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)

Proteasomes are the essential components of complexes involved in an extralysosomal energy- and ubiquitin-dependent proteolytic pathway. The first alpha-type proteasome subunit in plants has recently been described. In this work, the sequence of the first beta-type proteasome subunit in plants, isolated from Arabidopsis thaliana cDNA libraries is reported. The mRNA accumulation of both subunits was analysed and compared with those of the ubiquitin and histone mRNAs, in different tissues and during re-initiation of mitotic activity. It is demonstrated that in plants, as in animal cells, the transcripts of both the alpha-type and beta-type proteasome subunits accumulate to high levels during cell proliferation, in parallel with mRNAs coding for a ubiquitin fusion protein and several polyubiquitins, but earlier than those coding for histone H4 whose expression is known to be coupled to DNA synthesis. These results suggest that, as in animal cells, proteasomes may be involved in the progression of the cell cycle.
...
PMID:Molecular characterization of a beta-type proteasome subunit from Arabidopsis thaliana co-expressed at a high level with an alpha-type proteasome subunit early in the cell cycle. 798 12

A metalloendopeptidase (MEP) isolated from rabbit liver microsomes with substrate specificity for peptides containing Arg at the P1 and P4 positions has recently proved to be identical to soluble angiotensin-binding protein present in the cytosol. Here we describe the peptide-degrading specificity of MEP, determined using various bioactive peptides and novel fluorogenic substrates for the enzyme. MEP degraded oligopeptides, including bradykinin, alpha-neoendorphin, bovine adrenal medulla dodecapeptide, substance P, bombesin, neurotensin, and alpha-endorphin, but not polypeptides such as reduced lysozyme and histone H4, hence, MEP probably belongs to the family of endo-oligopeptidases. It cleaved most preferentially at the -Phe-Ser- bond of bradykinin (kcat/Km = 2.8 x 10(4) M-1.S-1) but did not cleave high molecular weight and low molecular weight kininogens, the precursors of bradykinin. MEP did not cleave angiotensin I, dynorphin A 1-13, somatostatin, and luteinizing hormone-releasing hormone, some of which are good substrates for metalloendopeptidase-24.15, metalloendopeptidase-24.16, N-arginine dibasic convertase, and yeast endopeptidase-24.15 related peptidase. An active site-directed inhibitor of metalloendopeptidase-24.15, N-[1-(R,S)-carboxyl-3-phenylpropyl]-Ala-Ala-Phe-p-aminobenzoate also had no effects on the amidolytic activity of MEP. Based on the cleavage sites of bioactive peptides and processing sites of vitamin K-dependent proproteins, intramolecularly quenched fluorogenic peptide substrates were newly synthesized. Among the thirteen substrates used, the most reactive was 2-aminobenzoyl-Ala-Arg-Val-Arg-Arg-Ala- Asn-Ser-2,4-dinitroanilinoethylamide (kcat/Km = 9.3 x 10(5) M-1.S-1). An angiotensin antagonist, [Sar1, Ala8]-angiotensin II, inhibited hydrolysis of the substrate by MEP in a competitive manner (Kl = 7.6 microM). MEP cleaved oligopeptides even on the carboxyl side of proline residue and these peptides are resistant to hydrolysis by the cytosol-derived proteasome, therefore MEP may participate in the catabolism of oligopeptides in the cytosol, together with other endo-oligopeptidases.
...
PMID:Substrate specificity of rabbit liver metalloendopeptidase and its new fluorogenic peptide substrates. 857 4

Quinidine inhibits proliferation and promotes cellular differentiation in human breast tumor epithelial cells. Previously we showed quinidine arrested MCF-7 cells in G(1) phase of the cell cycle and led to a G(1) to G(0) transition followed by apoptotic cell death. The present experiments demonstrated that MCF-7, MCF-7ras, T47D, MDA-MB-231, and MDA-MB-435 cells transiently differentiate before undergoing apoptosis in response to quinidine. The cells accumulated lipid droplets, and the cytokeratin 18 cytoskeleton was reorganized. Hyperacetylated histone H4 appeared within 2 h of the addition of quinidine to the medium, and levels were maximal by 24 h. Quinidine-treated MCF-7 cells showed elevated p21(WAF1), hypophosphorylation and suppression of retinoblastoma protein, and down-regulation of cyclin D1, similar to the cell cycle response observed with cells induced to differentiate by histone deacetylase inhibitors, trichostatin A, and trapoxin. Quinidine did not show evidence for direct inhibition of histone deacetylase enzymatic activity in vitro. HDAC1 was undetectable in MCF-7 cells 30 min after addition of quinidine to the growth medium. The proteasome inhibitors MG-132 and lactacystin completely protected HDAC1 from the action of quinidine. We conclude that quinidine is a breast tumor cell differentiating agent that causes the loss of HDAC1 via a proteasomal sensitive mechanism.
...
PMID:Rapid induction of histone hyperacetylation and cellular differentiation in human breast tumor cell lines following degradation of histone deacetylase-1. 1093 72

Intensive investigation of protein tyrosine, serine and threonine phosphorylation has lead to advances in signal transduction research and cancer treatment. This feature summarizes research on mammalian proteins exhibiting histidine phosphorylation. Histidine kinases are well known in prokaryotic and lower eukaryotic systems where they form the 'two-component' signal transduction system. The relative invisibility of histidine phosphorylation in mammalian cells may result from technical obstacles such as its acid lability, which precludes detection in electrophoretic systems, amino acid sequencing, etc. Emerging data have identified mammalian histidine kinases for the kinase suppressor of ras, a scaffold molecule for the Map kinase pathway, as well as histone H4, aldolase C and the beta-subunit of heterotrimeric G proteins. Additional mammalian proteins of interest to signal transduction and cancer research exhibit histidine phosphorylation, including P-selectin, annexin I and the 20S proteasome. Other candidate histidine phosphorylated proteins are identified. These data suggest the existence of another series of phosphorylation patterns in signal transduction.
...
PMID:Histidine kinases and histidine phosphorylated proteins in mammalian cell biology, signal transduction and cancer. 1253 71

Glucocorticoids potentiate the early steps of preadipocyte differentiation and promote obesity in Cushing's syndrome and during prolonged steroid therapy. We show that glucocorticoids stimulate 3T3 L1 preadipocyte differentiation through a non-transcriptional mechanism mediated through the ligand-binding domain of the glucocorticoid receptor. This enhanced the onset of CCAAT/enhancer binding protein (C/EBPalpha) expression by potentiating its initial transcriptional activation by C/EBPbeta. In the absence of steroid, C/EBPbeta associated with a transcriptional corepressor complex containing mSin3A and histone deacetylase 1 (HDAC1), but lacking HDAC2 and RbAp46/48. HDAC1/mSin3A were recruited to the C/EBPalpha promoter with C/EBPbeta and promoted the deacetylation of histone H4. Steroid induced the specific depletion of this corepressor by targeting the HDAC1 within the complex for degradation through the 26S proteasome. Treatment with histone deacetylase inhibitors replaced the effects of steroid treatment on preadipocyte differentiation and C/EBPalpha expression, while overexpression of HDAC1 abrogated the stimulatory effects of steroid. Recapitulation of the glucocorticoid effect by progestin treatment in the presence of the progesterone receptor ligand-binding domain suggests a conserved mechanism relevant to many aspects of steroid-mediated differentiation.
...
PMID:Stimulation of preadipocyte differentiation by steroid through targeting of an HDAC1 complex. 1272 80

In the present study, we investigated the involvement of protein degradation via the 26S proteasome during progesterone receptor (PR)-mediated transcription in T-47D cells containing a stably integrated MMTV-CAT reporter construct (CAT0 cells). Progesterone induced CAT and HSD11beta2 transcription while co-treatment with the proteasome inhibitor, MG132, blocked PR-induced transcription in a time-dependent fashion. MG132 treatment also inhibited transcription of beta-actin and cyclophilin, but not two proteasome subunit genes, PSMA1 and PSMC1, indicating that proteasome inhibition affects a subset of RNA polymerase II (RNAP(II))-regulated genes. Progesterone-mediated recruitment of RNAP(II) was blocked by MG132 treatment at time points later than 1 h that was not dependent on the continued presence of PR, associated cofactors, and components of the general transcription machinery, supporting the concept that proteasome-mediated degradation is needed for continued transcription. Surprisingly, progesterone-mediated acetylation of histone H4 was inhibited by MG132 with the concomitant recruitment of HDAC3, NCoR, and SMRT. We demonstrate that the steady-state protein levels of SMRT and NCoR are higher in the presence of MG132 in CAT0 cells, consistent with other reports that SMRT and NCoR are targets of the 26S proteasome. However, inhibition of histone deacetylation by trichostatin A (TSA) treatment or SMRT/NCoR knockdown by siRNA did not restore MG132-inhibited progesterone-dependent transcription. Therefore, events other than histone deacetylation and stability of SMRT and NCoR must also play a role in inhibition of PR-mediated transcription.
...
PMID:Inhibition of the 26S proteasome blocks progesterone receptor-dependent transcription through failed recruitment of RNA polymerase II. 1585 53

In a previous study, we demonstrated immunoreactivity of a subset of neuronal intranuclear rodlets (INRs) in the human substantia nigra for promyelocytic leukaemia (PML) protein, the signature protein of PML bodies. In the present study, we extend these observations and describe the ultrastructural features, immunohistochemical staining characteristics, and topographical pattern of distribution of PML-immunoreactive intranuclear rodlets (PML-INRs). Consistent with a purported role for PML bodies in nuclear proteolysis and/or transcriptional regulation, PML-INRs are immunoreactive for components of the ubiquitin-proteasome system, the transcriptional regulator CREB-binding protein, acetylated histone H4, and the eukaryotic translation initiation factor eIF4E. Immunoelectron microscopy reveals that they all possess a filamentous core and, in some, this is surrounded by a granular shell. We further demonstrate that a proportion of INRs in extranigral sites also show partial immunoreactivity for PML. These observations indicate an intimate association between two neuronal nuclear bodies, PML bodies and INRs. Because both of these structures have been implicated in neurodegenerative disease, PML-INRs may provide a tool with which to study changes in nuclear substructure in disease.
...
PMID:Promyelocytic leukaemia-immunoreactive neuronal intranuclear rodlets in the human brain. 1723 8

Class II transactivator (CIITA) is the master regulator of the major histocompatibility class II transcription complex (MHC-II) and is critical for initiation of adaptive immune responses. We have previously demonstrated that the 19S proteasome ATPase Sug1 plays a significant role in regulating CIITA activity and MHC-II expression. We now show that an additional component of the 19S complex, the 19S ATPase S6a (S6'/Tat-binding protein 1), is crucial for regulating cytokine-inducible transcription of CIITA. Lack of S6a negatively impacts CIITA activity and CIITA expression. Decreased expression of S6a significantly diminishes the recruitment of transcription factors to the CIITA interferon-gamma-inducible promoter [CIITA promoter IV (pIV)] and significantly decreases CIITApIV histone H3 and histone H4 acetylation, with a preferential loss of acetylation at H3 lysine 18 and H4 lysine 8. In addition, we provide evidence for the involvement of the 19S AAA (ATPases associated with diverse cellular activity) ATPase hexamer as the 19S ATPase S6b binds CIITApIV in an S6a-dependent fashion and has effects similar to S6a on CIITApIV histone acetylation. These analyses demonstrate the importance of 19S ATPases in the assembly of CIITApIV transcription machinery and provide additional insight into the regulatory mechanisms of the 19S proteasome in mammalian transcription.
...
PMID:The 19S ATPase S6a (S6'/TBP1) regulates the transcription initiation of class II transactivator. 1985 14

Inhibition of histone deacetylase (HDAC) is a promising mechanism for novel, anti-myeloma agents. We investigated the effects of the novel HDAC inhibitor resminostat on multiple myeloma (MM) cells in vitro. Resminostat is a potent inhibitor of HDACs 1, 3 and 6 [50% inhibitory concentration (IC50)=43-72 nmol/l] representing HDAC classes I and II and induces hyperacetylation of histone H4 in MM cells. Low micromolar concentrations of resminostat abrogated cell growth and strongly induced apoptosis (IC50=2.5-3 micromol/l in 3 out of 4 MM cell lines) in MM cell lines as well as primary MM cells. At 1 micromol/l, resminostat inhibited proliferation and induced G0/G1 cell cycle arrest in 3 out of 4 MM cell lines accompanied with decreased levels of cyclin D1, cdc25a, Cdk4 and pRb as well as upregulation of p21. Resminostat decreased phosphorylation of 4E-BP1 and p70S6k indicating an interference with Akt pathway signalling. Treatment with resminostat resulted in increased protein levels of Bim and Bax and decreased levels of Bcl-xL. Caspases 3, 8 and 9 were activated by resminostat. Furthermore, synergistic effects were observed for combinations of resminostat with melphalan and the proteasome inhibitors bortezomib and S-2209. In conclusion, we have identified potent anti-myeloma activity for this novel HDAC inhibitor.
...
PMID:The novel inhibitor of histone deacetylase resminostat (RAS2410) inhibits proliferation and induces apoptosis in multiple myeloma (MM) cells. 2020 41

Cks1, Cdk1 (Cdc28), and the proteasome are required for efficient transcriptional induction of GAL1 and other genes in Saccharomyces cerevisiae. We show here that one function of these proteins is to reduce nucleosome density on chromatin in a gene induction-specific manner. The transcriptional requirement for Cks1 can be bypassed if nucleosome density is reduced by an alternative pathway, indicating that this is the primary function of Cks1 in the context of gene induction. We further show that Cks1, Cdk1, and the 19S subunit of the proteasome are recruited to chromatin by binding directly to the histone H4 amino-terminal tail. However, this activity of the proteasome does not require the protease activity associated with the 20S subunit. These data suggest a model where binding of a complex consisting of Cks1, Cdk1, and the 19S proteasome to histone H4 leads to removal of nucleosomes via a nonproteolytic activity of the proteasome.
...
PMID:Cks1, Cdk1, and the 19S proteasome collaborate to regulate gene induction-dependent nucleosome eviction in yeast. 2085 29


1 2 Next >>

---