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)

Crucial event in the metastasis of cancer cells is the secretion of matrix metalloproteinases (MMPs), which are responsible for the degradation of extracellular matrix (ECM). Among them, matrix metalloproteinase-2 (MMP-2) is a gelatinase, which degrades basement membrane type-IV collagen. Immunohistochemistry was performed to detect MMP-2 protein in 135 infiltrative breast carcinomas. MMP-2 was studied along with clinicopathological parameters (tumor size, histological type, nuclear and histological grade, stage, lymph node status, ER, and PR), patients' survival and tissue inhibitor metalloproteinase-2 (TIMP-2), Ki-67, and p53 proteins. MMP-2 immunoreactivity was detected in the cytoplasm in cancer cells in 102 (75.6%) and in both tumor and tumor stromal cells in 37 (27.4%) of 135 cases respectively. MMP-2 reactivity in cancer cells displayed a statistically significant association with tumor size > 2 cm (p = 0.022). In tumor stromal cells a strong parallel association was observed between the expression of MMP-2 and TIMP-2 (p = 0.015), while an inverse correlation was found between MMP-2 and both Ki-67 and p53 (p = 0.033 and p = 0.034 respectively). In the subgroup with negative lymph nodes MMP-2 was also inversely associated with p53 in cancer cells (p = 0.045). Finally a statistically significant association was revealed using Kaplan-Meier and Cox's proportional hazard regression model between the MMP-2/TIMP-2 phenotype and patients' better survival (p = 0.021). Our results point out the strong relation between MMP-2 and TIMP-2 and the effect of the MMP-2/TIMP-2 phenotype in the patients' overall survival. The inverse correlation between MMP-2 and both Ki-67 and p53 can be explained by the potential inhibition of MMP-2 by TIMP-2. These results suggest the necessity of further investigation.
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PMID:MMP-2 protein in invasive breast cancer and the impact of MMP-2/TIMP-2 phenotype on overall survival. 1260 13

The prognosis of pancreatic carcinoma is dismal. Its main reason can be attributed to the difficult early diagnosis. In fact, at diagnosis most patients show advanced disease. In recent years, studies on the biomolecular characteristics of this disease have been conducted. The obtained results have favored the understanding of the basic mechanisms of the biologic aggressiveness and the resistance to chemoradiation of pancreatic carcinoma. They include the frequent oncogene activation as well as the similarly frequent suppressor gene inhibition. Based on this new knowledge, novel therapeutic strategies have been identified and treatments of targeting the ras oncoprotein or mutated p53, metalloproteinase inhibitors and tyrosine kinase receptor inhibitors (trastuzumab and cetuximab) together with antiangiogenic therapies are under experimentation.
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PMID:Biological factors and therapeutic modulation in pancreatic carcinoma radiotherapy. 1269 52

Owing to the easy accessibility and general importance of the vascular system, cardiovascular diseases, including postangioplasty and graft restenosis, have become one of the new areas for gene therapy and molecular medicine. Promising therapeutic effects have been obtained in animal models of vascular diseases and restenosis with the transfer of genes for vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), thymidine kinase, p53, retinoblastoma, bcl-x, tissue inhibitor of metalloproteinase (TIMP), hepatic growth factor (HGF) and nitric oxide synthase (NOS). Also, growth arrest homeobox gene and antisense oligonucleotides or antibodies against transcription factors or cell cycle regulatory proteins have produced beneficial therapeutic effects. However, further developments in gene delivery techniques and vectors are needed before the full therapeutic effects of gene therapy in vascular diseases can be obtained.
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PMID:Gene therapy for the treatment of peripheral vascular disease and coronary artery disease. 1284 66

C-terminal truncation of ADAMTS-4 from the p68 form to the p53 form is required for activation of its capacity to cleave the Glu(373)-Ala(374) interglobular domain bond of aggrecan. In transfected human chondrosarcoma cells, this process is not autoproteolytic because the same products form with an inactive mutant of ADAMTS4 (a disintegrin and metalloproteinase with thrombospondin-like motif 4) and truncation is completely blocked by tissue inhibitor of metalloproteinase-1. Instead, activation can be mediated by glycosylphosphatidyl inositol-anchored membrane type 4-matrix metalloproteinase (MT4-MMP, MMP-17) because co-transfection with the active form of MT4-MMP markedly enhanced activation, whereas an inactive mutant of MT4-MMP was ineffective. Treatment of co-transfected cells with phosphatidylinositol-specific phospholipase C liberated the complex of MT4-MMP and p68 ADAMTS4 from the cell membrane, but the p53 ADAMTS4 remained associated. Specific glycosaminoglycan lyase digestions, followed by product analyses using fluorescence-assisted carbohydrate electrophoresis and immunoprecipitation experiments, showed that the p53 form is associated with syndecan-1 through both chondroitin sulfate and heparan sulfate. We conclude that ADAMTS-4 activation in this cell system involves the coordinated activity of both glycosylphosphatidyl inositol-anchored MT4-MMP and the proteoglycan form of syndecan-1 on the cell surface.
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PMID:ADAMTS4 (aggrecanase-1) activation on the cell surface involves C-terminal cleavage by glycosylphosphatidyl inositol-anchored membrane type 4-matrix metalloproteinase and binding of the activated proteinase to chondroitin sulfate and heparan sulfate on syndecan-1. 1470 64

Hibernation is a potential protective strategy for the peripheral, as well as for the central nervous system. A protein factor termed hibernation induction trigger (HIT) was found to induce hibernation in summer-active ground squirrels. Purification of HIT yielded an 88-kD peptide that is enriched in winter hibernators. Partial sequence of the 88-kD protein indicates that it may be related to the inhibitor of metalloproteinase. Using opioid receptor antagonists to elucidate the mechanisms of HIT, it was found that HIT targeted the delta opioid receptors. Indeed, delta opioid (D-Ala 2, D-Leu 5) enkephalin (DADLE) was shown to induce hibernation. Specifically, HIT and DADLE were found to prolong survival of peripheral organs, such as the lung, the heart, liver, and kidney preserved en bloc or as a single preparation. In addition, DADLE has been recently demonstrated to promote survival of neurons in the central nervous system. Exposure to DADLE dose-dependently enhanced cell viability of cultured primary rat fetal dopaminergic cells. Subsequent transplantation of these DADLE-treated dopaminergic cells into the Parkinsonian rat brain resulted in a two-fold increase in surviving grafted cells. Interestingly, delivery of DADLE alone protected against dopaminergic depletion in a rodent model of Parkinson s disease. Similarly, DADLE blocked and reversed the dopaminergic terminal damage induced by methamphetamine (METH). Such neuroprotective effects of DADLE against METH neurotoxicity was accompanied by attenuation of mRNA expressions of a tumor necrosis factor p53 and an immediate early gene c-fos. In parallel to these beneficial effects of DADLE on the dopaminergic system, DADLE also ameliorated the neuronal damage induced by ischemia-reperfusion following a transient middle cerebral artery occlusion. In vitro replication of this ischemia cell death by serum-deprivation of PC12 cells revealed that DADLE exerted neuroprotection in a naltrexone-sensitive manner. These results taken together suggest that DADLE stands as a novel therapeutic agent. In this review paper, we present laboratory evidence supporting the use of DADLE for protection of peripheral and central nervous system.
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PMID:Delta opioid peptide (D-Ala 2, D-Leu 5) enkephalin: linking hibernation and neuroprotection. 1535 66

EphA2, a member of the large family of Eph receptor tyrosine kinases, is highly expressed in epithelial tissue and has been implicated in cell-cell and cell-matrix interactions, as well as cell growth and survival. Expression of EphA2 mRNA and protein was markedly upregulated by both hypertonic stress and by elevated urea concentrations in cells derived from the murine inner medullary collecting duct. This upregulation likely required transactivation of the epidermal growth factor (EGF) receptor tyrosine kinase and metalloproteinase-dependent ectodomain cleavage of an EGF receptor ligand, based on pharmacological inhibitor studies. A human EphA2 promoter fragment spanning nucleotides -4030 to +21 relative to the putative EphA2 transcriptional start site was responsive to tonicity but insensitive to urea. A promoter fragment spanning -1890 to +128 recapitulated both tonicity- and urea-dependent upregulation of expression, consistent with transcriptional activation. Neither the bona fide p53 response element at approximately -1.5 kb nor a pair of putative TonE elements at approximately -3 kb conferred the tonicity responsiveness. EphA2 mRNA and protein were expressed at low levels in rat renal cortex but at high levels in the collecting ducts of the renal medulla and papilla. Water deprivation in rats increased EphA2 expression in renal papilla, whereas dietary supplementation with 20% urea increased EphA2 expression in outer medulla. These data indicate that transcription and expression of the EphA2 receptor tyrosine kinase are regulated by tonicity and urea in vitro and suggest that this phenomenon is also operative in vivo. Renal medullary EphA2 expression may represent an adaptive response to medullary hypertonicity or urea exposure.
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PMID:EphA2: expression in the renal medulla and regulation by hypertonicity and urea stress in vitro and in vivo. 1556 74

Occupational exposure to nickel has been epidemiologically linked to increased cancer risk in the respiratory tract. Nickel-induced cell transformation is associated with both genotoxic and epigenetic mechanisms that are poorly understood. Prolidase [E.C.3.4.13.9] is a cytosolic Mn(II)-activated metalloproteinase that specifically hydrolyzes imidodipeptides with C-terminal proline or hydroxyproline and plays an important role in the recycling of proline for protein synthesis and cell growth. Prolidase also provides free proline as substrate for proline oxidase, whose gene is activated by p53 during apoptosis. The inhibition of prolidase activity by nickel has not yet been studied. We first showed that Ni(II) chloride specifically inhibited prolidase activity in CHO-K1 cells in situ. This interpretation was possible because CHO-K1 cells are proline auxotrophs requiring added free proline or proline released from added Gly-Pro by prolidase. In a dose-dependent fashion, Ni(II) inhibited growth on Gly-Pro but did not inhibit growth on proline, thereby showing inhibition of prolidase in situ in the absence of nonspecific toxicity. Studies using cell-free extracts showed that Ni(II) inhibited prolidase activity when present during prolidase activation with Mn(II) or during incubation with Gly-Pro. In kinetic studies, we found that Ni(II) inhibition of prolidase varied with respect to Mn(II) concentration. Analysis of these data suggested that increasing concentrations of Mn(II) stabilized the enzyme protein against Ni(II) inhibition. Because prolidase is an important enzyme in collagen metabolism, inhibition of the enzyme activity by nickel could alter the metabolism of collagen and other matrix proteins, and thereby alter cell-matrix and cell-cell interactions involved in gene expression, genomic stability, cellular differentiation, and cell proliferation.
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PMID:Inhibition of prolidase activity by nickel causes decreased growth of proline auxotrophic CHO cells. 1569

Zmpste24 (also called FACE-1) is a metalloproteinase involved in the maturation of lamin A (Lmna), an essential component of the nuclear envelope. Both Zmpste24- and Lmna-deficient mice exhibit profound nuclear architecture abnormalities and multiple histopathological defects that phenocopy an accelerated ageing process. Similarly, diverse human progeroid syndromes are caused by mutations in ZMPSTE24 or LMNA genes. To elucidate the molecular mechanisms underlying these devastating diseases, we have analysed the transcriptional alterations occurring in tissues from Zmpste24-deficient mice. We demonstrate that Zmpste24 deficiency elicits a stress signalling pathway that is evidenced by a marked upregulation of p53 target genes, and accompanied by a senescence phenotype at the cellular level and accelerated ageing at the organismal level. These phenotypes are largely rescued in Zmpste24-/-Lmna+/- mice and partially reversed in Zmpste24-/-p53-/- mice. These findings provide evidence for the existence of a checkpoint response activated by the nuclear abnormalities caused by prelamin A accumulation, and support the concept that hyperactivation of the tumour suppressor p53 may cause accelerated ageing.
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PMID:Accelerated ageing in mice deficient in Zmpste24 protease is linked to p53 signalling activation. 1607 96

In vitro and in vivo studies provide a body of evidence that adequate protection of the skin against ultraviolet (UV)-induced damage requires photostable broad-spectrum sunscreens with a proper level of UVA protection. UVA alone and UV solar simulated radiation (SSR) induce DNA lesions in keratinocytes and melanocytes as reflected by the comet assay and p53 accumulation. UVA and SSR impair the immune system as shown by significant alteration of Langerhans cells and inhibition of contact hypersensitivity response to chemical allergens and delayed-type hypersensitivity response to recall antigens. Any of these detrimental effects is more efficiently prevented by sunscreens with a higher level of protection in the UVA range. The involvement of UVA (fibroblast alteration, increased metalloproteinase expression) and the pivotal need for well-balanced UVA/UVB sunscreens were further demonstrated using reconstructed three-dimensional skin models.
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PMID:Protection of skin biological targets by different types of sunscreens. 1643 78

This study investigated the changes, if any, in the level of expression of a well defined panel of cell proliferation, differentiation and apoptosis markers between the primary breast tumor and the corresponding synchronous lymph node metastasis from a population of patients with a comparable disease status, in terms of clinical features, and natural history.Ninety pure invasive ductal carcinomas with 10 or more axillary lymph nodes involved and without evidence of distant metastasis were included in this study. Primary tumor and corresponding metastatic lymph node tissue specimens were evaluated for the expression of Cyclin B1, MMP1 metalloproteinase, ICAM-1, RARbeta, Ki67, ER, PgR, p53, bcl-2 and c-erbB2 by immunohistochemistry using standard methods. The bivariate Pearson correlation analysis demonstrated a close relationship between primary and matching corresponding metastatic node. A high grade of correlation has been maintained even when staining results where categorized as positive/negative according to each one marker cut-off level of staining expression. We report the most extensive immunohistochemical analysis of biological determinants in a well defined population of patients with invasive ductal carcinomas and involvement of 10 or more axillary nodes and no distant metastasis. We found a close correlation between the primary tumor and corresponding metastatic node in terms of the expression of all 10 of the markers investigated in this study. The not complete concordance observed could be explained by the gene expression modulation by extrinsic factors and by the microenvironment in which the cancer cells reside.
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PMID:Correlation between genetic and biological aspects in primary non-metastatic breast cancers and corresponding synchronous axillary lymph node metastasis. 1683 4


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