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)

Prognostic factors in organ confined prostate cancer will reflect survival after surgical radical prostatectomy. Gleason score, tumour volume, surgical margins and Ki-67 index have the most significant prognosticators. Also the origins from the transitional zone, p53 status in cancer tissue, stage, and aneuploidy have shown prognostic significance. Progression-associated features include Gleason score, stage, and capsular invasion, but PSA is also highly significant. Progression can also be predicted with biological markers (E-cadherin, microvessel density, and aneuploidy) with high level of significance. Other prognostic features of clinical or PSA-associated progression include age, IGF-1, p27, and Ki-67. In patients who were treated with radiotherapy the survival was potentially predictable with age, race and p53, but available research on other markers is limited. The most significant published survival-associated prognosticators of prostate cancer with extension outside prostate are microvessel density and total blood PSA. However, survival can potentially be predicted by other markers like androgen receptor, and Ki-67-positive cell fraction. In advanced prostate cancer nuclear morphometry and Gleason score are the most highly significant progression-associated prognosticators. In conclusion, Gleason score, capsular invasion, blood PSA, stage, and aneuploidy are the best markers of progression in organ confined disease. Other biological markers are less important. In advanced disease Gleason score and nuclear morphometry can be used as predictors of progression. Compound prognostic factors based on combinations of single prognosticators, or on gene expression profiles (tested by DNA arrays) are promising, but clinically relevant data is still lacking.
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PMID:Prognostic factors in prostate cancer. 1675 47

Dysregulation of pleiotropic growth factors, receptors and their downstream signaling pathway components represent a central protumorigenic principle in human hepatocarcinogenesis. Especially the Insulin-like Growth Factor/IGF-1 receptor (IGF/IGF-1R), Hepatocyte Growth Factor (HGF/MET), Wingless (Wnt/beta-catenin/FZD), Transforming Growth Factor alpha/Epidermal Growth Factor receptor (TGFalpha/EGFR) and Transforming Growth Factor beta (TGFbeta/TbetaR) pathways contribute to proliferation, antiapoptosis and invasive behavior of tumor cells. This review focuses on the relevant alterations in these pathways identified in human human hepatocellular carcinomas (HCCs). Resultant functional effects are modulated by multiple cross-talks between the different signaling pathways and additional tumor-relevant factors, such as cyclooxygenase-2 and p53. Several specific strategies are currently under development such as receptor kinase inhibitors, neutralizing antibodies and antagonistic proteins, which may improve the systemic treatment of human HCCs.
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PMID:Dysregulation of growth factor signaling in human hepatocellular carcinoma. 1679 20

Aging is due to a complex interaction of genetic, epigenetic, and environmental factors, but a strong genetic component appears to have an impact on survival to extreme ages. In order to identify "longevity genes" in humans, different strategies are now available. In our laboratory, we performed association studies on a variety of "candidate" polymorphisms in Italian centenarians. Many genes/polymorphisms gave negative results, while others showed a positive association with human longevity and a sometimes-positive association with unsuccessful aging (myocardial infarction, Alzheimer's disease, and type 2 diabetes). Results regarding genes involved in inflammation (IL-1 cluster, IL-6, IL-10, TNF-alpha, TGF-beta, TLR-4, PPARgamma), insulin/IGF-1 signaling pathway and lipid metabolism (apolipoproteins, CETP, PON1), and oxidative stress (p53, p66(shc)) will be described. In addition, a strong role of the interaction between nuclear and mitochondrial genomes (mtDNA haplogroups and the C150T mutation) emerged from our findings. Thus, the genetics of human longevity appears to be quite peculiar in a context where antagonistic pleiotropy can play a major role and genes can have a different biological role at different ages.
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PMID:The genetics of human longevity. 1680 95

Pancreatic ductal adenocarcinomas can display disseminated neuroendocrine (NE) cells. Controversies exist as to their relative incidence, histogenesis, hormone production, and the prognostic implications of their presence. These issues were elucidated by means of a broad immunohistochemical (IHC) investigation of the resected specimens from 47 patients. Chromogranin A (CgA) was chosen as the major NE marker. In addition, the sensitivity of the conventional IHC procedure was increased by means of the TSA (Tyramide Signal Amplification) technique. In tumours with CgA immunoreactive (IR) cells, detected by the conventional or the TSA methods, these NE cells were further IHC analyzed, using antisera raised against a broad spectrum of neurohormonal peptides, serotonin, and IGF-1. The IHC observations were correlated with clinical and histopathological data, the nuclear IR for the Ki67 antigen (proliferation) of the neoplastic cells, and their IR against the p53 protein. Distinct CgA IR cells were found in 5 out of 47 (11%) tumours when studied by the conventional method, and in 9 out of 47 (19%) when examined by the TSA technique. Corresponding figures, if tumours with only questionable IR against CgA were also included, were 14 (30%) and 23 (50%), respectively. Out of the 9 cases with unequivocal CgA IR, only 3 displayed an IR to an additional hormone or growth factor; this hormone turned out to be somatostatin (only minimal foci). Insulin and glucagon cells also appeared exceptionally. The NE differentiation was found to be unrelated to proliferation, p53 protein expression, and to the survival of the patients. It occurred mainly (7 out of 9) in poorly differentiated adenocarcinomas. Thus, the plain NE immunoprofile of the CgA IR cells, together with the increased IR observed when the TSA technique was used, indicates that the NE cells in these adenocarcinomas are only poorly differentiated. When the CgA IR cells exceptionally become highly differentiated, they can express islet hormones. Using strict structural and IHC criteria, a NE differentiation occurs in less than 20 % of cases; its clinico-pathological significance seems to be non relevant.
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PMID:Neuroendocrine cells in pancreatic duct adenocarcinoma: an immunohistochemical study. 1691 33

The insulin-like growth factor (IGF-1) signalling is highly implicated in cancer. In this signalling the IGF-1 receptor (IGF-1R) is unquestionable, the predominating single factor. IGF-1R is crucial for tumour transformation and survival of malignant cell, but is only partially involved in normal cell growth. This is in part due to the interactions with oncogenes. Recent findings suggest a close interplay with the p53/MDM2 pathway. Disturbances in components in the p53/MDM2/IGF-1R network may cause IGF-1R upregulation and growth advantage for the cancer cell. Targeting of IGF-1R is more and more seen as a promising option for future cancer therapy. Single chain antibodies and small molecules with selective effects on IGF-1R dependent malignant growth are of particular interest. Forthcoming clinical trials are welcome and will indeed be the only way to evaluate the impact of IGF-1R targeting in human cancer.
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PMID:Role of insulin-like growth factor 1 receptor signalling in cancer. 1595 62

Migration and proliferation of vascular smooth muscle cells (VSMCs) are important events in the progression of atherosclerosis. Insulin-like growth factor I (IGF-1) possesses both antiapoptotic and mitogenic/motogenic effects in VSMCs although the influence of life cycle on IGF-1-induced effects is unclear. This study was designed to evaluate the effect of IGF-1 on migration, proliferation, and signaling mechanisms in VSMCs from early (3-5) to late (20-22) passages. Migration, proliferation, and cell survival were measured using monolayer wounding, 3[H]-thymidine incorporation and MTT assay, respectively. Akt and ERK, which are critical to proliferation, differentiation and migration, were examined using Western blot analysis. DCF-DA fluorescence was used to quantify Reactive Oxygen Species (ROS) production. Late-passage VSMCs exhibited significantly higher basal cell proliferation and enhanced sensitivity to IGF-1-stimulated migration compared to cells from early-passages. Phosphorylated Akt and ERK levels were significantly higher in late-passage cells compared to early-passage, which was further enhanced by IGF-1 treatment. Late-passage cells exhibited higher levels of ROS production compared to early-passage, cells. IGF-1 did not significantly alter ROS levels in either passage. Expression of the cell cycle regulator p53, p21, and p16 was not affected by repeated passaging of cells. These results indicated that repeated passaging of VSMCs exhibits a phenotype which has higher proliferative capacity. Activation of trophic signaling molecules such as ERK1/2 and Akt and generation of ROS may represent the mechanisms by which repeated passages of VSMCs acquire a motogenic and mitogenic phenotype.
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PMID:Impact of insulin-like growth factor-I on migration, proliferation and Akt-ERK signaling in early and late-passages of vascular smooth muscle cells. 1796 Apr 99

The tumor suppressor p53 is important for inhibiting the development of breast carcinomas. However, little is known about the effects of increased p53 activity on mammary gland development. Therefore, the effect of p53 dosage on mammary gland development was examined by utilizing the p53+/m mouse, a p53 mutant which exhibits increased wild-type p53 activity, increased tumor resistance, a shortened longevity, and a variety of accelerated aging phenotypes. Here we report that p53+/m virgin mice exhibit a defect in mammary gland ductal morphogenesis. Transplants of mammary epithelium into p53+/m recipient mice demonstrate decreased outgrowth of wild-type and p53+/m donor epithelium, suggesting systemic or stromal alterations in the p53+/m mouse. Supporting these data, p53+/m mice display decreased levels of serum IGF-1 and reduced IGF-1 signaling in virgin glands. The induction of pregnancy or treatment of p53+/m mice with estrogen, progesterone, estrogen and progesterone in combination, or IGF-1 stimulates ductal outgrowth, rescuing the p53+/m mammary phenotype. Serial mammary epithelium transplants demonstrate that p53+/m epithelium exhibits decreased transplant capabilities, suggesting early stem cell exhaustion. These data indicate that appropriate levels of p53 activity are important in regulating mammary gland ductal morphogenesis, in part through regulation of the IGF-1 pathway.
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PMID:Altered mammary gland development in the p53+/m mouse, a model of accelerated aging. 1799 64

In the present study, we reported two cases of renal cell carcinoma (RCC) diagnosed in pregnant women (Pt) that were submitted to radical nephrectomy, in both cases within the fourth month. The patients, after 13 and 3 years, respectively, did not show evidence of recurrent disease. We performed an immunohistochemical study on RCC specimens in comparison to seven age-matched controls (Cl). The panel of antibodies included Ki-67, p53, bcl-2, ER, PgR, PCNA, and IGF-1. We describe a difference in the expression of p53 and Ki-67. Specifically, p53 was highly expressed in RCC of both Pt but scarcely present or absent in Cl; by contrast, Ki-67 was hardly expressed or negative in RCC of both Pt, being commonly positive in Cl. These results may correlate with a good outcome of the disease in Pt. Although the limited number of cases did not permit any statistical evaluation, we postulate that these differences have not to be underestimated since they may disclose a correlation between pregnancy and biological behavior of tumoral disease. Further study may (dis)prove this hypothesis.
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PMID:p53 and Ki-67 expression in renal cell carcinomas of pregnant women and their correlation with prognosis: a pilot study. 1807 50

Abstract Internal mammary artery (IMA) coronary artery bypass grafts (CABG) are remarkably resistant to intimal hyperplasia (IH) as compared to saphenous vein (SV) grafts following aorto-coronary anastomosis. The reason behind this puzzling difference still remains an enigma. In this study, we examined the effects of IGF-1 stimulation on the PI3K-AKT/PKB pathway mediating proliferation of smooth muscle cells (SMCs) of IMA and SV origin and the specific contribution of phosphatase and tensin homologue (PTEN) in regulating the IGF-1-PI3K-AKT/PKB axis under these conditions. Mitogenic activation with IGF-1, time-dependently stimulated the phosphorylation of PI3K and AKT/PKB in the SV SMCs to a much greater extent than the IMA. Conversely, PTEN was found to be significantly more active in IMA SMCs. Transient overexpression of PTEN in SMCs of SV and IMA inhibited AKT/PKB activity and upstream of AKT/PKB, caused a reduction of IGF-1 receptors. Downstream, PTEN overexpression in SV SMCs induced the transactivation of tumour suppressor protein p53 by down-regulating the expression of its inhibitor MDM2. However, PTEN overexpression had no significant effect on MDM2 and p53 expression in IMA SMCs. PTEN overexpression inhibited IGF-1-induced SMC proliferation in both SV and IMA. PTEN suppression, induced by siRNA transfection of IMA SMCs diminished the negative regulation of PI3K-PKB signalling leading to greater proliferative response induced by IGF-1 stimulation. Thus, we show for the first time that early inactivation of PTEN in SV SMCs leads to temporally increased activity of the pro-hyperplasia PI3K-AKT/PKB pathway leading to IH-induced vein graft occlusion. Therefore, modulation of the PI3K-AKT/PKB pathway via PTEN might be a novel and effective strategy in combating SV graft failure following CABG.
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PMID:Temporal PTEN inactivation causes proliferation of saphenous vein smooth muscle cells of human CABG conduits. 1836 44

In order to establish causal or protective treatments for Parkinson's disease (PD), it is necessary to identify the cascade of deleterious events that lead to the dysfunction and death of dopaminergic neurons. Paraquat (PQ) is a pesticide used as xenobiotic compound to model PD. However, the mechanism(s) of PQ-induced cell death and the mechanism(s) of cytoprotection in a single cell model are still unknown. In this study, lymphocytes were treated with (0.1-1 mM) PQ. Apoptotic morphology was assessed with acridine orange/ethidium bromide staining. Further evaluation included (i) superoxide radicals, reflected by nitroblue tetrazolium reduction to formazan, (ii) the production of hydrogen peroxide, reflected by rhodamine-positive fluorescent cells, (iii) the generation of hydroxyl radicals, reflected by dimethylsulfoxide and melatonin ( radical)OH scavengers, (iv) activation and/or translocation of NF-kappaB, p53 and c-Jun transcription factors showed by immunocytochemical staining, and by ammonium pyrrolidinedithiocarbamate, pifithrin-alpha and SP600125 inhibition and (V) caspase-3 activation, reflected by caspase Ac-DEVD-cho inhibition. To elucidate the mechanism of cytoprotection, lymphocytes were treated with PQ in the presence of cannabinoids, insulin-like growth factor-1 and glucose. We provide evidence that PQ induces apoptosis in lymphocytes in a concentration- and time-dependent fashion by an oxidative stress mechanism involving O(2)( radical - ), H(2)O(2)/(( radical)OH) generation, simultaneous activation of NF-kappaB/p53/c-Jun transcription factors, mitochondrial depolarization and caspase-3 activation leading to morphological apoptosis. Moreover, dying lymphocytes are protected and rescued from PQ noxious stimuli by direct antioxidant effect by cannabinoids, receptor mediated signaling by IGF-1, and/or energetic protection by glucose. It is concluded that PQ-induced apoptosis in lymphocytes by a mechanism involving reactive oxygen species generation, mitochondrial dysfunction, transcriptional factors and caspase-3 activation. However, this cell death routine can be reversed by the action of cannabinoids, IGF-1 and glucose. These data may provide innovating therapeutic strategies to intervene environmentally or genetically susceptible PD population to oxidative stress.
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PMID:Paraquat induces apoptosis in human lymphocytes: protective and rescue effects of glucose, cannabinoids and insulin-like growth factor-1. 1836 79


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