Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fas is expressed in various cells and transduces the cell death signal. p21 is a mediator of p53-dependent G1 arrest associated with deoxyribonucleic acid (DNA) damage. The upregulation of p53 and p21 associated with DNA damage in idiopathic pulmonary fibrosis has been described previously. In this study, p53, p21, and Fas expression and DNA damage were examined in interstitial pneumonia associated with collagen vascular diseases (CVD-IP). DNA damage was assessed by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate biotin nick end-labelling (TUNEL) and p53, p21 and Fas proteins were detected by immunohistochemistry in 13 cases of CVD-IP, 13 of sarcoidosis, seven of hypersensitivity pneumonitis (HP) and eight control patients with normal lung parenchyma. TUNEL-positive signals were found in bronchiolar or alveolar epithelial cells in 11 of 13 (85%) specimens of CVD-IP, but not in sarcoidosis, HP or controls, except for a case of chronic HP with pulmonary fibrosis. p53, p21 and Fas were detected in bronchiolar or alveolar epithelial cells in nine (69%), 10 (77%) and 12 (92%) of 13 specimens of CVD-IP, respectively, but not in sarcoidosis, HP or controls, except for a case of chronic HP. These results suggest that the upregulation of p53, p21 and Fas in bronchiolar and alveolar epithelial cells associated with deoxyribonucleic acid damage may participate in the process of pulmonary fibrosis in interstitial pneumonia associated with collagen vascular diseases and chronic hypersensitivity pneumonitis.
 ...
PMID:Expression of p53, p21 (Waf1/Cip1/Sdi1) and Fas antigen in collagen vascular and granulomatous lung diseases. 981 69

Cellular and molecular events contributing to tubulointerstitial fibrosis of the kidney during obstructive nephropathy are driven in large part through increased angiotensin II levels in the obstructed kidney. Angiotensin converting enzyme inhibition or AT1 receptor antagonism have been shown to ameliorate the fibrosis of the kidney due to obstruction of the ureter. In this investigation, we determine the effects of the AT2 receptor antagonist PD-123319 on pathophysiological events within the kidneys of rats with unilateral ureteral obstruction. Treatment with PD-123319 was found to exacerbate the increase in interstitial volume and collagen IV matrix score of the ureteral obstructed kidney. Monocyte/macrophage infiltration of the injured kidney was no different between treated and untreated animals. The AT2 receptor antagonist did, however, inhibit apoptosis of tubular cells, alpha-smooth muscle actin expression within the interstitium, and p53 expression in the ureteral obstructed kidney. These results suggest that angiotensin II operating through the AT2 receptor exerts an antifibrotic effect on the kidney during obstructive nephropathy in opposition to the profibrotic effects of angiotensin II operating through the AT1 receptor.
 ...
PMID:Effect of AT2 receptor blockade on the pathogenesis of renal fibrosis. 988 78

The binding of collagen to platelet glycoprotein VI (GPVI) leads to the subsequent activation of phospholipase Cgamma2 through a pathway that is dependent on the Fc receptor gamma (FcR gamma) chain and the tyrosine kinase p72syk. We have investigated the role of platelet Src-family kinases in this signalling pathway. The selective Src-family kinase inhibitor PP1 prevented collagen-stimulated increases in whole-cell tyrosine phosphorylation and tyrosine phosphorylation of the FcR gamma chain and p72syk. A similar set of observations was made for a collagen-related peptide (CRP), which binds to GPVI but not to the integrin alpha2beta1 (GPIa/IIa). These effects were seen at a concentration of PP1 that inhibited platelet aggregation, dense granule release and Ca2+ mobilization induced by CRP, but not aggregation and Ca2+ mobilization mediated by the G-protein-coupled receptor agonist thrombin. After stimulation by CRP or collagen, the Src-family kinases p59fyn and p53/56lyn became associated with several tyrosine-phosphorylated proteins including the FcR gamma chain. This was not true of the other platelet Src-family kinases. The association between the FcR gamma chain and p59fyn was also seen under basal conditions, and was stable only in the weak detergent Brij96 but not in Nonidet P40, suggesting a non-SH2-dependent interaction. These results provide strong evidence for the involvement of p59fyn and p53/56lyn in signalling via GPVI, with p59fyn possibly acting upstream of FcR gamma chain phosphorylation.
 ...
PMID:Evidence for the involvement of p59fyn and p53/56lyn in collagen receptor signalling in human platelets. 993 17

CD44 has diverse functions in cell-cell and cell-matrix interactions and may be a determinant of metastatic and invasive behaviour in carcinomas. The immunohistochemical expression of CD44 in a series of 110 colorectal carcinomas and 25 adenomas was examined using the monoclonal mouse anti-human phagocytic glycoprotein-1, CD44 (clone DF 1485) in correlation with the expression of basement membrane (BM) antigens (type IV collagen, laminin), fibronectin, cathepsin D, p53, Rb, bcl-2, c-erbB-2, EGFR, proliferation indices (Ki-67, PCNA) and with other conventional clinicopathological variables. In adenomas, low CD44 expression (<10% of neoplastic cells) was present in 16%, moderate (10-50% of neoplastic cells) in 52% and extensive (>50% of neoplastic cells) in 32% of cases. In carcinomas, low CD44 expression was found in 14.5%, moderate in 28.2% and extensive in 57.30%. Although the CD44 expression was higher in carcinomas than in adenomas, we found no statistically significant difference between these two groups. CD44 expression in carcinomas was positively correlated with tumour size (P=0.018), tumour cells cathepsin D (P=0.022), stromal cell cathepsin D (P=0.003) and Rb protein (P=0.021). An inverse correlation was observed between CD44 and the anti-apoptotic protein expression bcl-2 in adenocarcinomas (P=0.039) and in adenomas (P=0.021). These data suggest that CD44 may be involved in the process of invasion and metastasis, probably with the cooperation of cathepsin D. Its expression may be an indicator of poor prognosis in colorectal adenocarcinomas.
 ...
PMID:Glycoprotein CD44 expression in colorectal neoplasms. An immuno-histochemical study including correlation with cathepsin D, extracellular matrix components, p53, Rb, bcl-2, c-erbB-2, EGFR and proliferation indices. 1007 Dec 34

Recent studies show that the p53 tumor suppressor protein is overexpressed in rheumatoid arthritis (RA) synovium and that somatic mutations previously identified in human tumors are present in RA synovium (Firestein, G. S., Echeverri, F., Yeo, M., Zvaifler, N. J., and Green, D. R. (1997) Proc. Natl. Acad. Sci. U. S. A. 94, 10895-10900; Firestein, G. S., Nguyen, K., Aupperle, K. R., Yeo, M., Boyle, D. L., and Zvaifler, N. J. (1996) Am. J. Pathol. 149, 2143-2151; Reme, T., Travaglio, A., Gueydon, E., Adla, L., Jorgensen, C., and Sany, J. (1998) Clin. Exp. Immunol. 111, 353-3581). We hypothesize that the abnormality of p53 seen in RA synovium may contribute to joint degeneration through the regulation of human matrix metalloproteinase-1 (hMMP-1, collagenase-1) gene expression. Transcription assays were performed with luciferase reporters driven by the promoter of the hMMP-1 gene or by a minimal promoter containing tandem repeats of the consensus binding sequence for activator protein-1, cotransfected with p53-expressing plasmids. The results revealed that (i) wild-type (wt) p53 down-regulated the promoter activity of hMMP-1 in a dose-dependent fashion; (ii) four of six p53 mutants (commonly found in human cancers) lost this repression activity; and (iii) this p53 repression activity was mediated at least in part by the activator protein-1 sites found in the hMMP-1 promoter. These findings were further confirmed by Northern analysis. The down-regulation of hMMP-1 gene expression by endogenous wt-p53 was shown by treatment of U2-OS cells, a wt-p53-containing osteogenic sarcoma line, and Saos-2 cells, a p53-negative osteogenic sarcoma line, with etoposide, a potent inducer of p53 expression. p53, activated by etoposide, appears to block hMMP-1 promoter activity induced by etoposide in U2-OS cells. In summary, we have shown for the first time that the hMMP-1 gene is a p53 target gene, subject to p53 repression. Because MMP-1 is principally responsible for the irreversible destruction of collagen in articular tissue in RA, abnormality of p53 may contribute to joint degeneration through the regulation of MMP-1 expression.
 ...
PMID:p53 down-regulates human matrix metalloproteinase-1 (Collagenase-1) gene expression. 1020 59

In order to examine the spatial organisation of stem cells and their progeny in human epidermis, we developed a method for whole-mount epidermal immunofluorescence labelling using high surface beta1 integrin expression as a stem cell marker. We confirmed that there are clusters of high beta1 integrin-expressing cells at the tips of the dermal papillae in epidermis from several body sites, whereas alpha6 integrin expression is more uniform. The majority of actively cycling cells detected by Ki67 or bromodeoxyuridine labelling were found in the beta1 integrin-dull, transit amplifying population and integrin-negative, keratin 10-positive cells left the basal layer exclusively from this compartment. When we examined p53-positive clones in sun-exposed epidermis, we found two types of clone that differed in size and position in a way that was consistent with the founder cell being a stem or transit amplifying cell. The patterning of the basal layer implies that transit amplifying cells migrate over the basement membrane away from the stem cell clusters. In support of this, isolated beta1 integrin-dull keratinocytes were more motile on type IV collagen than beta1 integrin-bright keratinocytes and EGFP-labelled stem cell clones in confluent cultured sheets were compact, whereas transit amplifying clones were dispersed. The combination of whole-mount labelling and lineage marking thus reveals features of epidermal organisation that were previously unrecognised.
 ...
PMID:The spatial relationship between stem cells and their progeny in the basal layer of human epidermis: a new view based on whole-mount labelling and lineage analysis. 1022

A case of malignant melanoma arising from a congenital dermal nevus on the right forehead of a 16-year-old female is presented. In the mole, small pigmented nevoid cells gathered around the skin appendages and between the collagen fibers. From the age of 17, a verrucous nevoid melanoma consisting of lymphoblast-like large nevoid cells, which were positive for HMB-45 and had a high Ki-67 index up to 18.7%, gradually increased in size. The melanoma cells vertically invaded the dermis to a depth of 3 mm and radially spread in the papillary dermis. Twelve years after undergoing a wide local resection and additional chemotherapy, metastatic lesions were found in the lung and the anterior mediastinum, which gradually increased in size and caused death a few months later. Metastatic melanoma cells were positive for HMB-45 and had a high Ki-67 index up to 33.7%. Most metastatic melanoma cells were positive for p53 while the primary ones were negative. Deteriorating mutations probably accumulated during the latent period.
 ...
PMID:Small cell type malignant melanoma which developed in a 16-year-old female with a congenital dermal nevus and metastasized 12 years after excision. 1033 82

The protein MMP-2 (type IV collagenase) belongs to the family of metalloproteinases. Its function is related to cellular matrix degradation including basement membrane type IV collagen. Its presence in the neoplastic cells might enhance its capacity for dissemination. To find out some of its clinico-pathological and immunohistochemical behavior, 98 adenocarcinomas of the stomach were immunohistochemically studied, in search for MMP-2 in neoplastic cells. The results showed a correlation between MMP-2 with parietal depth of infiltration (p = 0.03) and with metastases in regional lymph nodes (p = 0.05). On the other hand, no correlation was found with sex, gastric localization, size of the tumor, histological type or grade neither with expression of MIB-1, c-erbB-2 nor p53 proteins, recurrence nor 5 year survival or no recurrency.
 ...
PMID:[MMP-2 expression (type IV collagenase) in gastric cancer]. 1034 87

The cell cycle regulatory genes p16/CDKN2 and RB are frequently deleted in prostate cancers. In this study, we examined the role of alterations in p16 and pRb during growth, senescence, and immortalization in vitro of human prostate epithelial cells (HPECs). HPECs are established from normal prostate tissues and cultured on collagen-coated dishes. Our results show that p16 is reproducibly elevated at senescence in HPECs. HPECs are immortalized using human papilloma virus 16 E6 and/or E7 as molecular tools to inactivate p53 and/or pRb, respectively. Immortalization occurs infrequently in this system and only after a latent period during which additional genetic/epigenetic changes are thought to occur. Notably, all of the E6-immortalized HPEC lines but none of the E7 lines show inactivation of p16/CDKN2 (by deletion, methylation, or mutation) in association with immortalization. In contrast, E7 lines, in which pRb function is abrogated by E7 binding, retain the high levels of p16 observed at senescence. Thus, all lines show either a p16 or pRb inactivation. Analysis of six independent lines from metastatic prostate cancers reveals a similar loss of either p16 or pRb. Comparative genomic hybridization of HPECs shows that gains of chromosomes 5q, 8q, and 20 are nonrandomly associated with bypassing senescence (probability = 0.95). These results suggest that high levels of the cyclin-dependent kinase inhibitor p16 mediate senescence G1 arrest in HPECs and that bypassing this block by a p16/pRb pathway alteration is required for immortalization in vitro and possibly tumorigenesis in vivo. Our results further indicate that inactivation of the p16/pRb pathway alone is not sufficient to immortalize HPECs and that additional genetic alterations are required for this process.
 ...
PMID:p16/pRb pathway alterations are required for bypassing senescence in human prostate epithelial cells. 1038 61

Adequate control of survival or programmed cell death (apoptosis) of cardiovascular cells appears as an important drug target. While prevention of apoptotic death of cardiomyocytes has been assessed in detail, selective induction of apoptosis of vascular smooth muscle cells or fibroblasts could also be of relevance. Thus, induction of apoptosis of vascular smooth muscle cells by p65 NF-kappa B and Bcl-xL antisense oligonucleotides or p53 overexpression could be useful for limiting vascular lesions associated with restenosis. Although fibroblasts represent the majority of cardiac cells, few attempts were made to induce fibroblast apoptosis in disorders associated with excessive collagen deposition and fibrosis. It is hypothesized that early interference with fibroblast proliferation after myocardial infarction or inflammatory heart disease limits fibrosis which further impairs cardiac performance. A candidate approach could involve growth factor analogues which are known to induce fibroblast apoptosis when an incomplete growth stimulus persists.
 ...
PMID:Control of apoptosis of cardiovascular fibroblasts: a novel drug target. 1041 46


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>