UNIPROT:P04637 - FACTA Search

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Query: UNIPROT:P04637 (p53)
77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:p53 down-regulates human matrix metalloproteinase-1 (Collagenase-1) gene expression. 1020 59

Matrix metalloproteinases (MMPs) are a family of secreted or transmembrane proteins that can degrade all the proteins of the extracellular matrix and have been implicated in many abnormal physiological conditions including arthritis and cancer metastasis. Recently we have shown for the first time that the human MMP-1 gene is a p53 target gene subject to repression by wild type p53 (Sun, Y., Sun, Y. I., Wenger, L., Rutter, J. L., Brinckerhoff, C. E., and Cheung, H. S. (1999) J. Biol. Chem. 274, 11535-11540). Here, we report that cotransfection of fibroblast-like synoviocytes with p53 expression and hMMP13CAT reporter plasmids revealed that (i) hMMP13, another member of the human MMP family, was down-regulated by wild type p53, whereas all six of the p53 mutants tested lost the wild type p53 repressor activity in fibroblast-like synoviocytes; (ii) this repression of hMMP-13 gene expression by wild type p53 could be reversed by overexpression of p53 mutants p53-143A, p53-248W, p53-273H, and p53-281G; (iii) the dominant effect of p53 mutants over wild type p53 appears to be a promoter- and mutant-specific effect. An intriguing finding was that p53 mutant p53-281G could conversely stimulate the promoter activity of hMMP13 up to 2-4-fold and that it was dominant over wild type p53. Northern analysis confirmed these findings. Although the significance of these findings is currently unknown, they suggest that in addition to the effect of cytokines activation, the gene expression of hMMP13 could be dysregulated during the disease progression of rheumatoid arthritis (or cancer) associated with p53 inactivation. Since hMMP13 is 5-10 times as active as hMMP1 in its ability to digest type II collagen, the dysregulation or up-modulation of MMP13 gene expression due to the inactivation of p53 may contribute to the joint degeneration in rheumatoid arthritis.
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PMID:Wild type and mutant p53 differentially regulate the gene expression of human collagenase-3 (hMMP-13). 1075 45

Basaloid squamous carcinoma (BSC) is an uncommon aggressive variant of squamous cell carcinoma (SCC) with a predilection for the head and neck. In the English literature, approximately 40 cases of BSC in the oral cavity have been described. In this study, the clinicopathologic features of 2 cases of BSC affecting the buccal mucosa are reported. In addition, we compare the proliferative and invasive potential of BSC cells with that of poorly differentiated SCC cells matched for age, sex, site, and TNM status. Proliferative activity was studied through use of the argyrophilic nuclear organizer region (AgNOR) method and immunohistochemical quantification of proliferating cell nuclear antigen (PCNA). The invasive potential was evaluated through use of the semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) for matrix metalloproteinases (MMPs). Alterations of p53 were also investigated through use of immunohistochemistry. The tumors showed many clinical and histopathologic similarities to tumors in cases previously reported. The AgNOR and PCNA indices were significantly higher in the 2 cases of BSC than in the cases of SCC. Immunostaining for p53 protein showed a higher percentage of positive cells and more intense staining in the BSC tissues than in the SCC tissues. RT-PCR studies clearly demonstrated that the expression of MMP-1, MMP-2, and MMP-9 was higher in cells from BSCs than in cells from SCCs. Taken together, the data described here are compatible with the concept that BSC has a more aggressive biologic behavior than conventional SCC.
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PMID:Basaloid squamous carcinoma of the oral cavity: report of 2 cases and study of AgNOR, PCNA, p53, and MMP expression. 1134 36

Squamous cell carcinomas (SCCs) of the head and neck are characterized by high tendency to invade locally and metastasize to lymph nodes. SCC cells express several matrix metalloproteinases (MMPs) and they often harbor mutations in p53 tumor suppressor gene. Collagenase-3 (MMP-13) is specifically expressed by tumor cells of SCCs and it apparently plays an important role in their invasion and metastasis. We used adenoviral gene delivery to examine the effect of wild-type p53 on MMP-13 expression in four head and neck SCC cell lines with mutated p53. Adenoviral delivery of p53 resulted in potent inhibition in production of proMMP-13 (by 71 to 92%) and collagenase-1 (MMP-1) (by 27 to 93%) by all cell lines in 24 h, whereas production of gelatinase-A (MMP-2) and gelatinase-B (MMP-9) was not altered. Adenoviral expression of p53 also suppressed invasion of SCC cells through Matrigel by 35%. Expression of cyclin-dependent kinase inhibitor p21(Waf1/Cip1) was induced 24 h after p53 gene delivery in all SCC cell lines, except one, which lacked detectable p21(Waf1/Cip1) expression. Number of viable cells was not altered and no apoptotic cells were seen 24 h after p53 delivery. These results show, that wild-type p53 potently inhibits expression of MMP-13 and MMP-1 by SCC cells independently of its pro-apoptotic effect. Together these results indicate, that p53 exerts a bi-phasic tumor suppressor effect on SCC cells: inhibition of cell invasion followed by induction of programmed cell death.
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PMID:Adenoviral delivery of p53 gene suppresses expression of collagenase-3 (MMP-13) in squamous carcinoma cells. 1185 Aug 38

The tumour suppressor ING1 shares many biological functions with p53, such as cell cycle arrest, DNA repair, apoptosis, and chemosensitivity. Since p53 inhibits invasion and angiogenesis of melanoma cells, we sought to investigate if p33ING1 (one of ING1 isoforms) is also involved in these biological processes. We first overexpressed p33ING1 in melanoma cells and assessed the protein levels in MMP-1, MMP-2, and MMP-9. Results from Western blot analysis showed no significant difference in these matrix metalloproteinase levels between cells transfected with vector, p33ING1, and antisense p33ING1. Wound healing assay was performed to examine if p33ING1 plays a role in migration and invasion. Results showed that there was no difference between vector, p33ING1, and antisense p33ING1 groups in melanoma cell migration across the wound. Western blot analysis also indicated that there is no difference in the levels of proteins which are directly involved in angiogenesis, such as VEGF, Flt-1, and Flk-1, between cells transfected with vector, p33ING1, and antisense p33ING1. Furthermore, functional studies indicated that cultured medium derived from p33ING1-transfected melanoma cells did not stimulate the growth of HUVEC cells, compared to controls, providing support to the lack of functional role of p33ING1 in angiogenesis. In conclusion, we demonstrate in vitro that p33ING1, unlike p53, does not play a role in angiogenesis and migration in melanoma cells.
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PMID:The tumour suppressor p33ING1 does not regulate migration and angiogenesis in melanoma cells. 1242 89

Arsenic trioxide (As2O3) has been implicated as a promising anticancer agent for treatment of many cancers including acute promylocytic leukemia. However, the molecular mechanisms are not yet fully defined in solid tumor cells, especially cervical cancer cells carrying human papillomavirus (HPV) genome. To analyze detailed mechanisms in vitro, we treated As2O3 to transformed HeLa cells, a well-studied cervical cancer cell line carrying HPV-18 sequence, and investigated its antiproliferative, antiviral and antimetastatic effects. As2O3 reduced survival and growth of HeLa cells in a dose- and time-dependent manner. Several indicatives of apoptosis were demonstrated by DNA fragmentation assay, DAPI nuclear staining and FACS analysis, respectively. Protein levels of p53 and cleavage of poly(ADP)-ribose polymerase were increased in a dose-dependent manner following treatment of As2O3. In parallel, semi-quantitative reverse transcription-polymerase chain reaction showed that the treatment inhibited HPV-18 E6/E7 viral gene expression in HeLa cells. Using transient transfection and CAT ELISA, we also found that AP-1 sites, located proximal to HPV-18 upstream regulatory region (URR) promoter, could be the major target sites for As2O3. Furthermore, As2O3-treated HeLa cells showed lesser capacity of invasion than those of untreated cells by in vitro invasion assay. Taken together, we proposed that antiviral effect, i.e. down-regulation of HPV E6/E7 oncogenes through targeting for AP-1 sites located in HPV URR might be associated with antiproliferative effect, i.e. induction of apoptosis as be resulted from the accumulation of p53, and that antimetastatic effect could be due to the targeted inactivation of AP-1, a transcription factor required for the expression of MMP-1 and -3. Therefore, our finding may provide a logical basis for the development of a new agent treating HPV-associated cervical neoplasia.
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PMID:Down-regulation of human papillomavirus E6/E7 oncogene by arsenic trioxide in cervical carcinoma cells. 1243 Jan 74

To gain insight into the transformation of epidermal cells into squamous carcinoma cells (SCC), we compared the response to ultraviolet B radiation (UVB) of normal human epidermal keratinocytes (NHEK) versus their transformed counterpart, SCC, using biological and molecular profiling. DNA microarray analyses (Affymetrix), approximately 12000 genes) indicated that the major group of upregulated genes in keratinocytes fall into three categories: (i). antiapoptotic and cell survival factors, including chemokines of the CXC/CC subfamilies (e.g. IL-8, GRO-1, -2, -3, SCYA20), growth factors (e.g. HB-EGF, CTGF, INSL-4), and proinflammatory mediators (e.g. COX-2, S100A9), (ii). DNA repair-related genes (e.g. GADD45, ERCC, BTG-1, Histones), and (iii). ECM proteases (MMP-1, -10). The major downregulated genes are DeltaNp63 and PUMILIO, two potential markers for the maintenance of keratinocyte stem cells. NHEK were found to be more resistant than SCC to UVB-induced apoptosis and this resistance was mainly because of the protection from cell death by secreted survival factors, since it can be transferred from NHEK to SCC cultures by the conditioned medium. Whereas the response of keratinocytes to UVB involved regulation of key checkpoint genes (p53, MDM2, p21(Cip1), DeltaNp63), as well as antiapoptotic and DNA repair-related genes - no or little regulation of these genes was observed in SCC. The effect of UVB on NHEK and SCC resulted in upregulation of 251 and 127 genes, respectively, and downregulation of 322 genes in NHEK and 117 genes in SCC. To further analyse these changes, we used a novel unsupervised coupled two-way clustering method that allowed the identification of groups of genes that clearly partitioned keratinocytes from SCC, including a group of genes whose constitutive expression levels were similar before UVB. This allowed the identification of discriminating genes not otherwise revealed by simple static comparison in the absence of UVB irradiation. The implication of the changes in gene profile in keratinocytes for epithelial cancer is discussed.
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PMID:Genome-wide comparison of human keratinocyte and squamous cell carcinoma responses to UVB irradiation: implications for skin and epithelial cancer. 1277 51

TNF-alpha is known to play an important role in UV-induced immunomodulation and photodamage. It plays a role in UVB-mediated induction of apoptosis and is a strong inducer of the c-Jun N-terminal kinase (JNK) pathway, which eventually leads to the loss of dermal collagen and elastin content. Recently chimeric anti-TNF-alpha has been introduced as a therapy for rheumatoid arthritis. The aim of the present study was to investigate the effect of anti-TNF-alpha treatment on UV-induced DNA damage, apoptosis, and induction of matrix metallo proteinases. Twelve patients with rheumatoid arthritis were included and irradiated with 2 MED broadband UVB before and after administration of 0.5 mg/kg anti-TNF-alpha monoclonal antibody. Twenty-four hours after irradiation biopsies were taken. Frozen and paraffin sections were stained for p53, c-Jun, phosphorylated c-Jun, sunburn cells and MMP-1. No significant changes were observed in the expression of p53 and sunburn cells and MMP-1 content after treatment with anti-TNF-alpha, whereas a slight but significant decrease in c-Jun and phosphorylated c-Jun expression was noted (P = 0.0250 and P = 0.0431, respectively). Our results showed no influence of anti-TNF-alpha on UV response at therapeutic doses in patients with rheumatoid arthritis.
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PMID:Adalimumab, a fully human anti-TNF-alpha monoclonal antibody, treatment does not influence experimental UV response in the skin of rheumatoid arthritis patients. 1293 Mar 3

With the advancing widespread use of photodynamic therapy, questions have arisen about the necessity to protect the adjacent healthy skin from high-dose long-wave light. The aim of the present study was to investigate the effects of high dose visible light on the skin of healthy volunteers with focus on apoptosis, DNA damage, inflammation, melanogenesis and induction of matrix metalloproteinases (MMP). Fourteen healthy volunteers were included and irradiated daily on their buttocks with 1300 kJ/m2 long wave visible light (560-780 nm) on five consecutive days with a cumulative dose of 6500 kJ/m2. In each volunteer six biopsies were taken before and 24 h after irradiation on days 1, 2, 3 and 5 and on day 8 and 12. Frozen and paraffin sections were investigated by measuring parameters for photodamage (apoptosis, p53, phosphorylated c-Jun), skin ageing (phosphorylated c-Jun, MMP-1, elastin content) melanogenesis (Melan A). Although no sunburn cells were seen, a significant increase in perinuclear vacuolization was noted (P < 0.0003) from day 5 till 7 days after the last irradiation. There was no expression of phosphorylated c-Jun, whereas the expression of p53, Melan A, MMP-1 and elastin content did not change. High-dose visible light induces a significant increase in perinuclear vacuolization, but does not result in apoptosis, photodamage or early induction of skin ageing.
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PMID:High-dose long wave visible light induces perinuclear vacuolization in vivo but does not result in early photoageing and apoptosis. 1470 1

Cyclooxygenase 2 (COX-2) is known to be increased in aged cells. Recent studies suggest that the increased expression of COX-2 may be involved in the pathogenesis of age-associated diseases such as rheumatoid arthritis and cancer. We investigated the role of COX-2 in cell cycle arrest and collagen deficiency during the aging process. Using the replicative senescence model of dermal fibroblasts, we demonstrated the increased expression of COX-2 and increased PGE(2) levels associated with replicative senescence. Replicative senescent cells showed a decreased ability to induce cell proliferation, probably due to the increased expression of the p53 protein and the decreased expression of the PCNA protein, and also showed increased expression of MMP-1, and decreased expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) and procollagen. The selective COX-2 inhibitor, NS-398, can inhibit the senescence-associated increases of COX-2, PGE(2), p53 and MMP-1 expression, and the senescence-associated decreases of PCNA, TIMP-1 and procollagen expression. These results suggest that the increased level of COX-2 and higher level of PGE(2) in aged cells may play an important role in cellular senescence, and that selective COX-2 inhibitors may be useful for the intervention of skin aging.
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PMID:Selective COX-2 inhibitor, NS-398, inhibits the replicative senescence of cultured dermal fibroblasts. 1513 Jul 53

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