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)

This study investigates whether insulin (a differentiation factor for lens epithelial cells) acts as a survival factor. In the absence of insulin, 6-day embryonic chicken lens epithelial explants undergo apoptosis as shown by changes in cell morphology, DNA fragmentation, and loss of trypan blue exclusion. Insulin inhibits these changes and promotes survival of the cells. Aurintricarboxylic acid suppresses the apoptosis of lens explants. In contrast to 6-day embryonic explants, 19-day embryonic explants survive in the absence of insulin, presumably due to an endogenous survival factor. To explore the mechanism of the action of insulin as a survival factor for 6-day embryonic lens explants, we compared the pattern of cell cycle markers (c-fos, c-jun, c-myc, p53, histone H3, thymidine kinase, and cyclin B) in both apoptotic and differentiating lens explants. In the presence of insulin, the expression of c-fos and c-jun was down-regulated after an initial induction. Expression of these genes was also induced in the absence of insulin, but mRNA levels remained elevated as the cells underwent apoptosis. In contrast, expression of c-myc, p53, histone H3, thymidine kinase, and cyclin B showed only minor differences in differentiating and apoptotic cells. Since c-fos and c-jun have been shown to play a role in apoptosis in other cell types, the ability of insulin to regulate expression of these genes may be central to its ability to act as a survival factor for lens epithelial cells.
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PMID:Insulin regulates expression of c-fos and c-jun and suppresses apoptosis of lens epithelial cells. 854 23

Proto-oncogenes, growth factors/receptors, and tumour suppressor genes were analysed in malignant metastatic insulinomas. Normal pancreas showed only a moderate immunoreaction for c-myc proto-oncogene and a strong reaction for insulin. Benign insulinomas were slightly or moderately positive for transforming growth factor alpha (TGF alpha), weakly positive for epidermal growth factor receptor (EGF-R), and strongly positive for c-myc and insulin. In malignant insulinomas, besides a strong immunoreaction for c-myc and TGF alpha, activation of c-K-ras and overexpression of p53 protein were found. Insulin reaction was moderate or strong. Three out of six malignant insulinomas displayed a c-K-ras point mutation at codon 12. All mutations were guanine to cytosine transversion, resulting in amino acid substitution, glycine to arginine. Mutations were present in metastatic insulinomas only. Patients with mutated c-K-ras oncogene had overexpression of p53 protein as well as c-myc and TGF alpha overexpression. Our results support the view that malignant progression is a consequence of more than one genetic lesion and suggest that activation of myc, TGF alpha an ras genes plays a role in a multistep process of tumour progression, perhaps serving as an initiating event.
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PMID:Multiple genetic alterations in malignant metastatic insulinomas. 856 94

Malignant insulinoma is an rare form of cancer with poor prognosis and a reported 5-year survival of 35%. Relatively little is known about the etiology of this disease or of the oncogenes and tumor suppressor genes that participate in its genesis and progression. To address this issue, several protooncogenes, including K-ras, N-ras, erbB-2, erbB-3,c-myc, c-fos, c-jun were examined. Also analyzed was the expression of the growth factors TGF-alpha, EGF, and insulin as well as the EGF receptor (EGF-R), p53 and the putative anti-metastasis gene nm23-H1. These were examined in malignant insulinomas, benign insulinomas, pancreatic B cell hyperplasias and in normal endocrine pancreas. Normal endocrine pancreas showed moderate immunoreaction for c-myc and a strong reaction for insulin. All other parameters were negative. Benign pancreatic B cell hyperplasias were slightly or moderately positive for N-ras and TGF-alpha, and were weakly positive for EGF-R. They were strongly positive for c-myc and insulin. In malignant insulinomas there was strong immunoreaction for c-myc, TGF-alpha, N-ras, K-ras and p53. Insulin reaction was moderate or strong. Molecular genetic studies have been performed for the presence of activating point mutations in codon 12 of the c-K-ras oncogene. Mutations were detected using primer-mediated, mutant-enriched, polymerase chain reaction-restriction fragment length polymorphism analysis and were further characterized by allele-specific oligonucleotide hybridization. Four out of six patients with malignant insulinoma and two out of eight patients with benign insulinoma harbored K-ras point mutations at codon 12. All patients with mutated K-ras oncogene also had elevated levels of p53 protein as well as c-myc and TGF-alpha. In one extremely malignant case we found concomitant mutation at codon 12 of K-ras and codon 61 of the N-ras gene. Our data are consistent with the idea that malignant progression is accompanied by the progressive accumulation of multiple genetic lesions and suggest that activation of myc, TGF-alpha and ras genes may be early events in the development of insulinoma.
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PMID:Molecular genetics of malignant insulinoma. 871 89

In this study we sought factors that determine the survival of human colonic epithelial cells. Normal colonic epithelial cells are dependent on cell-cell contacts and survival factors for the inhibition of apoptosis whereas, during colorectal tumorigenesis, cells develop mechanisms to evade these controls. The ability to survive loss of cell-cell contacts and/or growth factor deprivation is a marker of tumour progression. Many adenoma (premaligant) cultures survive only if cell-cell contacts are maintained in vitro and die by apoptosis if trypsinized to single cells. This also occurs in adenomas derived from familial adenomatous polyposis (FAP) patients, therefore APC mutations do not confer resistance to cell death in response to loss of cell-cell contacts. We show here that if cell-cell contacts are maintained such cells are capable of survival in suspension. Adenoma cells also undergo apoptosis in response to removal of serum and growth factors from the medium. After removal of serum and growth factors c-myc is down-regulated within 2 h. Therefore, the induction of apoptosis is not an inappropriate response of the cells due to a deregulated c-myc gene. The apoptotic response is also p53 independent. Such cultures have been used to determine specific survival factors for colonic epithelial cells. Insulin, the insulin-like growth factors I and II, hydrocortisone and epidermal growth factor (EGF) protect cells from the induction of apoptosis in the absence of serum over a short-term period of 24 h. This approach may give insight into the factors governing growth and survival of colonic epithelial cells in vivo. This is the first report of specific growth factors protecting against apoptosis in human colonic epithelial cells.
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PMID:Cell-cell contact and specific cytokines inhibit apoptosis of colonic epithelial cells: growth factors protect against c-myc-independent apoptosis. 908 30

Insulin-like growth factor (IGF) binding protein-3 (IGFBP-3) is known to block IGF action and inhibit cell growth. IGFBP-3 is thought to act by sequestering free IGFs or, possibly, act via a novel IGF-independent mechanism. Supporting its role as a primary growth inhibitor, IGFBP-3 production has been shown to be increased by cell growth-inhibitory agents, such as transforming growth factor-beta (TGF-beta), and the tumor suppressor gene p53. In this paper, we demonstrate, for the first time, a novel function of IGFBP-3 as an apoptosis-inducing agent and show that this action is mediated through an IGF.IGF receptor-independent pathway. In the p53 negative prostate cancer cell line, PC-3, the addition of recombinant IGFBP-3 resulted in a dose-dependent induction of apoptosis. 125I-IGFBP-3 bound with high affinity to specific proteins in PC-3 cell lysates and plasma membrane preparations. These membrane-associated molecules may serve as receptors that mediate the direct effect of IGFBP-3 on apoptosis. In addition, in an IGF receptor-negative mouse fibroblast cell line, treatment with recombinant IGFBP-3 as well as transfection of the IGFBP-3 gene induced apoptosis, suggesting that neither IGFs nor IGF receptors are required for this action. Furthermore, treatment with TGF-beta1, a known apoptosis-inducing agent, resulted in the induction of IGFBP-3 expression 6-12 h before the onset of apoptosis. This effect of TGF-beta1 was prevented by co-treatment with IGFBP-3-neutralizing antibodies or IGFBP-3-specific antisense thiolated oligonucleotides. These findings suggest that IGFBP-3 induces apoptosis through a novel pathway independent of either p53 or the IGF.IGF receptor-mediated cell survival pathway and that IGFBP-3 mediates TGF-beta1 induced apoptosis in PC-3 cells.
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PMID:Insulin-like growth factor (IGF)-binding protein-3 induces apoptosis and mediates the effects of transforming growth factor-beta1 on programmed cell death through a p53- and IGF-independent mechanism. 911 91

The incidentally detected adrenal mass is with a prevalence of 1% in the general population the most common pathological process of the adrenal gland. In more than 85% of the cases it is caused by benign adenomas of the adrenal cortex. These tumors have a monoclonal composition and are, therefore, caused by oncogenic mutations with consecutive clonal expansion of this cell clone. In contrast to adrenocortical carcinoma, in which mutations of the IGF II gene locus and the p53 tumor suppressor gene has been found, the oncogenes involved in the tumorigenesis of adrenal adenomas have not been identified yet. However, opposite to other endocrine tumors the receptor-cAMP-proteinkinase A signaling pathway is not involved in the pathogenesis of these tumors. Insulin may be an important growth factor of incidentally detected adrenal tumors. Heterozygote 21-hydroxylase deficiency, however, does not seem to play a major role in the tumorigenesis of adrenal incidentalomas.
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PMID:[Molecular biology of incidentally diagnosed adrenal gland space-occupying lesion]. 933 8

Insulin-like growth factor (IGF)-1 inhibits apoptosis, but its mechanism is unknown. Myocyte stretching activates p53 and p53-dependent genes, leading to the formation of angiotensin II (Ang II) and apoptosis. Therefore, this in vitro system was used to determine whether IGF-1 interfered with p53 function and the local renin-angiotensin system (RAS), decreasing stretch-induced cell death. A single dose of 200 ng/ml IGF-1 at the time of stretching decreased myocyte apoptosis 43% and 61% at 6 and 20 hours. Ang II concentration was reduced 52% at 20 hours. Additionally, p53 DNA binding to angiotensinogen (Aogen), AT1 receptor, and Bax was markedly down-regulated by IGF-1 via the induction of Mdm2 and the formation of Mdm2-p53 complexes. Concurrently, the quantity of p53, Aogen, renin, AT1 receptor, and Bax was reduced in stretched myocytes exposed to IGF-1. Conversely, Bcl-2 and the Bcl-2-to-Bax protein ratio increased. The effects of IGF-1 on cell death, Ang II synthesis, and Bax protein were the consequence of Mdm2-induced down-regulation of p53 function. In conclusion, the anti-apoptotic impact of IGF-1 on stretched myocytes was mediated by its capacity to depress p53 transcriptional activity, which limited Ang II formation and attenuated the susceptibility of myocytes to trigger their endogenous cell death pathway.
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PMID:Insulin-like growth factor-1 induces Mdm2 and down-regulates p53, attenuating the myocyte renin-angiotensin system and stretch-mediated apoptosis. 1002 14

Insulin-like growth factors (IGFs) regulate important cellular activities involving cell proliferation, differentiation, and apoptosis. Emerging evidence suggests that members of the IGF family, including IGF-1, IGF-2, the IGF-1 receptor (IGF-1R), and the IGF binding proteins (IGFBPs), play important roles in the development and progression of cancer. Both in vitro and in vivo studies show that IGFs are strong mitogens for a variety of cancer cells. IGF-1 also has an antiapoptotic action on cancer. IGF-1R, overexpressed in cancer cells, mediates the effects of IGFs and plays a role in cell transformation induced by tumor virus and oncogene products. IGFBPs inhibit the actions of IGFs and mediate the anti-proliferative effect of wild-type p53 protein, retinoic acid, vitamin D, and transforming growth factor-beta (TGF-beta). Findings from epidemiologic studies support the involvement of IGF in cancer etiology. Diet, nutrition, and other lifestyle features affect the expression and production of IGF-1 and other members of the IGF family. This may provide new approaches for cancer prevention. Growth hormone (GH) stimulates the production of IGF-1. Use of GH replacement therapy to improve physiological and psychological well-being and to prevent aging-related diseases has been recommended. Given the close relationship between GH and IGF-1, the long-term safety of GH treatment warrants a serious concern.
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PMID:Insulin-like growth factors and cancer. 1023 99

Insulin-like growth factors (IGF) are mitogenic peptides that have been implicated as positive regulators of cellular proliferation. In recent years, several studies have suggested an additional role for the IGF axis in the regulation of apoptosis. Signalling through the IGF receptor has been shown to have a potent survival function and protect cells from a variety of apoptotic stimuli. The actions of IGF are regulated by a family of high-affinity IGF binding proteins (IGFBP), which sequester the IGF from the IGF receptor. However, there is some evidence that one of these binding proteins, IGFBP-3, may have its own pro-apoptotic effects that are independent of its ability to modulate IGF bioavailability. In addition, it has been suggested that the tumour suppressor p53, a crucial mediator of apoptosis in response to cellular stress, may elicit several of its apoptotic effects through manipulation of components of the IGF axis. This review summarizes what is currently known about the role of the IGF system in the regulation of apoptosis, highlighting its implications in the context of tumorigenesis.
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PMID:The IGF axis and programmed cell death. 1036 Dec 58

Regulation of apoptosis is an important component of multistage hepatocarcinogenesis. The proto-oncogene c-myc has been shown to be important in apoptosis regulation and to be amplified and overexpressed in human and rodent liver neoplasia. The objectives of the study reported here were to determine whether apoptosis regulation is altered in transgenic hepatocytes that overexpress c-myc and whether growth factors or nongenotoxic carcinogens alter apoptosis regulation in c-myc versus wild-type hepatocytes. Hepatocytes isolated from c-myc transgenic mice had four fold more c-myc RNA and protein (at 12-48 h) in addition to increased apoptosis levels compared with wild-type hepatocytes. The increased apoptosis in c-myc hepatocytes was accompanied by increased p53, bax, and bak and decreased bcl-2 protein levels. Hepatocytes overexpressing c-myc were more sensitive to apoptosis induced by bleomycin but less sensitive to apoptosis induced by transforming growth factor (TGF)-beta. Phenobarbital, a potent liver tumor promoter, inhibited apoptosis in c-myc hepatocytes but not in wild-type hepatocytes, decreased p53 and bax, and increased bcl-2 protein levels. Nafenopin inhibited apoptosis in both c-myc and wild-type hepatocytes, whereas 2,3,7,8-tetrachlorodibenzo-pdioxin did not inhibit apoptosis in either wild-type or c-myc hepatocytes. TGF-alpha inhibited apoptosis and increased bcl-X(L) and decreased bak protein levels in c-myc hepatocytes but not in wild-type hepatocytes. Insulin-like growth factor-II did not affect apoptosis in c-myc or wild-type hepatocytes. In this study, overexpression of c-myc altered the response to apoptotic stimuli in transgenic hepatocytes. Furthermore, phenobarbital and TGF-alpha inhibited c-myc-induced apoptosis, which may have resulted in a selective growth advantage for an initiated cell population and which may be a mechanism for tumor promotion.
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PMID:Dysregulation of apoptosis by c-myc in transgenic hepatocytes and effects of growth factors and nongenotoxic carcinogens. 1044 34


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