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)

Apoptosis induced in myeloid leukemic cells by wild-type p53 was suppressed by different cleavage-site directed protease inhibitors, which inhibit interleukin-1 beta-converting enzyme-like, granzyme B and cathepsins B and L proteases. Apoptosis was also suppressed by the serine and cysteine protease inhibitor N-tosyl-L-phenylalanine chloromethylketone (TPCK) [corrected], but not by other serine or cysteine protease inhibitors including N alpha-p-tosyl-L-lysine chloromethylketone (TLCK), E64, pepstatin A, or chymostatin. Protease inhibitors suppressed induction of apoptosis by gamma-irradiation and cycloheximide but not by doxorubicin, vincristine, or withdrawal of interleukin 3 from interleukin 3-dependent 32D non-malignant myeloid cells. Induction of apoptosis in normal thymocytes by gamma-irradiation or dexamethasone was also suppressed by the cleavage-site directed protease inhibitors, but in contrast to the myeloid leukemic cells apoptosis in thymocytes was suppressed by TLCK but not by TPCK. The results indicate that (i) inhibitors of interleukin-1 beta-converting enzyme-like proteases and some other protease inhibitors suppressed induction of apoptosis by wild-type p53 and certain p53-independent pathways of apoptosis; (ii) the protease inhibitors together with the cytokines interleukin 6 and interferon-gamma or the antioxidant butylated hydroxyanisole gave a cooperative protection against apoptosis; (iii) these protease inhibitors did not suppress induction of apoptosis by some cytotoxic agents or by viability-factor withdrawal from 32D cells, whereas these pathways of apoptosis were suppressed by cytokines; (iv) there are cell type differences in the proteases involved in apoptosis; and (v) there are multiple pathways leading to apoptosis that can be selectively induced and suppressed by different agents.
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PMID:Differential suppression by protease inhibitors and cytokines of apoptosis induced by wild-type p53 and cytotoxic agents. 890 12

M1 myeloid leukemic cells overexpressing wild-type p53 undergo apoptosis. This apoptosis can be suppressed by some cytokines, protease inhibitors, and antioxidants. We now show that induction of apoptosis by overexpressing wild-type p53 is associated with activation of interleukin-1beta-converting enzyme (ICE)-like proteases, resulting in cleavage of poly(ADP- ribose) polymerase and the proenzyme of the ICE-like protease Nedd-2. Activation of these proteases and apoptosis were suppressed by the cytokine interleukin 6 or by a combination of the cytokine interferon gamma and the antioxidant butylated hydroxyanisole, and activation of poly(ADP-ribose) polymerase and apoptosis were suppressed by some protease inhibitors. In a clone of M1 cells that did not express p53, vincristine or doxorubicin induced protease activation and apoptosis that were not suppressed by protease inhibitors, but were suppressed by interleukin 6. In another myeloid leukemia (7-M12) doxorubicin also induced protease activation and apoptosis that were not suppressed by protease inhibitors, but were suppressed by granulocyte-macrophage colony-stimulating factor. The results indicate that (i) overexpression of wild-type p53 by itself or treatment with cytotoxic compounds in wild-type p53-expressing or p53-nonexpressing myeloid leukemic cells is associated with activation of ICE-like proteases; (ii) cytokines exert apoptosis-suppressing functions upstream of protease activation; (iii) the cytotoxic compounds induce additional pathways in apoptosis; and (iv) cytokines can also suppress these other components of the apoptotic machinery.
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PMID:Cytokine suppression of protease activation in wild-type p53-dependent and p53-independent apoptosis. 925 85

Overexpression of wild-type p53 in M1 myeloid leukemia cells induces apoptotic cell death that was suppressed by the calcium ionophore A23187 and the calcium ATPase inhibitor thapsigargin (TG). This suppression of apoptosis by A23187 or TG was associated with suppression of caspase activation but not with suppression of wild-type-p53-induced expression of WAF-1, mdm-2, or FAS. In contrast to suppression of apoptosis by the cytokines interleukin 6 (IL-6) and interferon gamma, a protease inhibitor, or an antioxidant, suppression of apoptosis by A23187 or TG required extracellular Ca2+ and was specifically abolished by the calcineurin inhibitor cyclosporin A. IL-6 induced immediate early activation of junB and zif/268 (Egr-1) but A23187 and TG did not. A23187 and TG also suppressed induction of apoptosis by doxorubicin or vincristine in M1 cells that did not express p53 by a cyclosporin A-sensitive mechanism. Suppression of apoptosis by A23187 or TG was not associated with autocrine production of IL-6. Apoptosis induced in IL-6-primed M1 cells after IL-6 withdrawal was not suppressed by A23187 or TG but was suppressed by the cytokines IL-6, IL-3, or interferon gamma. The results indicate that these Ca2+-mobilizing compounds can suppress some pathways of apoptosis suppressed by cytokines but do so by a different mechanism.
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PMID:Different mechanisms for suppression of apoptosis by cytokines and calcium mobilizing compounds. 953 84

Multifunctional cytokines play important and only partially defined roles in mammary tumour development and progression. Normal human mammary epithelial cells constitutively produce interleukin 6 (IL-6), IL-8 and a non-secreted form of tumour necrosis factor. Transformation of mammary epithelial cells by different oncogenes is frequently associated with alterations of cytokine/growth factor production and responsiveness. In the present study we analysed the expression of IL-6 in 149 cases of invasive breast carcinoma and the data have been correlated with clinico-pathological variables including tumour size, histological grade, nodal status, and oestrogen and progesterone receptors, Ki67 and p53, protein expression. Though the majority of breast carcinomas expressed at least low levels of immunoreactive IL-6, we found that expression of this cytokine was inversely associated with histological tumour grade (P = 0.0017), but not with tumour size and nodal status. Ki67 positivity was inversely correlated with IL-6 expression (P = 0.027). Among biological parameters analysed, a direct association was found between the percentage of IL-6-positive cells and that of oestrogen (P = 0.00005) and progesterone (P = 0.025) receptor-positive cells. No correlation was observed between IL-6 and p53 protein expression. These data indicate that down-regulation of IL-6 is associated with highly malignant mammary carcinomas. It will be of interest to evaluate whether alterations of cytokines that are constitutively produced by mammary cells are also associated with high-grade tumours.
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PMID:Expression of interleukin 6 (IL-6) correlates with oestrogen receptor in human breast carcinoma. 1040 69

Recent studies have shown that somatostatin (SOM) inhibits interleukin 6 (IL-6) and interferon gamma (IFNgamma) production by lymphocytes and peritoneal macrophages, whereas substance P (SP) enhances these cytokines production. To define the mechanism of the cytokine production enhancements and inhibitions by SOM and SP, we examined the expression of apoptosis modulator, p53, Bcl-2, Bax, inducible nitric oxide synthase (iNOS), Fas, caspase-8 and nitric oxide (NO) in thioglycolate-elicited peritoneal macrophages. SOM caused up-regulation of p53, Bcl-2, Fas and caspase-8 activities, and down-regulation of iNOS expression and NO production. On the other hand, SP slightly induces p53 and highly induces Bcl-2, iNOS expression and NO production. These data suggest that apoptosis by SOM may occur by a Bax- and NO-independent p53 accumulation, and through Fas and caspase-8 activation pathways, and that the inducible expression of Bcl-2 and NO production by SP may contribute to prevent the signals of apoptosis by Bax, and via Fas and caspase-8 activation.
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PMID:Regulation of apoptosis by somatostatin and substance P in peritoneal macrophages. 1149 78

Histone acetylation modulates gene expression, cellular differentiation, and survival and is regulated by the opposing activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs). HDAC inhibition results in accumulation of acetylated nucleosomal histones and induces differentiation and/or apoptosis in transformed cells. In this study, we characterized the effect of suberoylanilide hydroxamic acid (SAHA), the prototype of a series of hydroxamic acid-based HDAC inhibitors, in cell lines and patient cells from B-cell malignancies, including multiple myeloma (MM) and related disorders. SAHA induced apoptosis in all tumor cells tested, with increased p21 and p53 protein levels and dephosphorylation of Rb. We also detected cleavage of Bid, suggesting a role for Bcl-2 family members in regulation of SAHA-induced cell death. Transfection of Bcl-2 cDNA into MM.1S cells completely abrogated SAHA-induced apoptosis, confirming its protective role. SAHA did not induce cleavage of caspase-8, -9, or -3 in MM.1S cells during the early phase of apoptosis, and the pan-caspase inhibitor ZVAD-FMK did not protect against SAHA. Conversely, poly(ADP)ribose polymerase (PARP) was cleaved in a pattern indicative of calpain activation, and the calpain inhibitor calpeptin abrogated SAHA-induced cell death. Importantly, SAHA sensitized MM.1S cells to death receptor-mediated apoptosis and inhibited the secretion of interleukin 6 (IL-6) induced in bone marrow stromal cells (BMSCs) by binding of MM cells, suggesting that it can overcome cell adhesion-mediated drug resistance. Our studies delineate the mechanisms whereby HDAC inhibitors mediate anti-MM activity and overcome drug resistance in the BM milieu and provide the framework for clinical evaluation of SAHA, which is bioavailable, well tolerated, and bioactive after oral administration, to improve patient outcome.
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PMID:Molecular sequelae of histone deacetylase inhibition in human malignant B cells. 1253 99

Using DNA microarray and clustering of expressed genes we have analyzed the mechanism of inhibition of wild-type p53-induced apoptosis by the cytokine interleukin 6 (IL-6) and the calcium mobilizer thapsigargin (TG). Clustering analysis of 1,786 genes, the expression level of which changed after activation of wild-type p53 in the absence or presence of IL-6 or TG, showed that these compounds did not cause a general inhibition of the ability of p53 to up-regulate or down-regulate gene expression. Expression of various p53 targets implicated as mediators of p53-induced apoptosis was also not affected by IL-6 or TG. These compounds thus can bypass the effect of wild-type p53 on gene expression and inhibit apoptosis. IL-6 and TG activated different p53-independent pathways of gene expression that include up-regulation of antiapoptotic genes. IL-6 and TG also activated different differentiation-associated genes. The ability of compounds such as cytokines and calcium mobilizers to inhibit p53-mediated apoptosis without generally inhibiting gene expression regulated by p53 can facilitate tumor development and tumor resistance to radiation and chemotherapy in cells that retain wild-type p53.
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PMID:Inhibition of p53-induced apoptosis without affecting expression of p53-regulated genes. 1274 73

Intrahepatic cholangiocarcinoma (ICC) is the second most common malignant tumor of the liver, and ICC is reportedly increasing recently. ICC is usually adenocarcinoma with variable desmoplastic reaction, although there are several special or unusual histological features. ICC may arise at the large intrahepatic bile duct near the hepatic hilus and also from the bile ductules at the border of the hepatic parenchyma. On the anatomical level, the pathology of ICC differs depending on the region from which the ICC arises. At the large intrahepatic bile duct, ICC presents papillary growth and periductal infiltration. Some cases show extensive papillary growth and intraluminal spread with marked gastroenteric metaplasia. Mucus core protein 1 is expressed in aggressive ICC. ICC arising from ductules shares phenotypes of hepatocellular carcinoma. ICC in chronic biliary diseases, particularly arising in hepatolithiasis, presents precancerous lesions that include biliary epithelial dysplasia, as well as in-situ carcinoma. Chronic advanced hepatitis C is one of the background diseases of ICC. Chronic inflammation, with the upregulation of cyclooxygenase-2 and growth factors, and the formation of reactive oxygen species are one of the causative factors in the DNA damage of biliary epithelial cells. K- ras mutation and aberrant expression of p53 are found in one-third of ICCs. The latter may be due to mdm-2 upregulation. Hepatocyte growth factor/met and interleukin 6 (IL6)/IL6 receptor are involved in cell proliferation/mitoinhibition and apoptosis in ICC. Fibrous stroma formation and invasion involve the proliferation of Alpha-smooth muscle antigen-positive stromal cells, and cell-to-cell and cell-to-matrix interactions involving E-cadherin/catenin and CD44 and matrix proteinases may be involved in the invasion of ICC. Evasion of immune surveillance involving the Fas/FasL system is important in the malignant progression of ICC. Further molecular and genetic studies are mandatory to evaluate the pathogenesis and progression of ICC.
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PMID:Anatomic and molecular pathology of intrahepatic cholangiocarcinoma. 1459 45

In this study, we examined the effects of isoform-specific functional inhibitors of lysophosphatidic acid acyltransferase (LPAAT), which converts lysophosphatidic acid to phosphatidic acid, on multiple myeloma (MM) cell growth and survival. The LPAAT-beta inhibitors CT-32176, CT-32458, and CT-32615 induced >95% growth inhibition (P < 0.01) in MM.1S, U266, and RPMI8226 MM cell lines, as well as MM cells from patients (IC(50), 50-200 nM). We further characterized this LPAAT-beta inhibitory effect using CT-32615, the most potent inhibitor of MM cell growth. CT-32615 triggered apoptosis in MM cells via caspase-8, caspase-3, caspase-7, and poly (ADP-ribose) polymerase cleavage. Neither interleukin 6 nor insulin-like growth factor I inhibited CT-32615-induced apoptosis. Dexamethasone and immunomodulatory derivatives of thalidomide (IMiDs), but not proteasome inhibitor PS-341, augmented MM cell apoptosis triggered by LPAAT-beta inhibitors. CT-32615-induced apoptosis was associated with phosphorylation of p53 and c-Jun NH(2)-terminal kinase (JNK); conversely, JNK inhibitor SP600125 and dominant-negative JNK inhibited CT-32615-induced apoptosis. Importantly, CT-32615 inhibited tumor necrosis factor-alpha-triggered nuclear factor-kappaB activation but did not affect either tumor necrosis factor-alpha-induced p38 mitogen-activated protein kinase phosphorylation or interleukin 6-triggered signal transducers and activators of transcription 3 phosphorylation. Finally, although binding of MM cells to bone marrow stromal cells augments MM cell growth and protects against dexamethasone-induced apoptosis, CT-32615 induced apoptosis even of adherent MM cells. Our data therefore demonstrate for the first time that inhibiting LPAAT-beta induces cytotoxicity in MM cells in the bone marrow milieu, providing the framework for clinical trials of these novel agents in MM.
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PMID:Antitumor activity of lysophosphatidic acid acyltransferase-beta inhibitors, a novel class of agents, in multiple myeloma. 1467 6

The p53 gene product is overexpressed by almost 50% of cancers, making it an ideal target for cancer immunotherapy. We previously demonstrated rejection of established p53-overexpressing tumors without stimulating autoimmunity by immunization with modified vaccinia Ankara-expressing murine p53 (MVAp53). Tumor rejection was enhanced through antibody-mediated CTL-associated antigen 4 (CTLA-4) blockade. We examined the role of synthetic oligodeoxynucleotides (ODN) containing unmethylated cytosine-phosphate-guanine (CpG) motifs (CpG ODN) in enhancing MVAp53-mediated tumor rejection. CpG ODN with MVAp53 resulted in tumor rejection in BALB/c mice bearing poorly immunogenic 11A-1 murine mammary carcinomas or Meth A sarcomas and C57Bl/6 mice bearing MC-38 colon carcinomas. The effect was similar to that seen in tumor-bearing mice treated with MVAp53 along with CTLA-4 blockade. Monoclonal antibody depletion experiments demonstrated that the adjuvant effects of CpG ODN and CTLA-4 blockades were CD8 dependent. CpG ODN were partially natural killer cell dependent and ineffective in Toll-like Receptor 9(-/-) and interleukin 6(-/-) mice, whereas CTLA-4 blockade was partially CD4 dependent and functional in Toll-like Receptor 9(-/-) and interleukin 6(-/-) mice. In addition, when administered with MVAp53, both adjuvants enhanced p53-specific cytotoxicity and demonstrated an additive effect when combined. The combination of CpG ODN and CTLA-4 blockade worked synergistically to reject palpable 11A-1 and MC-38 tumors. These experiments demonstrate the potential for augmenting MVAp53-mediated antitumor immunity using CpG ODN and CTLA-4 blockade. This cell-free immunotherapy approach is a candidate for evaluation in cancer patients.
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PMID:Two distinct pathways of immuno-modulation improve potency of p53 immunization in rejecting established tumors. 1528 49


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