Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.25.1 (proteasome)
28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

MCP is a widely distributed regulatory glycoprotein of the complement system which binds C3b and C4b and has factor I-dependent co-factor activity. Monoclonal antibodies raised to lymphocytes (E4.3), chorionic microvilli (GB24) and an embryonal carcinoma cell line (TRA-2-10) recognize MCP (CD46). GB24 inhibited both the binding of MCP to its ligand iC3 and co-factor activity; E4.3 and TRA-2-10 did not. The binding of GB24 to cells bearing MCP was not cross-inhibited by E4.3 or TRA-2.10, but TRA-2-10 blocked binding and displaced pre-bound E4.3. Using these antibodies, we developed a radioassay for quantifying the number of MCP molecules/cells. Human peripheral blood mononuclear (PBMC) and polymorphonuclear cells (PMN) had about 10,000 MCP cell; platelets had about 600/cell, and no MCP was found on erythrocytes. Neoplastic hematopoietic cell lines, of myelocytic and T lymphocytic origin, had several-fold more (20-60,000) molecules cell than peripheral blood cells or B cell lines (about 12,000). Malignant epithelial cell lines. HeLa (about 100,000/cell) and HEp-2 (about 250,000 cell) had the highest MCP expression of any cells examined. These monoclonal antibodies--especially GB24, which blocks MCP function--and the direct binding assay will facilitate the further analysis of the biology of this complement regulatory protein.
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PMID:Characterization of three monoclonal antibodies to membrane co-factor protein (MCP) of the complement system and quantification of MCP by radioassay. 199 59

We have developed an approach to human developmental biology which exploits somatic cell genetics. With this system we have examined the production of the HLA-A,B,C antigens, A human-mouse somatic cell hybrid was constructed which contained a human X-7 chromosome translocation carrying the HLA region; this hybrid was used as a donor of the X-6 translocation in the technique of microcell transfer. The X-6 chromosome recipient was the mouse embryonal carcinoma cell line PCC4. The microcell hybrid MCP-6 retained the embryonal carcinoma phenotype as judged by shape and absence of H-2 expression. Nonetheless, the expression of the HLA-A,B,C genes was not extinguished. HLA-A,B,C antigen production of the cell surface, however, was not detected because this hybrid apparently could not make beta 2-microglobulin.
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PMID:Introduction of a human X-6 translocation chromosome into a mouse teratocarcinoma: investigation of control of HLA-A, B, C expression. 695 Nov 67

We examined changes in proteinase activities in P19 embryonal carcinoma cells during retinoic acid-induced differentiation. The interleukin-1 beta converting enzyme (ICE)-like Ac-YVAD-MCA hydrolytic activity was increased about 6-fold by treatment with retinoic acid. This activity was inhibited by N-ethylmaleimide and Ac-YVAD-H but not by E-64, EDTA, PMSF, or amastatin. The ICE-like activity in P19 cells eluted as a single peak just after the void volume on gel filtration. No ICE-like activity was observed at a molecular mass of 30-50 kDa. Enzymatic purification, Western blot analysis, and an immunoabsorption study demonstrated that the ICE-like activity in P19 cells is caused by the proteasome, and is stimulated during retinoic acid-induced differentiation. The proteasome purified from mouse liver also cleaved Ac-YVAD-MCA. These results strongly suggest that the proteasome is a major ICE-like proteinase in P19 cells and may be involved in the neural differentiation and the apoptotic pathway.
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PMID:Identification of an interleukin-1 beta converting enzyme-like activity that increases upon treatment of P19 cells with retinoic acid as the proteasome. 894 29

Neurons withdraw from the cell cycle immediately after differentiation from their proliferative precursors. E2F1, a principal transcription factor that promotes cell cycle progression, must be silenced in neurons. We investigated the E2F1 system in postmitotic neurons derived from murine embryonal carcinoma P19 cells. P19 cells highly expressed the E2F1 gene during neural differentiation, and enriched neurons contained a high abundance of E2F1 mRNA. In contrast, postmitotic neurons possessed extremely low levels of E2F1 protein as assessed by the electrophoretic mobility shift assay and Western blotting. A recombinant E2F1 fusion protein was ubiquitinated in vitro when incubated with neuronal lysates. In addition, treatment with the proteasome inhibitor MG132 increased the endogenous level of E2F1 protein in neurons. These results suggest that the ubiquitin-proteasome pathway contributes, at least in part, to the downregulation of E2F1 protein in postmitotic neurons. Adenovirus-mediated transfer of E2F1 cDNA into postmitotic neurons induced both bromodeoxyuridine incorporation and chromatin condensation, suggesting that deregulated E2F1 expression causes both aberrant S-phase entry and apoptosis of postmitotic neurons. Thus, downregulation of endogenous E2F1 protein in postmitotic neurons may be indispensable for the prevention of their reentry into the cell cycle.
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PMID:Regulation and deregulation of E2F1 in postmitotic neurons differentiated from embryonal carcinoma P19 cells. 1047 29

Retinoic acid (RA) treatment of embryonal carcinoma cell line NTERA-2 clone D1 (NT2/D1) induces growth arrest and terminal differentiation along the neuronal pathway. In the present study, we provide a functional link between RA and p27 function in the control of neuronal differentiation in NT2/D1 cells. We report that RA enhances p27 expression, which results in increased association with cyclin E/cyclin-dependent kinase 2 complexes and suppression of their activity; however, antisense clones, which have greatly reduced RA-dependent p27 inducibility (NT2-p27AS), continue to synthesize DNA and are unable to differentiate properly in response to RA as determined by lack of neurite outgrowth and by the failure to modify surface antigens. As to the mechanism involved in RA-dependent p27 upregulation, our data support the concept that RA reduces p27 protein degradation through the ubiquitin/proteasome-dependent pathway. Taken together, these findings demonstrate that in embryonal carcinoma cells, p27 expression is required for growth arrest and proper neuronal differentiation.
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PMID:Retinoic acid induces neuronal differentiation of embryonal carcinoma cells by reducing proteasome-dependent proteolysis of the cyclin-dependent inhibitor p27. 1106 25

The retinoids, natural and synthetic derivatives of vitamin A, are active in cancer therapy and prevention. Their biological effects are mediated through ligand-dependent interactions with retinoid receptors that associate with specific co-regulators. A better understanding of retinoid chemopreventive mechanisms is needed. Our prior work revealed that all-trans-retinoic acid (RA) prevented tobacco-specific carcinogenic transformation of cultured human bronchial epithelial cells. RA signaled G1 arrest that permitted repair of genomic DNA damage caused by these carcinogens. RA triggered G1 arrest at least partly through proteasome-dependent degradation of cyclin D1. Proteasomal inhibitors blocked RA-mediated cyclin D1 degradation. To confirm that a specific proteolysis pathway was induced by RA-treatment, a degradation assay was established using in vitro translated cyclin D1 and cellular extracts from RA-treated or untreated human bronchial epithelial cells. Incubation of RA-treated but not the control cellular extracts with in vitro translated cyclin D1 led to cyclin degradation. This degradation depended on the PEST domain of cyclin D1, implicating ubiquitination in this retinoid degradation. Retinoid receptor selective agonists demonstrated that retinoic acid receptor (RAR)beta and retinoid X receptor (RXR) but not RARalpha- or RARgamma-dependent pathways signaled this cyclin degradation. Findings were extended to the NT2/D1 human embryonal carcinoma differentiation model where a similar pathway was activated by RA-treatment. To determine whether G1 cyclins were involved directly in bronchial preneoplasia, immunohistochemical expression profiles for cyclins D1 and E were examined. Aberrant expression of these cyclins was frequent in bronchial preneoplasia. Taken together, these findings indicate that ubiquitin-dependent proteolysis of G1 cyclins is a retinoid chemoprevention mechanism. Whether the retinoids represent the optimal agents to activate this pathway is the subject of ongoing work. These findings provide a rationale for combining the retinoids in chemoprevention trials with other agents that do not activate this proteolysis pathway. What is now known about the retinoids as cancer prevention agents will be reviewed. Emphasis is placed on retinoid effects on cell cycle progression at G1.
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PMID:Cyclin proteolysis as a retinoid cancer prevention mechanism. 1179 32

The p300 and closely related CBP histone acetyltransferases (HAT) function as global transcriptional co-activators that play roles in many cell differentiation and signal transduction pathways. Despite their similarities, p300 and CBP have distinct functions during retinoic acid-induced differentiation of mouse F9 embryonal carcinoma cells. F9 cells constitute a well established model system for investigating the first steps of early development and retinoic acid signaling ex vivo. p300, but not CBP, was shown to be essential for F9 differentiation. In this study we have investigated the regulation of p300 during F9 differentiation. We report a dramatic decrease of p300, but not CBP protein levels, after 48 h of retinoic acid treatment. p300 is degraded via the ubiquitin-proteasome pathway. Although the large majority of p300 is degraded, its global HAT activity stays constant during F9 differentiation, which means that its specific HAT activity increases considerably. p300 is strongly phosphorylated in both undifferentiated and differentiated F9 cells; its HAT activity, however, is independent of phosphorylation before differentiation and becomes dependent on phosphorylation during differentiation. Furthermore, we show that protein kinase A affects p300 HAT activity both in vivo and in vitro as well as p300 phosphorylation in differentiated cells. Thus, we show that p300 is differentially phosphorylated in undifferentiated versus differentiated cells and that the changes in phosphorylation affect its HAT activity. Moreover, our study suggests an explanation for the functional switch of p300-mediated repression versus activation during F9 differentiation.
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PMID:Concomitant increase of histone acetyltransferase activity and degradation of p300 during retinoic acid-induced differentiation of F9 cells. 1288 59

Pre-B cell leukemia transcription factors (PBXs) are important co-factors for the transcriptional regulation mediated by a number of Hox proteins during embryonic development. It was previously shown that the expression of several Pbx genes is elevated in mouse embryo limb buds and embryonal carcinoma P19 cells upon retinoic acid (RA) treatment although the mechanism of this induction is not well understood. In this report, we demonstrate that PBX1a, PBX1b, PBX2, and PBX3 mRNAs and PBX1/2/3 proteins are induced during endodermal and neuronal differentiation of P19 cells in a RAR-dependent subtype-unspecific manner following RA treatment. The increases in both PBX1 mRNA and PBX3 mRNA levels are secondary responses to RA treatment requiring new proteins synthesis while the increase in PBX2 mRNA is a primary response. The RA-dependent increases in PBX1 mRNA, PBX2 mRNA, and PBX3 mRNA levels are likely to be transcriptionally regulated since the stability of these mRNAs does not change. In addition, the half-lives of PBX1/2/3 proteins are significantly extended by RA treatment. Two possible mechanisms could contribute to the stabilization of PBX proteins: PBX proteins associate with RA-dependent increased levels of MEIS proteins, and RA may decrease the proteasome dependent degradation of PBX proteins.
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PMID:Retinoic acid regulates the expression of PBX1, PBX2, and PBX3 in P19 cells both transcriptionally and post-translationally. 1509 11

NGN (neurogenin), a proneural bHLH (basic helix-loop-helix) transcription factor, plays a central role in promoting neuronal specification and differentiation in many regions of the central nervous system. NGN activity has been shown extensively to be controlled at the transcriptional level. However, in addition, recent findings have indicated that the levels of NGN protein may also be regulated. In the present study, we have demonstrated that NGN protein stability was regulated in both Xenopus embryos and P19 embryonal carcinoma cells, a mammalian neuronal model system. In both systems, NGN was a highly unstable protein that was polyubiquitinated for destruction by the proteasome. NGN binds to DNA in complex with its heterodimeric E-protein partners E12 or E47. We observed that NGN was stabilized by the presence of E12/E47. Moreover, NGN was phosphorylated, and mutation of a single threonine residue substantially reduced E12-mediated stabilization of NGN. Thus E-protein partner binding and phosphorylation events act together to stabilize NGN, promoting its accumulation when it can be active.
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PMID:Regulation of neurogenin stability by ubiquitin-mediated proteolysis. 1762 11

Emerging interest on the interrelationship between the apoptotic and autophagy pathways in the context of cancer chemotherapy is providing exciting discoveries. Complexes formed between molecules from both pathways present potential targets for chemotherapeutics design as disruption of such complexes could alter cell survival. This study demonstrates an important role of Beclin-1 and p53 interaction in cell fate decision of human embryonal carcinoma cells. The findings provide evidence for p53 interaction with Beclin-1 through the BH3 domain of the latter. This interaction facilitated Beclin-1 ubiquitination through lysine 48 linkage, resulting in proteasome-mediated degradation, consequently maintaining a certain constitutive level of Beclin-1. Disruption of Beclin-1-p53 interaction through shRNA-mediated down-regulation of p53 reduced Beclin-1 ubiquitination suggesting requirement of p53 for the process. Reduction of ubiquitination consequently resulted in an increase in Beclin-1 levels with cells showing high autophagic activity. Enforced overexpression of p53 in the p53 down-regulated cells restored ubiquitination of Beclin-1 reducing its level and lowering autophagic activity. The Beclin-1-p53 interaction was also disrupted by exposure to cisplatin-induced stress resulting in higher level of Beclin-1 because of lesser ubiquitination. This higher concentration of Beclin-1 increased autophagy and offered protection to the cells from cisplatin-induced death. Inhibition of autophagy by either pharmacological or genetic means during cisplatin exposure increased apoptotic death in vitro as well as in xenograft tumours grown in vivo confirming the protective nature of autophagy. Therefore, Beclin-1-p53 interaction defines one additional molecular subroutine crucial for cell fate decisions in embryonal carcinoma cells.
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PMID:Beclin-1-p53 interaction is crucial for cell fate determination in embryonal carcinoma cells. 2520 72


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