-1, derived from the same prostate as our previously described epithelial cell lines. The WPMY-1 cells were determined to be myofibroblasts on the basis of co-expression of smooth muscle alpha-actin and vimentin. They also show positive staining for androgen receptor, large-T antigen, and positive but heterogeneous staining for p53 and pRb. Their growth is stimulated by the synthetic androgen mibolerone to 145% of control (100%). Platelet-derived growth factor BB, epidermal growth factor and basic fibroblast growth factor, at 10 ng/ml, stimulated growth to 138, 143 and 146% of control, respectively. Transforming growth factor-beta, at 10 ng/ml, inhibited serum-induced growth to 65% of control in the presence of 1% serum, and bFGF-induced growth to 30% of control. A serum-free medium was developed for optimal growth of WPMY-1 cells. They show anchorage-independent growth in soft agar. Studies on paracrine interactions show that myofibroblast-conditioned medium causes a marked inhibition of growth in WPE1-10 cells, while conditioned medium from WPE1-10 prostatic epithelial cells caused only a small increase in the growth of WPMY-1 cells. WPMY-1 cells secrete very low levels of MMP-9 but high levels of MMP-2, markedly higher than the epithelial cells. These epithelial and myofibroblast cell lines, derived from the same prostate, provide novel and useful models for studies on paracrine stromal-epithelial interactions in carcinogenesis, tumor progression, prevention and treatment of prostate cancer and benign prostatic hyperplasia.
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PMID:A human prostatic stromal myofibroblast cell line WPMY-1: a model for stromal-epithelial interactions in prostatic neoplasia. 1038 88

Serum-free mouse embryo (SFME) cells are a neural stem cell line that is dependent upon epidermal growth factor (EGF) for survival. Removal of EGF results in the G1 arrest and apoptosis of SFME cells. We have shown that the expression of simian virus 40 large T antigen in SFME cells blocks apoptosis and allows cell survival and division in the absence of EGF. Therefore the presence of T antigen abrogates the EGF requirement. The steady-state levels of p53, p21, and mdm-2 do not increase as SFME cells undergo apoptosis upon EGF withdrawal. Furthermore, the amino-terminal 136 amino acids (N136) of T antigen are sufficient to block death and to promote proliferation in the absence of EGF, while the carboxy-terminal fragment (C251-708), which contains the p53 binding site, is unable to block death. Taken together, these data suggest that SFME cells deprived of EGF undergo p53-independent apoptosis. Mutations that disrupt either the J domain or Rb family binding abolish the ability of T antigen to block SFME cell apoptosis and to promote cell growth. We conclude that T antigen must act on one or more members of the Rb family to inhibit SFME cell apoptosis.
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PMID:Simian virus 40 large T antigen J domain and Rb-binding motif are sufficient to block apoptosis induced by growth factor withdrawal in a neural stem cell line. 1040 Jul 77

Transgenic mice overexpressing transforming growth factor-alpha (TGF-alpha) display an expansion of intrapancreatic fibroblasts and a progressive accumulation of extracellular matrix. This massive fibrosis is associated with an increase in pancreatic size and weight. In parallel, tubular complexes appear that are composed of acinar cells with a decreased height. These acinar cell lose zymogen granules and become transitional cells, which subsequently gain duct cell features. In animals older than one year dysplastic lesions develop, which originate from tubular complexes. Occasionally these dysplastic foci transform to papillary and cystic pancreatic carcinoma. These tumors are positive for the duct-specific antigen Duct-1 and carbonic anhydrase activity indicative of ductal differentiation. Tumors overexpress the epidermal growth factor (EGF)-receptor and p53, but lack K-ras mutations. These data suggest an acinar-ductal-carcinoma sequence in TGF-alpha transgenic mice.
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PMID:Acinar-ductal-carcinoma sequence in transforming growth factor-alpha transgenic mice. 1041 67

Previously, we demonstrated that human breast cancer cells with progressively elevated levels of constitutively tyrosine phosphorylated erbB-2 are independent of growth factors required by normal human mammary epithelial (HME) cells for proliferation in serum-free medium. To determine whether erbB-2 overexpression alone is sufficient to confer the growth factor-independence phenotype in HME cells, the spontaneously immortalized MCF-10A cell line and the HPV-16-immortalized H16N2 cell line were infected with the bicistronic retroviral vector pTPerbB-2 and tested for their ability to grow in the absence of specific factors. Selection of infected cells in G418-containing medium resulted in moderate levels of erbB-2 overexpression in approximately 40% of cells. The subpopulation of erbB-2 overexpressing cells could be selected for by culturing the cells in medium devoid of insulin. When MCF-10A or H16N2 cells were infected with pTPerbB-2 and directly selected in growth factor-deficient medium over long periods of time, populations of both cell lines emerged that expressed levels of erbB-2 protein equivalent to levels expressed by breast cancer cells with an erbB-2 gene amplification. Furthermore, overexpressed p185(erbB-2) was constitutively tyrosine phosphorylated in these cells. The levels of tyrosine phosphorylated p185(erbB-2) differed in the two recipient lines, with H16N2-erbB-2 cells having higher levels of activated receptor than MCF-10AerbB-2 cells. Furthermore, only the H16N2-erbB-2 cells were independent of both insulin and epidermal growth factor for growth in serum-free medium. Overexpression of erbB-2 also resulted in progressively increasing levels of tyrosine-phorphorylated erbB-3, without any significant changes in p180(erbB-3) levels. These studies demonstrate a direct relationship between the level of expression and activation of p185(erbB-2) and the requirements of HME cells for insulin-like and epidermal growth factor-like growth factors. The results also suggest that genetic alterations present in breast cancer cells, or mediated by HPV-16-induced alterations in pRb and p53, can influence the expression level and activation status of erbB-2 as well as erbB-3 and, in turn, their degree of growth factor independence.
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PMID:erbB-2 overexpression in human mammary epithelial cells confers growth factor independence. 1043 19


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