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

---

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

The cell cycle has been the object of extensive studies for the past years. A complex network of molecular interactions has been identified. In particular, a class of cell cycle inhibitory proteins has been cloned and characterized but details of the molecular mechanism of their action have yet to be resolved. These inhibitors regulate the progression through G1 and the G1/S transition via the inhibition of the cyclin-dependent kinase (Cdk) activity. The potential function of these negative regulators as tumor suppressors provides new insights into the link between the cell cycle and oncogenesis. p27 is a potent inhibitor of Cdks. In quiescent cells p27 accumulates without an increase in mRNA or protein synthesis. Cell cycle regulation of p27 levels, both in normal and transformed human cells, occurs via the ubiquitin-proteasome pathway and, compared to proliferating cells, quiescent cells contain a far lower amount of p27 ubiquitinating activity. The specific proteolysis of p27 is probably involved in the pathway of activation of Cdks. p27 is a phosphoprotein and its phosphorylation is cell cycle regulated. Often phosphorylation is a signal for ubiquitination. p27 is phosphorylated exclusively on serine by Erk1 and almost exclusively on threonine by Cdk1 in in vitro experiments. This finding raises the question of whether and how phosphorylation by these kinases is involved in the process of p27 proteolysis.
Leukemia 1997 Mar
PMID:Regulation of the cyclin-dependent kinase inhibitor p27 by degradation and phosphorylation. 906 71

The cell cycle has been the object of extensive studies for the past years. A complex network of molecular interactions has been identified. In particular, a class of cell cycle inhibitory proteins has been identified but details of the molecular mechanism of their action have yet to be resolved. These inhibitors regulate the progression through G1 and the G1/S transition via the inhibition of the cyclin-dependent kinase (Cdk) activity. The potential function of these negative regulators as tumor suppressors provides new insights into the link between the cell cycle and oncogenesis. Kip1 is a potent inhibitor of Cdks. In quiescent cells Kip1 accumulates without an increase in mRNA or protein synthesis. We demonstrated that cell cycle regulation of Kip1 levels, both in normal and transformed human cells, occurs via the ubiquitin-proteasome pathway. In a crude in vitro system, Kip1 is ubiquitinated and degraded in an ATP dependent manner and inhibition or depletion of the proteasome blocks Kip1 degradation. Human Ubc2 and Ubc3, the homologs of yeast Rad6 and Cdc34 gene products respectively, are specifically involved in the ubiquitination of Kip1. Compared to proliferating cells, quiescent cells contain a far lower amount of Kip1 ubiquitinating activity. These results represent the first demonstration that the ubiquitin-proteasome pathway plays a role in the regulation of a cell cycle protein in human cells, namely the Cdk inhibitor Kip1. The specific proteolysis of Kip1 may be involved in the pathway of inactivation of Cdks.
Leukemia 1997 Apr
PMID:Kip1 degradation via the ubiquitin-proteasome pathway. 920 91

When an effective concentration of doxorubicin (DXR) was added into L1210 of a mouse leukemia cell line, DXR was rapidly distributed much more in the nuclei than in the other organelle within a few minutes. A [14C]DXR-binding fraction was obtained from the cytosol prepared from L1210 cells. The fraction was adsorbed to hydroxylapatite matrix and eluted from the matrix by 50-150 mM potassium phosphate buffer. The fraction showed high DXR-binding and Suc-Leu-Leu-Val-Tyr-MCA-degrading activity. The binding of [14C]DXR was inhibited by unlabeled DXR. Gel chromatography of the fraction with Sephacryl S-300 separated two fractions of high molecular weight (Peak I, approx. 750 kDa) and low molecular weight (Peak II). Peak I showed proteolytic activity. [14C]DXR-binding Peak I had much higher affinity to DNA-cellulose than [14C]DXR-binding Peak II. [14C]DXR-Peak I complex also was retained into the nuclei isolated from L1210 cells, temperature-dependently. These results suggest that a specific carrier to translocate DXR from cytoplasm into nucleus exists in L1210 cell and the carrier is proteasome.
...
PMID:Proteasome is a carrier to translocate doxorubicin from cytoplasm into nucleus. 960 Mar 27

CD437-induced apoptosis has been investigated in NB4, a human t(15;17) acute promyelocytic leukemia (APL) cell line, and in the retinoic acid (RA)-resistant NB4-R1 derivative subclone. Both NB4 and NB4-R1 cells underwent rapid apoptosis in response to low doses of CD437 (10(-7)M). This apoptosis did not require the activation of classical retinoid receptors and like arsenic (As)-induced apoptosis was preceded by the rapid activation of a caspase-3-like enzymatic activity as indicated by the increase of DEVD-pNA hydrolytic activity, by the processing of procaspase-3 protein and by the cleavage of poly(ADP-ribose) polymerase (PARP). Furthermore, it was demonstrated that the caspase-3-like proteolytic activity is responsible for the degradation of both the PML/RARalpha oncogenic protein and the normal RARalpha proteins. In CD437-treated cells, PML proteins were not degraded and PML relocalization on PMLNBs occurred in all the cells before death. CD437-induced apoptosis and receptor degradation were proteasome independent and not influenced either by inhibitors of protein tyrosine kinases (PTK), protein tyrosine phosphatases (PTPases) and serine proteases or by glutathione levels. Moreover, our data suggested that as for As2O3-induced apoptosis Bc12 modulation is not significant for CD437-induced apoptosis of NB4 cells. Since CD437 induces in vitro the rapid apoptosis of both RA-sensitive and -resistant APL cells, it could represent the first retinoid potentially able to eradicate in vivo malignant leukemia blasts.
Leukemia 1999 May
PMID:In acute promyelocytic leukemia NB4 cells, the synthetic retinoid CD437 induces contemporaneously apoptosis, a caspase-3-mediated degradation of PML/RARalpha protein and the PML retargeting on PML-nuclear bodies. 1037 79

Inhibitors of proteases are currently emerging as a potential anti-cancer modality. Nonselective protease inhibitors are cytotoxic to leukemia and cancer cell lines and we found that this cytotoxicity is correlated with their potency as inhibitors of the proteasome but not as inhibitors of calpain and cathepsin. Highly selective inhibitors of the proteasome were more cytotoxic and fast-acting than less selective inhibitors (PS341>>ALLN>>ALLM). Induction of wt p53 correlated with inhibition of the proteasome and antiproliferative effect in MCF7, a breast cancer cell line, which was resistant to apoptosis caused by proteasome inhibitors. In contrast, inhibitors of the proteasome induced apoptosis in four leukemia cell lines lacking wt p53. The order of sensitivity of leukemia cells was: Jurkat>HL60> or =U937>>K562. The highly selective proteasome inhibitor PS-341 induced cell death with an IC50 as low as 5 nM in apoptosis-prone leukemia cells. Cell death was preceded by p21WAF1/CIP1 accumulation, an alternative marker of proteasome inhibition, and by cleavage of PARP and Rb proteins and nuclear fragmentation. Inhibition of caspases abrogated PARP cleavage and nuclear fragmentation and delayed, but did not completely prevent cell death caused by PS-341. Reintroduction of wt p53 into p53-null PC3 prostate carcinoma cells did not increase their sensitivity to proteasome inhibitors. Likewise, comparison of parental and p21-deficient cells demonstrated that p21WAF1/CIP1 was dispensable for proteasome inhibitor-induced cytotoxicity. We conclude that accumulation of wt p53 and induction of apoptosis are independent markers of proteasome inhibition.
Leukemia 2000 Jul
PMID:Protease inhibitor-induced apoptosis: accumulation of wt p53, p21WAF1/CIP1, and induction of apoptosis are independent markers of proteasome inhibition. 1091 53

Biochemical and genetic analysis of apoptosis has determined that intracellular proteases are key effectors of cell death pathways. In particular, early studies have pointed to the primacy of caspase proteases as mediators of execution. More recently, however, evidence has accumulated that noncaspases, including cathepsins, calpains, granzymes, and the proteasome complex, also have roles in mediating and promoting cell death. An important goal is to understand the importance of distinct noncaspases in various forms of apoptosis, and to determine whether pathways mediated by noncaspase proteases intersect with those mediated by caspases. In this review the roles of noncaspase proteases in the biochemistry of apoptosis will be discussed.
Leukemia 2000 Sep
PMID:Noncaspase proteases in apoptosis. 1099 18

Adriamycin (ADM), an anthracycline anticancer agent, is selectively stored in the nuclei of a variety of proliferating cells, but the precise mechanism of specific nuclear transport of ADM is not well known. Recently, we demonstrated that ADM shows high binding affinity to the cytoplasmic proteasomes of L1210 mouse leukemia cells and that taken up ADM by the cells selectively binds to proteasomes. Nuclear targeting of proteasome in proliferating cells may be mediated by the nuclear localization signals that are found in several of the alpha-type subunits of the 20S proteasome. To confirm nuclear transport of the ADM-proteasome complex, we synthesized a photoactive ADM analogue, N-(p-azidohenzoyl)-ADM, and generated a photoaffinity-labeled proteasome complex. The 26S proteasome purified from the cytosol of L1210 cells had a high affinity to N-(p-azidobenzoyl)-ADM. SDS-PAGE analysis of the photoaffinity-labeled proteasome showed that low molecular weight bands (approximately 21-31 kDa) of 20S proteasome had the highest photoaffinity. The photoaffinity-labeled proteasome was distributed in the cytoplasm and nuclei of digitonin-permeabilized L1210 and B-16 mouse melanoma cells in the presence of the cytosolic fraction and ATP. The rate of nuclear translocation of the proteasome was low in the absence of ATP. These results suggest that the proteasome is a specific translocator of ADM from the cytoplasm to the nucleus and that 20S proteasome components are the dominant ADM-binding sites. The nuclear transport of ADM-proteasome complex is regulated by an ATP-dependent nuclear pore-mediated mechanism.
...
PMID:Mechanism of specific nuclear transport of adriamycin: the mode of nuclear translocation of adriamycin-proteasome complex. 1128 16

Proteasome inhibitors, including lactacystin and MG132 (carbobenzoxyl-leucinyl-leucinyl-leucinal), potently induce apoptosis in leukaemic B cells from patients with B cell chronic lymphocytic leukaemia (B-CLL). This pro-apoptotic effect occurs in cells from patients at all stages of the disease, including those resistant to conventional chemotherapy, suggesting that proteasome inhibitors may be useful for treatment of B-CLL. Following initial inhibition of proteasomal activity, these agents induce mitochondrial cytochrome c release and caspase-dependent apoptosis, involving cleavage/activation of caspases -2, -3, -7, -8 and -9. Pre-treatment with the cell permeable caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp (OMe)fluoromethyl ketone (Z-VAD.fmk), did not prevent the release of cytochrome c or partial processing of caspase-9 but prevented activation of effector caspases and the induction of apoptosis. These results suggest that the release of cytochrome c is caspase independent and that caspase-9 is the initiator caspase in proteasome inhibitor-induced apoptosis of B-CLL cells. Activation of B-CLL lysates with dATP results in the formation of an approximately 700 kDa caspase-activating apoptosome complex containing Apaf-1. We describe for the first time the formation of a similar approximately 700 kDa caspase-activating apoptosome complex in B-CLL cells induced to undergo apoptosis by proteasome inhibitors.
Leukemia 2001 Sep
PMID:Proteasome inhibitor-induced apoptosis of B-chronic lymphocytic leukaemia cells involves cytochrome c release and caspase activation, accompanied by formation of an approximately 700 kDa Apaf-1 containing apoptosome complex. 1151 99

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.
Leukemia 2002 Apr
PMID:The proteasome: a novel target for cancer chemotherapy. 1196 Mar 20

4'-O-tetrahydropyranyladriamycin (THP) showed an approximately 10-fold greater inhibitory effect on DNA synthesis in L1210 mouse leukemia cells than adriamycin (ADM). The intracellular transfer rate and nuclear accumulation of THP were approximately 5-fold higher than those of ADM. The intensity of in vitro inhibition of topoisomerase II activity by ADM was almost the same as that by THP. There were no significant differences between the uptake of either of these agents by the isolated nuclei of L1210 cells. The nuclear uptake of both agents in the presence of the cytosolic fraction of L1210 cells consisted of both simple diffusion and carrier-mediated components, and the carrier-mediated component of THP was approximately 2-fold higher than that of ADM. THP showed approximately 5-fold higher affinity to the proteasome than ADM, and interfered with ADM binding in a competitive manner. These results suggest that the binding affinity of these anticancer agents to the proteasome is an important factor in their transport to the nucleus and determines their specificity of action for the nuclear DNA.
...
PMID:Correlation between nuclear action of anthracycline anticancer agents and their binding affinity to the proteasome. 1237 Jul 58


1 2 3 4 5 6 7 8 Next >>

---