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)

The ubiquitin-proteasome system is an important regulator of cell growth and apoptosis. The potential of specific proteasome inhibitors to act as novel anti-cancer agents is currently under intensive investigation. Several proteasome inhibitors exert anti-tumour activity in vivo and potently induce apoptosis in tumour cells in vitro, including those resistant to conventional chemotherapeutic agents. By inhibiting NF-kappaB transcriptional activity, proteasome inhibitors may also prevent angiogenesis and metastasis in vivo and further increase the sensitivity of cancer cells to apoptosis. Proteasome inhibitors also exhibit some level of selective cytotoxicity to cancer cells by preferentially inducing apoptosis in proliferating or transformed cells or by overcoming deficiencies in growth-inhibitory or pro-apoptotic molecules. High expression of oncogene products like c-Myc also makes cancer cells more susceptible to proteasome inhibitor-induced apoptosis. The induction of apoptosis by proteasome inhibitors varies between cell types but often occurs following an initial accumulation of short-lived proteins such as p53, p27, pro-apoptotic Bcl-2 family members or activation of the stress kinase JNK. These initial events often result in a perturbation of mitochondria with concomitant release of cytochrome c and activation of the Apaf-1 containing apoptosome complex. This results in activation of the apical caspase-9 followed by activation of effector caspases-3 and -7, which are responsible for the biochemical and morphological changes associated with apoptosis.
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PMID:The proteasome: a novel target for cancer chemotherapy. 1196 Mar 20

We previously reported that therapy of human cervical carcinoma HeLa cells with CP induced segregation of nucleoli and changes of nuclei characteristic of apoptosis. We raised the question of whether p53 can be reactivated by chemotherapy in HeLa cells despite the presence of HPV-encoded E6 activity. Cellular levels of p53 protein increased after CP treatment, reaching a maximum after 6 hr. p53 protein accumulated preferentially in the nucleoli, with a peak after 15 hr. CP-induced nucleolar targeting of p53 appears to be selective because p73, another member of the p53 gene family, accumulated primarily in nuclei in response to CP. Monitoring of the intranuclear distribution of Hdm-2, a negative regulator of p53, revealed this protein in the nucleoli of untreated controls translocated into chromatin during CP therapy. Interestingly, p14(ARF) showed an inverse intranuclear redistribution. Proteasome inhibitors were not able to mimic the effect of CP on p53 levels. Since the reduced stability of wild-type p53 protein in HeLa cells is a consequence of its enhanced ubiquitination by virally encoded E6 protein, resulting in its accelerated degradation, we checked the cellular level of E6 during CP therapy. Six hours after application of CP, E6 protein expression was markedly reduced. This coincided with the increase of cellular p53 and preceded the nucleolar accumulation of p53 protein, indicating that repression of virally coded E6 protein by CP contributes to the restoration of p53 expression.
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PMID:Escape of p53 protein from E6-mediated degradation in HeLa cells after cisplatin therapy. 1220 89

Oxidants such as H(2)O(2) play a role in the toxicity of certain DNA-damaging agents, a process that often involves the tumor suppressor p53. H(2)O(2) is rapidly degraded by catalase, which protects cells against oxidant injury. To study the effect of catalase on apoptosis induced by DNA-damaging agents, HepG2 cells were infected with adenovirus containing the cDNA of catalase (Ad-Cat). Forty-eight hours after infection, catalase protein and activity was increased 7-10-fold compared with control cells infected with Ad-LacZ. After treatment with Vp16 or mitomycin C, control cells underwent apoptosis in a p53-dependent manner; however, overexpression of catalase inhibited this apoptosis. Basal levels as well as Vp16- or mitomycin C-stimulated levels of p53 and p21 protein were decreased in the catalase-overexpressing cells as compared with control cells; however, p53 mRNA levels were not decreased by catalase. There was no difference in p53 protein synthesis between catalase-overexpressing cells and control cells. However, pulse-chase experiments indicated that p53 protein degradation was enhanced in the catalase-overexpressing cells. Proteasome inhibitors but not calpeptin prevented the catalase-mediated decrease of p53 content. Whereas Vp16 increased, catalase overexpression decreased the phosphorylation of p53. The protein phosphatase inhibitor okadaic acid did not prevent the catalase-mediated down-regulation of p53 or phosphorylated p53. These results demonstrate that catalase protects HepG2 cells from apoptosis induced by DNA-damaging agents in association with decreasing p53 phosphorylation; the latter may lead to an acceleration in the degradation of p53 protein by the proteasome complex. This suggests that the level of catalase may play a critical role in cell-induced resistance to the effects of anti-cancer drugs which up-regulate p53.
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PMID:Catalase protects HepG2 cells from apoptosis induced by DNA-damaging agents by accelerating the degradation of p53. 1246 45

The effects of a number of substances on neointima formation following angioplasty have been investigated in animal models. It was suggested that delivering of proteasome inhibitor to the site of vascular injury would be a potential therapeutic approach in prevention of vascular restenosis. But the mechanisms underlying biologic activities of proteasome inhibition in vascular smooth muscle cells (VSMCs) are largely unknown. We have investigated effects of proteasome inhibition on VSMCs using proteasome inhibitor MG115. MG115 induced apoptotic death in VSMCs as determined by viability, morphology, and DNA fragmentation. Proteasome inhibition was accompanied by up-regulation of p53, p21, and p27. In contrast, there were no appreciable alterations in the levels of Bcl-2 and Bax. Proteasome inhibition was followed by activation of caspase-3 but not of -8. The induction of apoptosis was suppressed by treatment with a selective inhibitor of the caspase-3 family, z-DEVD-fmk but not by NG-monomethyl-L-arginine. These results indicate that proteasome inhibition induces apoptosis in VSMCs by activation of caspase-3.
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PMID:Caspase-3-dependent apoptosis in vascular smooth muscle cell by proteasome inhibition. 1450 42

Targeting the ubiquitin-proteasome pathway has emerged as a promising approach for treating cancer. Bortezomib (VELCADE, formerly known as PS-341), a potent and reversible proteasome inhibitor, is being evaluated in clinical trials for treating multiple myeloma, and various other types of hematologic and solid tumors. Proteasome inhibitors are known to induce apoptosis in human cancer cells. Nevertheless, the mechanisms of apoptosis induced by proteasome inhibitors remain unclear. In this study, we investigated the role of p53 and its downstream targets in bortezomib-induced apoptosis in HCT116 human colon cancer cells. We demonstrated that bortezomib induced p53, and activated its downstream genes p21, PUMA and Bax in a p53-dependent fashion. However, apoptotic response to bortezomib was not affected by the deletion of p53. Surprisingly, we found that bortezomib-induced apoptosis was markedly enhanced in the p21-knockout cells, while significantly decreased in the BAX-knockout cells. Furthermore, in the cells deficient for both Bax and p21, apoptosis was restored to the level in the parental or the p53-deficient cells. The opposite effects of Bax and p21 were unrelated to the extent of proteasome inhibition, and were also observed in cells treated with different proteasome inhibitors. These results indicate that p53 downstream targets can collectively modulate apoptotic response to bortezomib and other proteasome inhibitors.
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PMID:Differential apoptotic response to the proteasome inhibitor Bortezomib [VELCADE, PS-341] in Bax-deficient and p21-deficient colon cancer cells. 1468 80

Proteasome inhibitors represent potential novel anti-cancer therapy. These agents inhibit the degradation of multi-ubiquitinated target proteins mediating cell cycle progression, apoptosis, NF-kappa B activation, inflammation, cell cycle regulatory proteins such as cyclins and cyclin dependent kinase inhibitors, as well as immune surveillance; and regulate anti-apoptosis and cell cycle progression. Proteasome inhibitors also directly induce caspase-dependent apoptosis of tumor cells, despite the accumulation of p21 and p27 and irrespective of the p53 wild type or mutant status. Recent studies demonstrate that PS-341, peptide boronate, has remarkable anti-tumor activity in preclinical and clinical studies, not only in multiple myeloma but also in other malignancies.
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PMID:Targeting proteasome inhibition in hematologic malignancies. 1476 62

Proteasome inhibitor PS-341 induces growth arrest and apoptosis of multiple myeloma (MM) cells via inactivation of NF-kappaB in vitro and has afforded some objective responses in individuals with relapsed, refractory MM. However, the activity of PS-341 against non-hematological malignancies remains to be fully elucidated. In this study, we found that PS-341 induced growth arrest and apoptosis of NCI-H520 and -H460 non-small cell lung cancer (NSCLC) cells in conjunction with markedly up-regulated levels of p21(waf1) and p53, and down-regulation of bcl-2 protein in these cells. Also, PS-341 caused phosphorylation of c-Jun NH(2)-terminal kinase (JNK) and c-Jun, and enhanced AP-1/DNA binding activities in these cells as measured by western blotting and enzyme-linked immunosorbent assay (ELISA), respectively. Interestingly, when the JNK/c-Jun/AP-1 signal pathway was disrupted by the JNK inhibitor SP600125, the ability of PS-341 to inhibit the growth of NSCLC cells and to up-regulate the levels of p21(waf1) in these cells was blunted, but the expression of p53 was sustained at a high level, suggesting that the JNK/c-Jun/AP-1 signal pathway might mediate the anti-lung cancer effects of PS-341, with p21(waf1) playing the central role. Thus, PS-341 might be useful for the treatment of individuals with NSCLC.
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PMID:Proteasome inhibitor PS-341 induces growth arrest and apoptosis of non-small cell lung cancer cells via the JNK/c-Jun/AP-1 signaling. 1496 69

Proteasome inhibitor PS-341 induces growth arrest and apoptosis of multiple myeloma (MM) cells via inactivation of nuclear factor kappaB (NF-kappaB) in vitro. In addition, recent clinical studies of PS-341 have demonstrated some objective responses in individuals with relapsed, refractory MM. However, the activity of PS-341 against non-hematological malignancies remains to be fully elucidated. In this study, we found that PS-341 induced growth arrest and apoptosis of androgen-dependent human prostate cancer LNCaP cells in conjunction with markedly up-regulated levels of p21(waf1) and p53. In addition, we found that PS-341 down-regulated both 5alpha-dihydrotestosterone (DHT)- and interleukin-6 (IL-6)-induced expression of prostate-specific antigen (PSA) as measured by western blot analysis. PS-341 down-regulated basal levels of the androgen receptor (AR) in the nucleus; however, it did not affect DHT-induced nuclear translocation of AR in these cells. Reporter assays using a series of promoters of the PSA gene showed that down-regulation of PSA by PS-341 was caused by inhibition of the transcriptional activity of the androgen receptor response element (ARE) in these cells. Taken together, the results indicate that PS-341 induced growth arrest and apoptosis of LNCaP cells by blockade of the AR signaling pathway. The proteasome may be a molecular target for treatment of a variety of cancers including prostate cancer.
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PMID:Proteasome inhibitor PS-341 down-regulates prostate-specific antigen (PSA) and induces growth arrest and apoptosis of androgen-dependent human prostate cancer LNCaP cells. 1501 28

Proteasomes play important roles in a variety of cellular processes such as cell cycle progression, signal transduction and immune responses. Proteasome activity is important in maintaining rapid turnover of short-lived proteins, as well as preventing accumulation of misfolded or damaged proteins. Alteration in ubiquitin-proteasome function may be detrimental to its crucial role in maintaining cellular homeostasis. Here, we have found that treatment of pyrrolidine dithiocarbamate (PDTC), a zinc ionophore, resulted in the accumulation of several proteasome substrates including p53 and p21 in HeLa cells. The PDTC effect was due to an extended half-life of these proteins through the mobilization of zinc. PDTC and/or zinc also increased fluorescence intensity of Ub(G76V)-GFP fusion protein that is degraded rapidly by the ubiquitin-proteasome system. Treatment of cells with zinc induced formation of ubiquitinated inclusions in the centrosome, a histological marker of proteasome inhibition. Western blotting showed zinc-induced increase in laddering bands of polyubiquitin-conjugated proteins. In vitro study, zinc inhibited the ubiquitin-independent proteasomal degradations of p21 and alpha-synuclein. These results suggest that zinc may modulate cell functions through its action on the turnover of proteins that are susceptible to proteasome-dependent proteolysis.
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PMID:Pyrrolidine dithiocarbamate and zinc inhibit proteasome-dependent proteolysis. 1524 77

The proteasome is responsible for the degradation of intracellular proteins, including several involved in cell cycle control and the regulation of apoptosis. Preclinical studies have shown that the proteasome inhibitor bortezomib decreases proliferation, induces apoptosis, enhances the activity of chemotherapy and radiation, and reverses chemoresistance in a variety of hematologic and solid malignancy models in vitro and in vivo. Proteasome inhibition with bortezomib has specifically promoted apoptosis of tumor cells through the stabilization of p53, p21, p27, Bax, and IkappaBalpha, resulting in nuclear factor kappaB inhibition. Bortezomib was the first proteasome inhibitor to enter clinical trials. In two Phase II trials, SUMMIT and CREST, it was found that treatment with bortezomib, alone or in combination with dexamethasone, produced durable responses with meaningful survival benefits in patients with recurrent and/or refractory multiple myeloma. In the APEX Phase III trial, bortezomib produced significant survival benefits and improved response rates over high-dose dexamethasone at first recurrence and beyond in patients with multiple myeloma. Clinical trials evaluating the safety and activity of bortezomib alone or in combination regimens with dexamethasone, doxorubicin, melphalan, prednisone, and/or thalidomide in the treatment of patients with newly diagnosed multiple myeloma have shown encouraging results. Preliminary studies suggest that bortezomib may serve as induction therapy before stem cell transplantation. Proteasome inhibition with bortezomib also has shown activity with manageable toxicity in mantle cell and other lymphomas, leukemias, and solid malignancies, including nonsmall cell lung carcinoma. Further studies with bortezomib as monotherapy and in combination regimens in the treatment of solid and hematologic malignancies are warranted.
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PMID:Proteasome inhibition and its clinical prospects in the treatment of hematologic and solid malignancies. 1617 3


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