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)

The early growth response-1 (EGR-1) protein is an anti-proliferative signal for certain tumor cells and is required for apoptosis induced by stimuli that elevate intracellular Ca2+. We present evidence that EGR-1 transactivates the promoter of the p53 gene and up-regulates p53 RNA and protein levels. Inhibition of p53 function with dominant-negative p53 mutants abrogates EGR-1-dependent apoptosis. These findings establish a direct functional link between EGR-1 and the p53-mediated cell death pathway and suggest that mutant forms of p53 in tumor cells may provide resistance to the anti-proliferative effects of EGR-1.
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PMID:Early growth response-1-dependent apoptosis is mediated by p53. 924 87

The p21(CIP1/WAF1) protein is considered a downstream effector of tumor suppression by p53. We have previously demonstrated that p53 null keratinocytes have lower basal p21(CIP1/WAF1) mRNA levels and that tumors derived from these cells following transduction with the v-ras(Ha) oncogene grow faster than wildtype keratinocytes and rapidly progress to undifferentiated carcinomas (Cancer Res 54: 5584-5592, 1994). In this study, primary keratinocytes differing in p21(CIP1/WAF1) gene dose were transduced with v-ras(Ha) encoding retrovirus and grafted to nude mouse hosts to test whether the p53 null phenotype is mediated through p21(CIP1/WAF1). Resulting tumors from all genotypes were well differentiated papillomas; focal carcinomas were observed in 43, 30 and 44% of papillomas derived from +/+, +/- and -/- keratinocytes, respectively. p21(CIP1/WAF1) deficient keratinocytes expressing v-ras(Ha) do not display the degree of increased growth observed in p53 deficient tumors in vivo or the decreased responsiveness to negative growth regulation by Ca2+ in vitro. These results suggest that p21(CIP1/WAF1) does not regulate the differentiated phenotype or malignant progression of v-ras(Ha) initiated keratinocytes and that additional functions of the p53 protein other than transcriptional regulation of the p21(CIP1/WAF1) gene are required for p53 mediated tumor suppression.
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PMID:Loss of p21CIP1/WAF1 does not recapitulate accelerated malignant conversion caused by p53 loss in experimental skin carcinogenesis. 926 9

Here we report that we could obtain a highly differentiated smooth muscle cell line by screening the expression of a-smooth muscle actin from p53 knook out mice aorta. This cell revealed extended bipolar shape and expressed h-caldesmon and calponin as well as a-smooth muscle actin as protein markers of differentiated smooth muscle. Further intracellular calcium increase was induced by application of noradrenaline in a dose dependent manner and calcium oscillation was also observed in a higher dose (100 microM). Appropriate application of 5-azacytidine enhanced these tendencies and induced slow contraction by endothelin-1 and phenylephrine.
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PMID:A novel aortic smooth muscle cell line obtained from p53 knock out mice expresses several differentiation characteristics. 929 70

Peroxynitrite (0.5-50 microM) induced dose-dependent cytotoxic effects in rat pancreatic acinar AR4-2J cells. Glutathione (2 mM) and ebselen (10 microM) partially reduced the cytotoxicity caused by 1-10 microM concentrations of peroxynitrite. Higher concentrations (10-50 microM) of peroxynitrite induced DNA smear suggestive of necrosis, while lower concentrations (2-5 microM) induced DNA fragmentations suggestive of apoptosis. The effects of peroxynitrite on [Ca2+]i showed a similar dose dependency. Peroxynitrite concentrations > 10 microM rapidly increased [Ca2+]i in a dose-dependent manner, while concentrations < 5 microM did not affect [Ca2+]i. In contrast, the presentation of wild-type P53 was accelerated at lower concentrations of peroxynitrite (< or = 10 microM) but not at higher concentrations (50 microM). The present study suggests that peroxynitrite at lower concentrations (2-5 microM) induces wildtype P53 and apoptosis, which is potentially a protective response toward the DNA damage caused by peroxynitrite. On the other hand, higher concentrations of peroxynitrite (10-50 microM) rapidly increase [Ca2+]i and eventually induce necrosis.
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PMID:Cytotoxicity of peroxynitrite in rat pancreatic acinar AR4-2J cells. 933 92

The aim of this study was to determine the mechanisms responsible for the growth inhibitory effect of hyperthermia and verapamil in human colon cancer cell line HT-29. Apoptotic cell death was verified by flow cytometry analysis. The effect of treatment with hyperthermia and verapamil on the expression of apoptosis-associated proteins including Bcl-2, p53, bax, and c-Myc was studied by Western blot analysis. Changes in intracellular calcium homeostasis was analysed by fluorescence microscopy. The combination of 42 degrees C hyperthermia and verapamil caused a significant delay of human colon cancer cell proliferation as a result of apoptosis. Administration of these agents alone did not cause any cell inhibitory effect. Our experiments have shown that HT-29 cells constitutively express apoptosis-promoting proteins, such as Bax and c-Myc, while they fail to produce Bcl-2. Therefore, we hypothesize that HT-29 cells must have Bcl-2 independent pathways to protect cells against death-inducing signals. Also, apoptosis of HT-29 cells produced by hyperthermia in the presence of verapamil is a p53-independent process. Verapamil, when it did not act as a calcium channel blocker or inhibitor of release from intracellular storages under hyperthermic conditions, accelerated the increase of [Ca2+]i in HT-29 cells which resulted in programmed cell death (apoptosis).
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PMID:Apoptosis induced by hyperthermia and verapamil in vitro in a human colon cancer cell line. 935 39

We have recently shown that human papillomavirus (HPV16) E6 oncoprotein exhibits two separate biological activities in genital keratinocytes (PHKs). E6 protein by itself is capable of inducing colonies of proliferating cells resistant to serum and calcium-induced differentiation, whereas both E6 and E7 are required for immortalization of PHK. Using epitope-tagged E6 carboxy-terminal truncation mutants, we mapped the domain between amino acid residues 132 and 141 as being essential for the induction of differentiation resistance (L. Sherman and R. Schlegel, J. Virol. 70, 3269-3279, 1996). To determine whether E6 protein's ability to alter PHK response to serum and calcium was associated with its ability to inactivate p53, we evaluated each of the above E6 mutants and three E6 natural variants in these respective assays. Our results demonstrate that the E6 region spanning residues 132-141 is required for p53 degradation and for abrogation of p53 transactivation, suggesting a possible correlation between E6 biological activity in altering differentiation and loss of p53 function. To evaluate whether selective inactivation of p53 is sufficient for altering the response of PHK to serum and calcium we investigated the capacity of plasmids encoding a dominant mutant human p53 and human MDM-2 to functionally substitute for E6 in colony formation in PHK. Plasmids were verified for their ability to inactivate wild-type p53 by testing their capacity to abrogate the p53 transactivation function. The results obtained showed that vectors encoding human MDM-2 and mutant p53, while active in inhibition of p53-dependent transactivation and capable of expressing stable proteins in PHK, failed to induce colonies of proliferating cells resistant to serum and calcium differentiation. These data argue that p53 inactivation may not be the sole E6 function required for altering the response of PHK to serum- and calcium-triggered differentiation.
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PMID:Inhibition of serum- and calcium-induced differentiation of human keratinocytes by HPV16 E6 oncoprotein: role of p53 inactivation. 935 41

Apoptosis is well described in invertebrates and recently documented in mammals. The prevalence and pathophysiology of mammalian apoptosis is unknown and may have clinical ramifications. The aim of this study is to investigate the apoptotic response during kidney ischemia-reperfusion (I/R) injury. Kidney I/R was initiated in anesthetized rats by occlusion of the renal pedicle for 45 min with or without pretreatment with .2 mg/kg verapamil: control animals received sham exposure. Flow was re-established after ischemia and the animals were allowed to recover for 24 h. Bilateral kidneys were harvested for DNA electrophoresis, Western analysis for p53, Northern analysis for c-myc expression, and light and electron microscopic analysis. Kidney I/R caused characteristic DNA laddering in the clamped kidney, and less extensive laddering was seen in the contralateral kidney. Light and electron microscopic analysis confirmed apoptotic morphology in the reperfused tissues. Verapamil pretreatment completely abolished DNA laddering and attenuated the microscopic evidence of apoptosis. p53 levels were increased by I/R in the ischemic kidney and moderately increased in the contralateral organ. c-myc mRNA levels were increased by the I/R insult. Kidney I/R injury may induce global apoptosis, which seems to be associated with an alteration in calcium homeostasis. The increase in p53 and c-myc mRNA levels seen with I/R may facilitate apoptosis. Calcium modulation seems to reduce apoptosis during I/R and may have therapeutic implications.
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PMID:Calcium blockade reduces renal apoptosis during ischemia reperfusion. 937 65

This study evaluated the action of menadione on cell proliferation and integrity of the rat pancreatic acinar cell line, AR4-2J. Menadione at 1-20 microM dose- and time-dependently inhibited cell proliferation of AR4-2J cells. In contrast, a high concentration of menadione (100 microM) caused rapid cell death (> 90% of cells took up trypan blue within 4-h). While the high concentration of menadione (100 microM) induced DNA smear in electrophoresis indicative of necrosis, lower concentrations (10-20 microM) induced a DNA ladder indicative of apoptosis. Similar results were obtained using a DNA fragmentation ELISA. Glutathione (1 mM), the calcium chelator EGTA (500 microM), and the cysteine protease inhibitor NCO-700 (5 mM) partly inhibited the effect of 1-10 microM menadione on cell proliferation and DNA fragmentation. Menadione at 1-20 microM induced wild-type P53, whereas the 100 microM menadione had a minor effect on wild-type P53. It is concluded that menadione induced necrosis at high concentrations and apoptosis at low concentrations in AR4-2J cells. Apoptosis induced by lower concentrations of menadione may be mediated by wild-type P53, intracellular calcium, and mechanisms which decrease the intracellular concentration of reduced glutathione.
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PMID:Menadione induces both necrosis and apoptosis in rat pancreatic acinar AR4-2J cells. 937 63

Studies of programmed cell death in the developing retina in vitro are currently reviewed. The results of inhibiting protein synthesis in retinal explants indicate two mechanisms of apoptosis. One mechanism depends on the synthesis of positive modulators ('killer proteins'), while a distinct, latent mechanism appears to be continuously blocked by negative modulators. Extracellular modulators of apoptosis include the neurotrophic factors NT-4 and BDNF, while glutamate may have either a positive or a negative modulatory action on apoptosis. Several protein kinases selectively modulate apoptosis in distinct retinal layers. Calcium and nitric oxide were also shown to affect apoptosis in the developing retinal tissue. The protein c-Jun was found associated with apoptosis in various circumstances, while p53 seems to be selectively expressed in some instances of apoptosis. The results indicate that the sensitivity of each retinal cell to apoptosis is controlled by multiple, interactive, cell type- and context-specific mechanisms. Apoptosis in the retina depends on a critical interplay of extracellular signals delivered through neurotrophic factors, neurotransmitters and neuromodulators, several signal transduction pathways, and the expression of a variety of genes.
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PMID:Death in a dish: controls of apoptosis within the developing retinal tissue. 939 92

Many signals and external stimuli regulate the apoptosis activity by interaction with the genome. These stimuli include morphogenetic signals, physiological factors, and environmental influence. The signals mediate their effect on cells with suitable receptors, relevant signalling pathways, and competence to execute the apoptosis cascade. Apoptosis is triggered indirectly by deprivation of survival factors, or directly by intercellular cell death signalling factors, and also by unbalanced intracellular messenger molecules, which are, more or less, involved in regulation of both programmed cell death and survival. Several genes are involved in regulation of cell survival and apoptosis: bcl-2/bax, p53, c-myc and transcription factors such as cdk, c-myc, c-fos and c-jun. Apparently, apoptosis could be triggered by increased or inhibited gene expression as well as biochemical reactions without changed gene expression. The morphological changes during apoptosis reflect a cascade of genetic and biochemical reactions in the cell. In the signal transduction pathway both secondary messenger Ca2+, different kinases, and polyamines are involved. Cysteine proteases cleave cytoskeletal proteins, endonucleases divide DNA into fragments, and transglutaminases cross-link macromolecules. Degradative enzymes such as proteases, endonucleases and transglutaminases are activated during apoptosis, leading to cellular collapse and formation of vesicular apoptotic bodies. Both increased and inhibited apoptosis activity may have pathological consequences. New therapeutic strategies aim to counteract dysregulation of apoptosis in specific tissues by pharmacological intervention. Thus there is a need for identification of molecules and gene products involved in regulation of apoptosis activity and clarification of the conditions where this knowledge may be used.
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PMID:[Apoptosis: molecular aspects]. 941 94


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