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)

The use of herbs has been the mainstay of treatment for a variety of human illnesses and is an essential part of culturally-based healing traditions in many societies and countries. Also, herbs, including Chinese herbs, are being incorporated as remedies for disease management and treatment in Western countries. In Traditional Chinese Medicine (TCM), herbal prescriptions are most frequently given to patients as complex formulations containing multiple herbs. Notably and unwittingly, this approach amounts to the administration of several chemical entities at once; the underlying theory is that interactions among the chemicals present in different herbs in a formula exert synergistic pharmacodynamic actions and neutralize the adverse effects and toxicities of specific individual chemicals. The effectiveness and mechanisms of this approach have not been well investigated or understood. A primary interest of this laboratory is to obtain experimental evidence that supports the fundamental mechanistic theme for the combinatorial herbal strategy described above and its potential application in preventing and treating breast cancer (BCa). In this study, we investigated the effects of 70% ethanolic extracts prepared from medicinal mushroom extract denoted I'm-Yunity and Danshen (Salvia miltiorrhizae Binge), alone and in combination, using MCF-7 cells as an in vitro model of estrogen receptor positive (ER+), low invasive BCa. Combination of I'm-Yunity and Danshen (referred to as I'm-Yunity-Plus) suppressed clonogenicity to a comparable degree as Danshen alone; both being significantly more active than I'm-Yunity. However, extract of Danshen was more active in inhibiting MCF-7 cell growth than I'm-Yunity-Plus. In comparison, I'm-Yunity elicited less growth inhibition. Flow cytometric analysis showed that I'm-Yunity-Plus induced partial block of G1/S transition in MCF-7 cells, whereas Danshen slowed down cell progression from G1/S into G2/M phases of the cell cycle. Treatment by I'm-Yunity did not affect cell cycle progression in MCF-7 cells; however, it promoted active induction of apoptosis. In addition, treatment with Danshen alone resulted in a pronounced reduction in the expression of Rb, cyclin D1, and p53, and also led to a diminution of p65 and p50 forms of NF-kappaB. The pronounced suppressive effects of Danshen on expression of the aforementioned genes were largely attenuated in cells treated with I'm-Yunity-Plus suggesting that ingredients in Danshen must have interacted with those in I'm-Yunity as to culminate in neutralization of the gene suppressive effects of Danshen. Additional support for such interactions was obtained by targeted cDNA array analysis using human tumor metastasis and BCa/ER signaling gene arrays. Taken together, our results are consistent with the interpretation that interaction exists between Danshen and I'm-Yunity and that I'm-Yunity-Plus may have efficacy in the treatment of BCa, particularly for patients with ER+ status.
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PMID:Differential control of growth, cell cycle progression, and gene expression in human estrogen receptor positive MCF-7 breast cancer cells by extracts derived from polysaccharopeptide I'm-Yunity and Danshen and their combination. 1701 54

The retrovirus human T-cell lymphotrophic virus type-1 (HTLV-1) causes adult T-cell leukemia (ATL), which remains with no cure. This study evaluates the effects of l-lysine on proliferation and induction of apoptosis using non-cytotoxic concentrations of the test compound against HTLV-1 positive and negative malignant cell lines. The anti-proliferative effect of lysine was established and confirmed by studying the effects of the test compound on the expression of TGF mRNA expression by RT-PCR. To investigate the effect of l-lysine on the induction of apoptosis, DNA flow cytometry analyses was done and the results verified by cell death ELISA. The results indicated that a significant increase in the preG(1) phase and a decrease in the S phase of the cell cycle in all of the ATL cells tested. l-Lysine up-regulated p53, p21, and Bax protein levels and a down-regulation of Bcl-2alpha in all the cell lines tested. l-Lysine was found to exert its effect through the NF-kappaB pathway by inhibiting the p65 subunit specifically. Also l-lysine caused a decrease in the levels MMP-2 and MMP-9 as well as their enzymatic activity.
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PMID:Mechanistic aspects of apoptosis induction by l-lysine in both HTLV-1-positive and -negative cell lines. 1704 5

The apoptosis stimulating proteins of p53 (ASPP) family consists of three members, ASPP1, ASPP2 and iASPP. They bind to proteins that are key players in controlling apoptosis (p53, Bcl-2 and RelA/p65) and cell growth (APCL, PP1). So far, the best-known function of the ASPP family members is their ability to regulate the apoptotic function of p53 and its family members, p63 and p73. Biochemical and genetic evidence has shown that ASPP1 and ASPP2 activate, whereas iASPP inhibits, the apoptotic but not the cell-cycle arrest function of p53. The p53 tumour suppressor gene, one of the most frequently mutated genes in human cancer, is capable of suppressing tumour growth through its ability to induce apoptosis or cell-cycle arrest. Thus, the ASPP family of proteins helps to determine how cells choose to die and may therefore be a novel target for cancer therapy.
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PMID:ASPP: a new family of oncogenes and tumour suppressor genes. 1721 78

The forkhead associated (FHA) domain-containing protein Smad nuclear interacting protein 1 (SNIP1) has multiple cellular functions, including the ability to interact with DNA-binding transcription factors and transcriptional coactivators. Moreover, we have demonstrated previously that SNIP1 regulates cyclin D1 expression and promoter activity. Here, we identify a new function for SNIP1 as a regulator of ATR checkpoint kinase-dependent pathways in human U-2 OS osteosarcoma cells: SNIP1 is required for p53 induction in response to ultraviolet light treatment and selectively regulates the phosphorylation of known ATR target proteins, including p53, Chk1 and the histone variant H2AX. These activities are independent of its ability to regulate cyclin D1 expression. Significantly, SNIP1 is also required for ATR-dependent functions of the human p14(ARF) tumour suppressor, including its ability to modulate the activity of the RelA(p65) NF-kappaB subunit. This, together with its other described functions, suggests that SNIP1 could have an important role during tumorigenesis and cancer therapy.
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PMID:Regulation of ATR-dependent pathways by the FHA domain containing protein SNIP1. 1726 16

Bortezomib (Velcade) exploits proteasome inhibition as a unique mechanism of anticancer activity. The effectiveness of bortezomib is, however, limited, therefore, the search for therapeutic regimens combining bortezomib with other agents. In the present work we demonstrate enhanced anticancer activity of bortezomib by its combination with tumor necrosis factor (TNF) in the experimental model of C-26 colon carcinoma in mice. This interaction likely relies on the induction of a dysregulated response to ER stress, leading to apoptosis of cancer cells, evidenced by caspase-3 cleavage, p53 accumulation as well as increased SAPK/JNK phosphorylation. ER stress induced by the combination of TNF and bortezomib is corroborated by upregulation of BiP, PDI and calnexin as well as cleavage of caspase-12; however, in contrast to the classic pathway, it is also associated with decreased phosphorylation of eIF2 alpha and prevention of XBP-1 splicing. TNF prevented the upregulation of Hsp27 induced by bortezomib, which may contribute to enhanced ER stress. Moreover, TNF interfered with bortezomib-induced upregulation of distinct subunits of the 26S proteasome. Bortezomib concentration used in this study was not sufficient to prevent TNF from inducing nuclear translocation of p65/RelA; however, the combination of both agents reduced total p65/RelA levels. Combined treatment of tumor-bearing mice with bortezomib and TNF not only inhibited tumor growth but also significantly prolonged animal survival. Therefore, combination of bortezomib with TNF is an attractive option for further clinical studies.
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PMID:TNF potentiates anticancer activity of bortezomib (Velcade) through reduced expression of proteasome subunits and dysregulation of unfolded protein response. 1737 61

Both genotoxic and oncogenic stress activates the nuclear factor-kappa B (NF-kappaB) and p53 proteins; however, the p53 activity is antagonized by NF-kappaB signaling. Dmp1 is a Myb-like transcription factor that activates the Arf-p53 pathway. The Dmp1 promoter was activated by a classical NF-kappaB activator tumor necrosis factor alpha, but repressed by treatment of cells with non-classical NF-kappaB activators, anthracyclins and UV-C. p65 and other subsets of NF-kappaB proteins were bound to the Dmp1 promoter following anthracyclin/UV-C treatment of rodent fibroblasts. This resulted in the downregulation of Dmp1 mRNA and protein. Repression of the Dmp1 transcription by anthracyclins depended on the unique NF-kappaB site on the promoter. Downregulation of p65 significantly attenuated the repression of the Dmp1 promoter by anthracyclins/UV-C. The amount of Dmp1 bound to the Arf promoter decreased significantly upon anthracyclin treatment; this, in turn, downregulated the Arf levels. Repression of the Arf promoter by p65 or anthracyclins depended on Dmp1, which was significantly attenuated in Dmp1(-/-) cells. Both Dmp1(-/-)and Arf(-/-)cells showed resistance to anthracyclin-induced cell death compared to wild-type cells; non-immortalized p65-knockdown cells were much more sensitive. Thus, the Dmp1-Arf pathway is repressed by p65 in response to genotoxic stress, which implicates a novel mechanism of p53 inactivation by NF-kappaB.
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PMID:Repression of Dmp1 and Arf transcription by anthracyclins: critical roles of the NF-kappaB subunit p65. 1754 45

During rat hepatocarcinogenesis preneoplastic lesions (PNL) emerge which may persist (pPNL) and be sites of progress to cancer or suffer remodeling (rPNL) tending to disappear. Cellular and molecular mechanisms involved in both phenotypes are not sufficiently elucidated. pPNL and rPNL cellular proliferation and apoptosis were evaluated in rats submitted to the resistant hepatocyte (RH) model, and an adjusted growth index (AGI) was established. p53, Bcl-2, and NF-kappaB p65 subunit expression was evaluated by immunohistochemistry in pPNL and rPNL. p65 expression and NF-kappaB activation was evaluated by Western blot assays in whole livers. A lower number of BrdU-stained hepatocyte nuclei/mm(2) and higher number of apoptotic bodies (AB) per mm(2) were observed in remodeling compared to pPNL. Cytoplasmic p53 accumulation is related to increased hepatocarcinoma malignancy. We observed that 71.3% pPNL and 25.4% rPNL (P < 0.05) presented p53 staining in the cytoplasm. Similarly, 67.7% pPNL and 23.1 % rPNL (P < 0.05) presented increased Bcl-2 staining. Thirty-two percent pPNL and 15.6% rPNL (P < 0.05) presented p65 staining. Compared to normal rats, increase (P < 0.05) of hepatic p65 expression and NF-kappaB activation in rats submitted to the RH model was observed. In agreement to previous studies hepatic pPNL and rPNL differ regarding cell proliferation and apoptosis. Moreover, persistence and remodeling involve differences in p53, Bcl-2, and NF-kappaB pathways. These data point to molecular pathways that may direct preneoplastic lesions to spontaneously regress or to progress to cancer. J. Cell. Biochem. 103: 538-546, 2008. (c) 2007 Wiley-Liss, Inc.
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PMID:Persistent and remodeling hepatic preneoplastic lesions present differences in cell proliferation and apoptosis, as well as in p53, Bcl-2 and NF-kappaB pathways. 1754 82

The respective pro- and antiapoptotic functions of the transcription factors p53 and nuclear factor kappaB (NF-kappaB), and their potential impact on tumorigenesis and response to tumor therapy are well recognized. The capacity of the RelA(p65) subunit of NF-kappaB to specify a pro-apoptotic outcome in response to some stimuli is less well recognized, but needs to be understood if rational manipulation of the NF-kappaB pathway is to be deployed in cancer therapy. In this report, we provide evidence that the growth-responsive nuclear protein, proenkephalin (Penk), is required, in part, for apoptosis induction, in response to activation or overexpression of p53 and RelA(p65). We describe UV-C-inducible physical associations between endogenous Penk and p53 and RelA(p65) in mammalian cell lines. Depletion of Penk by RNA interference (RNAi) substantially preserves viable cell number following exposure to UV-C irradiation or hydrogen peroxide and confers transient protection in cells exposed to the genotoxin etoposide. In virally transformed and human tumor cell lines, overexpression of nuclear Penk with overabundant or activated p53, or RelA(p65) even in the absence of p53, enhances apoptosis to the point of synergy. We have further shown that Penk depletion by RNAi substantially derepresses transcription of a range of antiapoptotic gene targets previously implicated in repression-mediated apoptosis induction by NF-kappaB and p53. Physical association of endogenous Penk with the transcriptional co-repressor histone deacetylase suggests that it may be a component of a transcriptional repression complex that contributes to a pro-apoptotic outcome, following activation of the NF-kappaB and p53 pathways, and could therefore help to facilitate an antitumor response to a broad range of agents.
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PMID:Proenkephalin assists stress-activated apoptosis through transcriptional repression of NF-kappaB- and p53-regulated gene targets. 1759

The tumor suppressor protein p53 regulates the sensitivity of embryos to such human teratogens as ionizing radiation, diabetes, and cytostatics. Yet, the molecular mechanisms whereby it fulfills this function remain undefined. We used p53 heterozygous (p53(+/-)) female mice mated with p53(+/-) males and then exposed to cyclophosphamide (CP) to test whether caspases 3, 8, and 9 and the transcription factor nuclear factor (NF)-kappaB may serve as p53 targets. Mice were exposed to CP on day 12 of pregnancy and killed on days 15 and 18 of pregnancy to evaluate CP-induced teratogenic effect. The brain and limbs of embryos harvested 24 h after CP treatment were used to evaluate NF-kappaB (p65) DNA-binding activity by an ELISA-based method, the activity of the caspases by appropriate colorimetric kits, apoptosis, and cell proliferation by TUNEL, and 5'-bromo-2'-deoxyuridine incorporation respectively. We observed that the activation of caspases 3, 8, and 9 and the suppression of NF-kappaB DNA binding following CP-induced teratogenic insult took place only in teratologically sensitive organs of p53(+/+) but not p53(-/-) embryos. CP-induced apoptosis and suppression of cell proliferation were also more intensive in the former, and they exhibited a higher incidence of structural anomalies, such as open eyes, digit, limb, and tail anomalies. The analysis of the correlations between the p53 embryonic genotype, the activity of the tested molecules, and the CP-induced dysmorphic events at the cellular and organ level suggests caspases 3, 8, and 9 and NF-kappaB as components of p53-targeting mechanisms in embryos exposed to the teratogen.
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PMID:p53 regulates cyclophosphamide teratogenesis by controlling caspases 3, 8, 9 activation and NF-kappaB DNA binding. 1766 Feb 47

Nutlins were identified as the first potent and specific small molecule Mdm2 antagonists that inhibit the p53-Mdm2 interaction. We show in this study that Nutlin-3 can downregulate TNFalpha induced activation of the NFkappaB reporter in lung cancer cells. Activation of p53 dependent transcription is not compromised when Nutlin-3 is combined with TNFalpha. Instead, this combination treatment decreases cell viability in a p53 dependent manner. We show that Nutlin-3 strikingly inhibits the protein expression of NFkappaB target genes ICAM-1 and MCP-1 while other targets like Bcl-xL and FLIP are not affected, thereby suggesting that the inhibition is promoter specific. This inhibition of ICAM-1 and MCP-1 by Nutlin-3 is again dependent on the p53 status in cells. Furthermore, we show that Nutlin-3 strongly inhibits protein expression of ICAM-1 and MCP-1 induced by IL1, another NFkappaB activating stimuli. Nutlin-3 does not inhibit Akt phosphorylation, IkappaB alpha phosphorylation, IkappaB alpha degradation, p65 modification or p65 DNA binding in the cell lines tested. This study suggests the potential of Nutlin-3 as a bitargeted anti-cancer drug by simultaneously causing p53 activation and NFkappaB suppression. It also suggests that Nutlin-3 could be evaluated for treatment of lung cancer as a single agent or in combination therapy by targeting its effect on ICAM-1 and MCP-1 which are known to be critical for cancer cell invasion, thereby downregulating tumor formation and metastasis. This study also suggests biomarkers of response for evaluation of Nutlin-3 in the clinic.
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PMID:Nutlin-3 inhibits the NFkappaB pathway in a p53-dependent manner: implications in lung cancer therapy. 1778 42


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