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)

Drug-induced disturbances in reproductive hormones and gonadal morphology have been observed both in patients with epilepsy and in non-epileptic animals. Less is known about the influence of newer antiepileptic drugs including lamotrigine on reproduction. Lamotrigine is now increasingly used both in epilepsy and psychiatric disorders. Sixty-five Wistar rats were fed by gastric tube either 5 mg kg(-1) lamotrigine solution (males=15, females=20) or 0 (vehicle control, males=15, females=15) twice daily for 90 days. In males, no significant differences were found in body or testicular weight. Testicular atrophy was observed in one control animal and in two of the rats receiving lamotrigine. No morphological changes were seen in the other organs investigated (liver, kidney, pancreas, brain, lymphatic tissue, heart). None of the animals showed over-expression of p53. No significant differences were observed between the control rats and the male rats receiving lamotrigine regarding testosterone, FSH and LH. In females, no changes in ovarian morphology or alterations in other tissues were observed. Serum testosterone, FSH, LH, insulin and progesterone remained unchanged in the lamotrigine treated animals, while serum estrogen was significantly reduced.
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PMID:Gonadal morphology and sex hormones in male and female Wistar rats after long-term lamotrigine treatment. 1463 May 7

The signaling pathway of insulin/insulin-like growth factor-1/phosphatidylinositol-3 kinase/Akt is known to regulate longevity as well as resistance to oxidative stress in the nematode Caenorhabditis elegans. This regulatory process involves the activity of DAF-16, a forkhead transcription factor. Although reduction-of-function mutations in components of this pathway have been shown to extend the lifespan in organisms ranging from yeast to mice, activation of Akt has been reported to promote proliferation and survival of mammalian cells. Here we show that Akt activity increases along with cellular senescence and that inhibition of Akt extends the lifespan of primary cultured human endothelial cells. Constitutive activation of Akt promotes senescence-like arrest of cell growth via a p53/p21-dependent pathway, and inhibition of forkhead transcription factor FOXO3a by Akt is essential for this growth arrest to occur. FOXO3a influences p53 activity by regulating the level of reactive oxygen species. These findings reveal a novel role of Akt in regulating the cellular lifespan and suggest that the mechanism of longevity is conserved in primary cultured human cells and that Akt-induced senescence may be involved in vascular pathophysiology.
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PMID:Akt negatively regulates the in vitro lifespan of human endothelial cells via a p53/p21-dependent pathway. 1471 53

In vertebrates insulin-like growth factors (IGFs) regulate important cellular activities involving proliferation, differentiation, and antiapoptosis and their biological activities are mediated through the insulin-like growth factor-I receptor (IGF-IR). To understand the functions of IGF-IR in zebrafish embryogenesis, the polymerase chain reaction (PCR) cloning technique was applied to isolate the IGF-IR gene. A 5'-truncated 3285-nucleotide zebrafish IGF-IR sequence was assembled from 3 overlapping clones. This contained a partial coding region of 1550 nucleotides and a 1735-nucleotide 3' untranslated region. The deduced 515 amino acid residues included the conserved kinase domain and shared 60.9%, 61.1%, and 59.9% homology to human, mouse, and frog, respectively. To understand the relationship of IGF-IR with p53 suppressor gene during embryogenesis, expression of both genes was analyzed in parallel by semicompetitive reverse transcriptase PCR and whole-mount in situ hybridization. This analysis indicated that messenger RNA of both genes was of maternal origin, but the p53 suppressor mRNA was relatively more abundant than the IGF-IR message in most of the developmental stages, except possibly at 28 hours postfertilization. At this stage the IGF-I receptor message was highly expressed and visible in whole internal organ regions by whole-mount in situ hybridization, while p53 message was concentrated in the head portion and barely detectable in the trunk portion. The results suggest that IGF-IR and p53 mRNA are expressed at different places and different times. However, the temporal and spatial relationship of IGF-IR and its relationship to p53 suppressor protein during developmental processes remain unknown.
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PMID:Gene expression of insulin-like growth factor-I receptor and p53 suppressor during zebrafish (Danio rerio) embryogenesis. 1496 Dec 57

Reduction-of-function mutations in components of the insulin/insulin-like growth factor-1/Akt pathway have been shown to extend the lifespan in organisms ranging from yeast to mice. It has also been reported that activation of Akt induces proliferation and survival of mammalian cells, thereby promoting tumorigenesis. We have recently shown that Akt activity increases with cellular senescence and that inhibition of Akt extends the lifespan of primary cultured human endothelial cells. Constitutive activation of Akt promotes senescence-like arrest of cell growth via a p53/p21-dependent pathway, leading to endothelial dysfunction. This novel role of Akt in regulating the cellular lifespan may contribute to various human diseases including atherosclerosis and diabetes mellitus.
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PMID:Akt-induced cellular senescence: implication for human disease. 1500 30

Insulin regulates metabolism through homologous receptor tyrosine kinases, and plays a role in proliferation of breast cancer cells. Our research studied whether insulin, administered separately or in combination with paclitaxel, interferes with paclitaxel-mediated biological activity in human breast cancer cells. Not only did insulin influence paclitaxel-mediated cell microtubule reorganization, but it also influenced MCF-7 cell sensitivity to paclitaxel. Furthermore, combined administrations of insulin and paclitaxel affected MAPK pathway, Raf-1 activation and p53 expression levels. Our findings indicate that insulin seems to modulate MCF-7 cell response to paclitaxel; consequently, elevated levels of insulin could influence tumor cell resistance.
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PMID:Insulin can modulate MCF-7 cell response to paclitaxel. 1515 15

Tuberous sclerosis complex (TSC) is a genetic disorder caused by mutations in either TSC1 or TSC2 tumor suppressor gene. TSC1 and TSC2 products, Harmatin and Tuberin, form the functional complex to serve as the negative regulator for insulin-induced phosphorylation of S6 kinase and elF4E-binding protein 1. High-risk human papillomavirus (HPV) infection is the necessary cause for cervical cancer. E6 oncoprotein encoded by HPV plays a pivotal role in carcinogenesis by interference with the host intracellular protein functions. In this study, we show that HPV16 E6 interacts with tumor suppressor gene TSC2 product, Tuberin, and results in the phosphorylation of S6 kinase and S6 even in the absence of insulin. The overexpression of Tuberin overcomes the effect of E6 on S6 kinase phosphorylation. Binding with HPV16 E6 causes the proteasome-mediated degradation of Tuberin. A DILG motif and an ELVG motif located in the carboxyl-terminal of Tuberin are required for E6 binding. In addition, the Tuberin interaction region in E6 has been mapped in the amino-terminal portion of HPV16 E6, which is different from the binding domain with p53. These results provide a possible link between E6-induced oncogenesis and the insulin-stimulated cell proliferation signaling pathway.
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PMID:Human papillomavirus 16 E6 oncoprotein interferences with insulin signaling pathway by binding to tuberin. 1517 23

Alzheimer-associated neuronal thread protein, AD7c-NTP, accumulates in cortical neurons and co-localizes with phospho-tau-containing cytoskeletal lesions in brains with AD. Over-expression of AD7c-NTP results in increased neuronal death mediated by apoptosis and mitochondrial dysfunction. Empirical studies demonstrating differential growth factor responses to AD7c-NTP led to us to further investigate the effects of insulin, insulin-like growth factor, type 1 (IGF-1), nerve growth factor (NGF), and platelet-derived growth factor (PDGF) stimulation on neuronal survival mechanisms in relation to AD7c-NTP expression. PNET2 human CNS-derived neuronal cells were stably transfected with a cDNA encoding AD7c-NTP or chloramphenicol acetyl transferase (CAT) whereby gene expression was regulated by an inducible promoter. In cells that expressed AD7c-NTP, insulin or IGF-1 stimulation was associated with reduced viability with increased levels of p53, p21/Waf-1, phospho-JNK, and phospho-tau, and reduced levels of Bcl-2 and phospho-Erk MAPK. In contrast, AD7c-NTP-transfected cells stimulated with NGF or PDGF, and CAT-transfected cells stimulated with any one of the four growth factors remained viable and had low levels of p53, p21/Waf-1, phospho-JNK, and phospho-tau, and abundant Bcl-2 and phospho-Erk expression. The results suggest that reduced survival in neurons that over-express AD7c-NTP may be mediated by impaired insulin/IGF-1 signaling, and that CNS neurons with abundant insulin or IGF-1 receptors may be particularly vulnerable to the adverse effects of AD7c-NTP.
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PMID:Alzheimer-associated neuronal thread protein mediated cell death is linked to impaired insulin signaling. 1520 78

Diabetes mellitus is one of the most common chronic diseases affecting millions of people worldwide. Cardiovascular complication including myocardial infarction is one of the major causes of death in diabetic patients. Diabetes mellitus induces abnormal pathological findings including cell hypertrophy, neuropathy, interstitial fibrosis, myocytolysis and apoptosis and lipid deposits in the heart. In addition, the cytoplasmic organelles of cardiomyocytes including the plasma membrane, mitochondrion and sarcoplasmic reticulum are also impaired in both type I and type II diabetes. Hyperglycaemia is a major aetiological factor in the development of diabetic cardiomyopathy in patients suffering from diabetes. Hyperglycaemia promotes the production of reactive oxygen (ROS) and nitrogen species (RNS). The release of ROS and RNS induces oxidative stress leading to abnormal gene expression, faulty signal transduction and apoptosis of cardiomyocytes. Hyperglycaemia also induces apoptosis by p53 and the activation of the cytochrome c-activated caspase-3 pathway. Stimulation of connective tissue growth factor and the formation of advanced glycation end products in extracellular matrix proteins induces collagen cross-linking and contribute to the fibrosis observed in the interstitium of the heart of diabetic subjects. In terms of signal transduction, defects in intracellular Ca2+ signalling due to alteration of expression and function of proteins that regulate intracellular Ca2+ also occur in diabetes. All of these abnormalities result in gross dysfunction of the heart. Beta-adrenoreceptor antagonists, ACE inhibitors, endothelin-receptor antagonist (Bonestan), adrenomedullin, hormones (insulin, IGF-1) and antioxidants (magniferin, metallothionein, vitamins C and E) reduce interstitial fibrosis and improve cardiac function in diabetic cardiomyopathy.
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PMID:Molecular and cellular basis of the aetiology and management of diabetic cardiomyopathy: a short review. 1536 3

Pten is an important phosphatase, suppressing the phosphatidylinositol-3 kinase/Akt pathway. Here, we generated adipose-specific Pten-deficient (AdipoPten-KO) mice, using newly generated Acdc promoter-driven Cre transgenic mice. AdipoPten-KO mice showed lower body and adipose tissue weights despite hyperphagia and enhanced insulin sensitivity with induced phosphorylation of Akt in adipose tissue. AdipoPten-KO mice also showed marked hyperthermia and increased energy expenditure with induced mitochondriagenesis in adipose tissue, associated with marked reduction of p53, inactivation of Rb, phosphorylation of cyclic AMP response element binding protein (CREB) and increased expression of Ppargc1a, the gene that encodes peroxisome proliferative activated receptor gamma coactivator 1 alpha. Physiologically, adipose Pten mRNA decreased with exposure to cold and increased with obesity, which were linked to the mRNA alterations of mitochondriagenesis. Our results suggest that altered expression of adipose Pten could regulate insulin sensitivity and energy expenditure. Suppression of adipose Pten may become a beneficial strategy to treat type 2 diabetes and obesity.
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PMID:Enhanced insulin sensitivity, energy expenditure and thermogenesis in adipose-specific Pten suppression in mice. 1593 75

Radiotherapy plays an important role in the management of breast cancer. Whilst its role in achieving local control following surgery in patients with early stage cancer is well established, there is still unclear evidence to explain the factors governing radioresistance in patients who develop recurrences both in the breast and axilla. Radiotherapy induces damage to the DNA. Various cell cycle damage check points and DNA damage repair pathways have been demonstrated. Ataxia telangiectasia mutant (ATM) kinase, which is a member of phosphatidylinositol-3 kinase (PI-3K) family appears to play a central role in DNA damage check point pathways. Over-expression of Insulin like growth factor-I receptor (IGF-IR), Human Epidermal Growth factor receptors (HERS), Vascular Endothelial growth factor (VEGF) on the cell surface and increased concentration of Epidermal Growth factor in the extracellular fluid have been associated with radioresistance. Specific genes such as p53, BRCA, Bcl-2 and chromosomal characteristics like telomere lengths have also been identified as playing significant roles in radiation responsiveness of a cell. This article reviews the current data on general principles of radiotherapy, the cellular mechanisms that operate in response to radiation damage and various molecular markers, intranuclear and extranuclear which have been demonstrated to influence radiation sensitivity in breast cancer cells.
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PMID:Radioresistance in carcinoma of the breast. 1556 51


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