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)

Differentiation and luteinization of granulosa cells are induced by gonadotrophic hormones and other substances elevating intracellular levels of cyclic AMP (cAMP). We have investigated the correlation between the potency of these substances to enhance steroidogenesis and to induce apoptosis in primary granulosa cell cultures obtained from rat preovulatory follicles. The cAMP analog, 8-Br cAMP, induced apoptosis in more than 90% of the cell population within 15 h of incubation at 37 degrees C in serum-free medium. The physiological stimulants of these cells, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), which caused a moderate cAMP response in these cells, followed by a desensitization period, increased progesterone production by fourfold with no apparent effect on cell death. In contrast, forskolin, a potent activator of adenylate cyclase, stimulated both the cAMP and steroidogenic response by an order of magnitude greater than the gonadotropin stimulation, concomitantly with a pronounced increase in cell death (25%). Moreover, blocking of the cellular phosphodiesterase activity in forskolin-stimulated cells by isobutylmethylxanthine (IBMX), which maintains high levels of intracellular cAMP, led to further enhancement of cell death following 40 h of incubation (50%). Basic fibroblast growth factor (bFGF) and gonadotropin-releasing hormone (GnRH), which stimulated steroidogenesis in these cells in a cAMP-independent manner, did not promote cell death. Moreover, costimulation of the cells with forskolin and bFGF led to a substantial decrease in the incidence of apoptosis relative to forskolin alone. In order to examine whether the expression of tumor suppressor genes is involved in granulosa cell differentiation and apoptosis induced by cAMP, we examined the effect of cAMP in SV40 transformed granulosa cells, in which T-antigen expression is expected to block the activity of p53 as well as of the retinoblastoma gene product (pRB) and its related proteins. Cultures of three different cell lines established by SV40 transformation demonstrated resistance to 8-Br-cAMP- or forskolin plus IBMX-induced apoptosis, in contrast to the severe apoptotic response in primary cells. We suggest that stimulation of primary granulosa cells by high levels of cAMP catalyzes programmed cell death, while stimulation of the cells by gonadotropic hormones, which result in a moderate cAMP response, followed by desensitization to further stimulation, can prolong the lifespan of the luteinized granulosa cells. Moreover, one or more tumor suppressor proteins may mediate the cAMP generated signal leading to cell death.
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PMID:cAMP-mediated signals as determinants for apoptosis in primary granulosa cells. 753 93

PDGF-B released from colon tumor cells regulated tumor growth in athymic mice in a paracrine manner by inducing blood vessel formation. A positive correlation was found between expression of PDGF B-chain in cells grown in vitro and the number of factor VIII-positive blood vessels in tumors induced by three classes of colon carcinoma cell lines. Elevated expression of PDGF-B was also correlated with tumor size. Each cell line had the same mutations in the colon cancer genes APC, DCC, and p53 and had wild type c-K-ras genes (Huang et al. [1994] Oncogene, 9:3701-3706.) eliminating the possibility that any differences in tumor blood vessel formation were due to mutations and/or deletions in these genes. Colon carcinoma cells released biologically active PDGF capable of stimulating the growth of NIH3T3 cells, which was inhibited by neutralizing antisera to PDGF-AB chains. An inverse correlation was found between induction of factor VIII-positive blood vessels and expression of vascular endothelial growth factor (VEGF), while no correlation was seen with expression of either TGF alpha or k-FGF. Basic fibroblast growth factor (FGF) expression was not detected in these tumor cells. TGF beta 1 was capable of inducing PDGF-B expression in the undifferentiated U9 colon carcinoma cell line, but this sensitivity was not seen in differentiated cells. In contrast, TGF beta 1 inhibited VEGF expression in both undifferentiated cells and differentiated colon cancer cells. Thus, TGF beta 1 has two roles in the growth of undifferentiated U9 colon carcinoma cells in vivo: direct stimulation of cell proliferation as we have showed in earlier studies, and an increase in angiogenesis by inducing PDGF-B.
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PMID:Platelet-derived growth factor-B increases colon cancer cell growth in vivo by a paracrine effect. 759 1

Prostatic cancer is the second most frequent cancer in men in industrialised countries. The histological analysis of its initial development demonstrates the existence of precancerous lesions, PIN. The initial presence of several different cell populations accounts for the development of contingents of hormone-sensitive and hormone-resistant cells. The presence of numerous neuroendocrine cells appears to be a factor of poor prognosis. Hormones are intimately involved in the development of prostatic cancer and are an integral part of its treatment. Progress in molecular biology has furthered out knowledge of this disease. In particular, growth factors such as EGF and FGF are particularly involved and are starting to have a clinical application. The oncogene and anti-oncogene system is currently being explored (particularly p53 abd BCL 2). They are the basis for carcinogenesis and analysis of these factors will allow a better approach to the mechanisms of tumour induction and development.
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PMID:[Cancer of the prostate. 2. Physiology and cellular development]. 771 57

Cells and tissues have developed a variety of ways of responding to a hostile environment, be it from drugs (toxins) or radiation (summarized in Fig. 1). Three categories of radiation damage limitation are: (i) DNA repair (ii) changes in cellular metabolism (iii) changes in cell interaction (cell contact or tissue-based resistance; whole organism based resistance). DNA repair has been evaluated predominantly by the study of repair-deficient mutants. The function of the repair genes they lack is not fully understood, but some of their important interactions are now characterized. For example, the interaction of transcription factors with nucleotide excision repair is made clear by the genetic syndromes of xeroderma-pigmentosum groups B, D and G. These diseases demonstrate ultraviolet light sensitivity and general impairment of transcription: they are linked by impaired unwinding of the DNA required for both transcription and repair. The transfer of DNA into cells is sometimes accompanied by a change in sensitivity to radiation, and this is of special interest when this is the same genetic change seen in tumors. DNA repair has a close relationship with the cell cycle and cell cycle arrest in response to damage may determine sensitivity to that damage. DNA repair mechanisms in response to a variety of drugs and types of radiation can be difficult to study because of the inability to target the damage to defined sequences in vivo and the lack of a satisfactory substrate for in vitro studies. Changes in cellular metabolism as a result of ionizing radiation can impart radiation resistance, which is usually transient in vitro, but may be more significant in vivo for tissues or tumors. The mechanisms by which damage is sensed by cells is unknown. The detection of free radicals is thought likely, but distortion to DNA structure or strand breakage and a direct effect on membranes are other possibilities for which there is evidence. Changes in extracellular ATP occur in response to damage, and this could be a direct membrane effect. External purinergic receptors can then be involved in signal transduction pathways resulting in altered levels of thiol protection or triggering apoptosis. Changes in the functional level of proteins as a consequence of ionizing radiation include transcription factors, for example c-jun and c-fos; cell cycle arrest proteins such as GADD (growth arrest and DNA damage inducible proteins) and p53; growth factors such as FGF, PDGF; and other proteins leading to radioresistance.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The biology of radioresistance: similarities, differences and interactions with drug resistance. 776 55

Mutations of the p53 gene are found in various human cancers. The frequency of its mutation is reported to increase during tumor progression in most tumors. In human gliomas, mutations of the p53 gene are found in about one-third of the malignant forms and in few of the benign ones, indicating their possible involvement in tumor progression. On the other hand, we have recently shown that basic fibroblast growth factor (basic FGF) plays a crucial role in tumor progression as an autocrine growth factor in tissues of human gliomas. Therefore, we hypothesized that p53 might regulate the promoter activity of the basic FGF gene, which has several GC boxes and no typical TATA box. In this study, cotransfection assays using human glioblastoma and hepatocellular carcinoma cells and establishment of stable cell lines expressing mutant-type p53 were performed. The basic FGF gene promoter was demonstrated to be regulated by p53 at the transcriptional level and its basal core promoter was found to be responsive to p53. Expression of endogenous basic FGF was also demonstrated to be activated by mutant type p53. Wild-type p53 repressed gene expression of the basic FGF and its mutant activated it in vitro, implying one of the possible pathways in tumor progression.
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PMID:Transcriptional regulation of basic fibroblast growth factor gene by p53 in human glioblastoma and hepatocellular carcinoma cells. 809 Jul 61

Basic fibroblast growth factor (bFGF) can exert mitogenic and viability-promoting effects in a wide range of biological systems. The biochemical activities mediating the cell survival function of bFGF are largely unknown. We report here that exposure of fibroblasts to bFGF, which confers upon them increased survival, also causes at the same time an increase in cellular levels of the Mdm2 oncoprotein. Cells constitutively exposed to a bFGF autocrine loop are more refractory to killing by cisplatin. This increased chemoresistance coincides with elevated Mdm2 and reduced activation of the endogenous p53, resulting in inefficient transcriptional activation of the bax gene promoter. Importantly, unlike Mdm2 accumulation in fibroblasts exposed to DNA damage, induction of Mdm2 by bFGF does not occur through a p53-mediated pathway. The role of p53 in DNA damage-induced apoptosis and the ability of Mdm2 to block p53-mediated cell death are well established. These findings therefore suggest that induction of Mdm2 and the subsequent inhibition of p53 function may contribute, at least partially, to the anti-apoptotic effects of bFGF and possibly some other survival factors.
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PMID:Induction of Mdm2 and enhancement of cell survival by bFGF. 940 Sep 98

The activity of the tumor suppressor gene p53 is implicated in arrest of the cell cycle and the induction of apoptosis. The mdm2 oncogene is transcriptionally activated by p53, and the protein products of this gene can down-modulate biochemical activities and biological effects of p53 in a cell context-dependent manner. We have established highly steroidogenic human granulosa cell lines expressing the Ha-ras oncogene and a temperature sensitive (ts) mutant of p53 (p53val135) to test the involvement of p53-downstream genes in the modulation of apoptosis in these cells. We find that ras-transformed granulosa cells expressing p53val135 undergo apoptosis following a shift from 37 C to 32 C, a temperature at which p53val135 exerts its wild-type activity. Elevating the cellular content of cAMP at 32 C markedly enhances apoptosis. Basic fibroblast growth factor (bFGF) effectively blocks the p53/cAMP-induced apoptosis, but suppresses steroidogenesis. A naturally produced basement membrane-like extracellular matrix (ECM) containing immobilized bFGF exerts a similar antiapoptotic effect, but unlike soluble bFGF, it enhances steroidogenesis in these cells. While cAMP markedly suppresses the p53-induced Mdm2 expression, bFGF and ECM elevate Mdm2 expression 3-5-fold. These effects on Mdm2 expression are most pronounced 2-4 h after the shift to 32 C, before nuclear fragmentation is detected. Cells grown at 32 C in contact with ECM have a more developed actin cytoskeleton both in the absence and presence of cAMP stimulation, compared with cells grown on plastic dishes. We conclude that bFGF and components of the ECM can cross-talk with p53/cAMP-generated signals for apoptosis. These signals may, at least in part, be coordinated by the modulation of Mdm2 expression, which precedes the biochemical events characteristic of apoptosis. The multicomponent ECM also induced differentiation in these ras-transformed cells, while soluble bFGF inhibited differentiation, suggesting that ECM components other than bFGF stimulate differentiation. Organization of the actin cytoskeleton is likely to play an important role in the cross-talk between p53/cAMP- and bFGF/ECM-generated signals. Because the tumor suppressor gene p53 is implicated with apoptosis of primary granulosa cells and the ECM is involved in the prevention of this process, the newly established cell lines can serve as a useful model for apoptosis in highly luteinized granulosa cells.
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PMID:Modulation of Mdm2 expression and p53-induced apoptosis in immortalized human ovarian granulosa cells. 979 81

Adenocarcinoma of the pancreas carries a grave prognosis for affected patients. Certain oncogenes (K-ras and HER-2/neu) are mutated in a large proportion of these aggressive tumors. Adenocarcinoma of the pancreas has also been associated with loss of tumor suppressor genes (p53, DPC4, p16/MTS), either by deletion or by mutation and loss of function. Growth factors (EGF, TGF-alpha, HGF) and growth factor receptors (EGF-R, c-met, CCK) are expressed at levels not found in the normal pancreas. Finally, factors important for angiogenesis (FGF, integrins, selectins) are likely to play an important role in the growth and metastasis of clinically relevant tumors. This review attempts to summarize and assimilate current research into the molecular and cellular biology of pancreatic cancer.
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PMID:The molecular and cellular biology of pancreatic cancer. 980 1

Fibroblast growth factor-2 (FGF-2) is a powerful mitogen and angiogenic factor whose expression is strongly regulated at the translational level. The constitutive upregulation of FGF-2 isoforms in transformed cells prompted us to investigate the post-transcriptional effects of a tumour suppressor, p53, on FGF-2 expression. We show here in human primary skin fibroblasts that the cell density-dependent variation of FGF-2 mRNA translatability was inversely correlated with endogenous p53 expression. Transient cell transfection revealed an inhibitory effect of wild-type p53 on the expression of chimeric FGF--CAT proteins. RNAse mapping experiments ruled out any effect of p53 on FGF--CAT mRNA accumulation, suggesting a translational inhibition. This inhibition was mediated by the FGF-2 mRNA leader, but not by vascular endothelial growth factor or platelet derived growth factor mRNA leaders. Neither p53-like protein p73, nor p21/waf had any inhibitory activity. Furthermore a set of hot spot mutants of p53 bearing mutations in the DNA binding domain had no post-transcriptional inhibitory effect. In contrast a p53 mutant of the transactivating domain was still able to block FGF--CAT expression, indicating that the post-transcriptional activity of p53 described here was independent of the trans-activation of target genes. Such data reveal a novel mechanism by which p53 efficiently blocks the expression of a major proliferating, anti-apoptotic and angiogenic gene.
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PMID:Tumour suppressor p53 inhibits human fibroblast growth factor 2 expression by a post-transcriptional mechanism. 1131 15

Pituitary tumors constitute 10% of intracranial neoplasms and are mostly benign, monoclonal adenomas derived from single mutant cells. Pituitary oncogenes have been intensively studied and three of them, gsp, ccnd1, and PTTG are abundant in significant numbers of cases. gsp is present in approximately 40% of Caucasian patients with GH-secreting tumors and results from a mutated, constitutively active alpha subunit of Gs protein. Persistent activation of the cAMP-PKA-CREB pathway may lead to uncontrolled cell proliferation and GH secretion. ccnd1 is overexpressed cyclin D1, and cyclin D1 gene is amplified in some pituitary tumors. PTTG is expressed in most pituitary tumors. PTTG is localized to both the nucleus and cytoplasm and interacts with several protein partners. At least three tumorigenesis mechanisms are proposed for human PTTG. 1) PTTG and FGF form a positive feedback loop and stimulate tumor vascularity. 2) PTTG transactivates c-myc or other pro-proliferation genes. 3) PTTG overexpression causes aneuploidy. PTTG expression activates p53 and causes p53-dependent and -independent apoptosis. Due to lack of functional human pituitary cell cultures and appropriate animal models for pituitary tumors, many of the results reviewed here are obtained from heterologous systems.
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PMID:Oncogene activation in pituitary tumors. 1141 75


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