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)

The oncogene derived protein Bcl2 and its family members such as Bcl-xL or Mcl-1 can confer negative control in the pathway of cellular suicide machinery. The reversible phosphorylation of the components in the apoptotic-signaling pathway is likely to be an important regulatory mechanism to control the fate of a cell. Previous reports by others and us demonstrate that phosphorylation of anti-apoptotic proteins such as Bcl2, Bcl-xL or Mcl-1 can regulate their function depending on the apoptotic trigger or cell type. Also, evidence is now accumulating that the ubiquitin proteasome pathway can play an important role in apoptosis. In order to understand whether any cross-talk exists between proteasome and Bcl2 phosphorylation pathways, studies were undertaken employing cell permeable proteasome inhibitors. When proteasomes were inactivated, enhanced accumulation of slower mobility forms of Bcl2 was clearly evident. Due to substitution of the major phosphorylation sites Ser 70, 87 to Ala, no such effect was observed. It is known that in contrary to phospho Bcl2, native Bcl2 (non-phosphoform) is unable to associate with cis-trans peptidyl prolyl isomerase Pin1-a key factor to regulate the fate of phosphoforms of Bcl2 and apoptosis. Thus the enhanced resistance to cell death exhibited by phosphorylation defective mutant Bcl2 might be attributed to its inability to associate with Pin1.
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PMID:Signal-induced site specific phosphorylation targets Bcl2 to the proteasome pathway. 1216 5

Bim, a "BH3-only" protein, is expressed de novo following withdrawal of serum survival factors and promotes cell death. We have shown previously that activation of the ERK1/2 pathway promotes phosphorylation of Bim(EL), targeting it for degradation via the proteasome. However, the nature of the kinase responsible for Bim(EL) phosphorylation remained unclear. We now show that Bim(EL) is phosphorylated on at least three sites in response to activation of the ERK1/2 pathway. By using the peptidylprolyl isomerase, Pin1, as a probe for proline-directed phosphorylation, we show that ERK1/2-dependent phosphorylation of Bim(EL) occurs at (S/T)P motifs. ERK1/2 phosphorylates Bim(EL), but not Bim(S) or Bim(L), in vitro, and mutation of Ser(65) to alanine blocks the phosphorylation of Bim(EL) by ERK1/2 in vitro and in vivo and prevents the degradation of the protein following activation of the ERK1/2 pathway. We also find that ERK1/2, but not JNK, can physically associate with GST-Bim(EL), but not GST-Bim(L) or GST-Bim(S), in vitro. ERK1/2 also binds to full-length Bim(EL) in vivo, and we have localized a potential ERK1/2 "docking domain" lying within a 27-amino acid stretch of the Bim(EL) protein. Our findings provide new insights into the post-translational regulation of Bim(EL) and the role of the ERK1/2 pathway in cell survival signaling.
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PMID:Extracellular signal-regulated kinases 1/2 are serum-stimulated "Bim(EL) kinases" that bind to the BH3-only protein Bim(EL) causing its phosphorylation and turnover. 1468 Dec 25

The c-Myc transcription factor is a potent regulator of cellular proliferation and cell fate decision. Precise regulation of c-Myc protein levels is essential to maintain normal cell function. In order to maintain proper levels of c-Myc, its protein stability is tightly controlled. c-Myc is degraded through the ubiquitin-proteasome pathway. This perspective discusses a sophisticated and complex signaling pathway that controls the life cycle of c-Myc from protein synthesis to ubiquitin-mediated degradation. The pathway involves Ras-activated kinases, the Pin1 prolyl isomerase, the PP2A phosphatase and a series of c-Myc phosphorylation and dephosphorylation events that control its stability.
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PMID:The life cycle of C-myc: from synthesis to degradation. 1546 47

Peptidyl-prolyl isomerases (PPIase) facilitate the cis-trans interconversion of the peptidyl-prolyl bond and in such way affect protein folding. Pin1 is a PPIase, which specifically recognizes phosphorylated S/T-P bonds. The transcription factor TFIIH mediates phosphorylation of the retinoic acid receptor alpha (RARalpha) at position Ser77. In the presence of retinoic acid ligand (RA), the Ser77 non-phosphorylated receptor is suggested to undergo degradation through the proteasome pathway. Here we provide evidence that Pin1 is able to selectively destabilize RARalpha in a ligand independent-manner. We show that this is caused by RARalpha ubiquitination, which in turn is phosphorylation dependent. The single mutation Ser77>A completely abolishes RARalpha degradation whereas the mutation Ser77>E rescues this effect. In addition, we correlate RARalpha stability to Ser77 phosphorylation required for the ligand independent transcriptional activity on fgf8 promoter. Finally, we show that the ligand-independent Ser77 phosphorylation requires the genuine ligand-binding domain.
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PMID:The peptidyl-prolyl isomerase Pin1 regulates phospho-Ser77 retinoic acid receptor alpha stability. 1567 Jul 42

Recognition of double-stranded RNA activates interferon-regulatory factor 3 (IRF3)-dependent expression of antiviral factors. Although the molecular mechanisms underlying the activation of IRF3 have been studied, the mechanisms by which IRF3 activity is reduced have not. Here we report that activation of IRF3 is negatively regulated by the peptidyl-prolyl isomerase Pin1. After stimulation by double-stranded RNA, induced phosphorylation of the Ser339-Pro340 motif of IRF3 led to its interaction with Pin1 and finally polyubiquitination and then proteasome-dependent degradation of IRF3. Suppression of Pin1 by RNA interference or genetic deletion resulted in enhanced IRF-3-dependent production of interferon-beta, with consequent reduction of virus replication. These results elucidate a previously unknown mechanism for controlling innate antiviral responses by negatively regulating IRF3 activity via Pin1.
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PMID:Negative regulation of interferon-regulatory factor 3-dependent innate antiviral response by the prolyl isomerase Pin1. 1671 65

Antigen-specific B cells are selected in germinal centers, the structure in which these cells proliferate while accomplishing genome-remodeling processes such as class-switch recombination and somatic hypermutation. These events are associated with considerable genotoxic stress, which cells tolerate through suppression of DNA-damage responses by Bcl-6, a transcription factor required for the formation of germinal centers. Here we show that the expression of Bcl-6 is regulated by DNA damage through a signaling pathway that promotes Bcl-6 degradation. After DNA damage accumulated, the kinase ATM promoted Bcl-6 phosphorylation, leading to its interaction with the isomerase Pin1 and its degradation by the ubiquitin-proteasome system. Because Bcl-6 is required for the maintenance of germinal centers, our findings suggest that the extent of genotoxic stress controls the fate of germinal center B cells by means of Bcl-6.
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PMID:Genotoxic stress regulates expression of the proto-oncogene Bcl6 in germinal center B cells. 1782 69

The death-associated protein Daxx is a multifunctional factor that regulates a variety of cellular processes, including transcription and apoptosis. Several previous reports have indicated that Daxx is induced upon oxidative stress and is then subjected to phosphorylation-based functional modification. However, the precise molecular events underlying these phosphorylation events remain largely unknown. We report in our current study that the peptidyl-prolyl isomerase Pin1 is highly overexpressed in malignant human gliomas and inhibits Daxx-mediated cellular apoptosis. The targeted inhibition of Pin1 by small interfering RNA in A172 glioblastoma cells significantly enhances the apoptotic response induced by hydrogen peroxide or stimulatory Fas antibodies. This is in turn accompanied by the increased induction of Daxx and the activation of the apoptosis signal-regulating kinase 1/c-Jun N-terminal kinase pathway. Furthermore, Pin1 binds to the phosphorylated Ser178-Pro motif in the Daxx protein, and Pin1 overexpression results in the rapid degradation of Daxx via the ubiquitin-proteasome pathway. Moreover, a Daxx-S178A mutant, which cannot interact with Pin1, demonstrates higher proapoptotic activity and is refractory to Pin1-mediated antiapoptotic effects. We further found that the expression levels of Pin1 inversely correlate with the degree of Daxx nuclear accumulation in human glioblastoma tissues. These results together indicate that Pin1-mediated prolyl isomerization plays an important role in the negative regulation of Daxx and thereby inhibits the oxidative stress-induced cellular apoptotic response, particularly in malignant tumor cells where Pin1 is often overexpressed.
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PMID:A suppressive role of the prolyl isomerase Pin1 in cellular apoptosis mediated by the death-associated protein Daxx. 1793 71

Cyclin E is the Cdk2-regulatory subunit required for the initiation of DNA replication at the G1/S transition. It accumulates in late G1 phase and gets rapidly degraded by the ubiquitin/proteasome pathway during S phase. The degradation of cyclin E is a consequence of its phosphorylation and subsequent isomerization by the peptidyl-prolyl isomerase Pin1. We show that in the colon cancer cells HT-29 the inhibition of the chaperone function of Hsp90 by geldanamycin (GA) enhances the ubiquitinylation of cyclin E and triggers active degradation via the proteasome pathway. As Hsp90 forms multiprotein complexes with and regulates the function and cell contents of numerous signaling proteins, this observation suggests a direct interaction between Hsp90 and cyclin E. However, experiments using cell lysate fractionation did not reveal the presence of complexes containing both Hsp90 and cyclin E. Coupled transcription/translation experiments also failed to detect the formation of complexes between newly synthesized cyclin E and Hsp90. We conclude that Hsp90 can regulate the degradation of cellular proteins without binding to them, by an indirect mechanism. This conclusion postulates a new category of proteins that are affected by the inactivation of Hsp90. Our observations do not support the possible involvement of a PPIase in this indirect mechanism. Besides, we did not observe active geldanamycin-dependent degradation of cyclin E in the prostate cancer-derived cell line DU-145, indicating that the Hsp90-dependent stabilization of cyclin E requires specific regulatory mechanism which may be lost in certain types of cancer cells.
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PMID:Indirect participation of Hsp90 in the regulation of the cyclin E turnover. 1897 5

Transforming growth factor-beta (TGF-beta) is crucial in numerous cellular processes, such as proliferation, differentiation, migration, and apoptosis. TGF-beta signaling is transduced by intracellular Smad proteins that are regulated by the ubiquitin-proteasome system. Smad ubiquitin regulatory factor 2 (Smurf2) prevents TGF-beta and bone morphogenetic protein signaling by interacting with Smads and inducing their ubiquitin-mediated degradation. Here we identified Pin1, a peptidylprolyl cis-trans isomerase, as a novel protein binding Smads. Pin1 interacted with Smad2 and Smad3 but not Smad4; this interaction was enhanced by the phosphorylation of (S/T)P motifs in the Smad linker region. (S/T)P motif phosphorylation also enhanced the interaction of Smad2/3 with Smurf2. Pin1 reduced Smad2/3 protein levels in a manner dependent on its peptidyl-prolyl cis-trans isomerase activity. Knockdown of Pin1 increased the protein levels of endogenous Smad2/3. In addition, Pin1 both enhanced the interaction of Smurf2 with Smads and enhanced Smad ubiquitination. Pin1 inhibited TGF-beta-induced transcription and gene expression, suggesting that Pin1 negatively regulates TGF-beta signaling by down-regulating Smad2/3 protein levels via induction of Smurf2-mediated ubiquitin-proteasomal degradation.
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PMID:Pin1 down-regulates transforming growth factor-beta (TGF-beta) signaling by inducing degradation of Smad proteins. 1912 40

The peptidyl-prolyl-isomerase Pin1 interacts with phosphorylated proteins, altering their conformation. The retinoic acid receptor RARalpha and the acute-promyelocytic-leukemia-specific counterpart PML-RARalpha directly interact with Pin1. Overexpression of Pin1 inhibits ligand-dependent activation of RARalpha and PML-RARalpha. Inhibition is relieved by Pin1-targeted short interfering RNAs and by pharmacologic inhibition of the catalytic activity of the protein. Mutants of Pin1 catalytically inactive or defective for client-protein-binding activity are incapable of inhibiting ligand-dependent RARalpha transcriptional activity. Functional inhibition of RARalpha and PML-RARalpha by Pin1 correlates with degradation of the nuclear receptors via the proteasome-dependent pathway. In the acute myelogenous leukemia cell lines HL-60 and NB4, Pin1 interacts with RARalpha in a constitutive fashion. Suppression of Pin1 by a specific short hairpin RNA in HL-60 or NB4 cells stabilizes RARalpha and PML-RARalpha, resulting in increased sensitivity to the cytodifferentiating and antiproliferative activities of all-trans retinoic acid. Treatment of the two cell lines and freshly isolated acute myelogenous leukemia blasts (M1 to M4) with ATRA and a pharmacologic inhibitor of Pin1 causes similar effects. Our results add a further layer of complexity to the regulation of nuclear retinoic acid receptors and suggest that Pin1 represents an important target for strategies aimed at increasing the therapeutic index of retinoids.
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PMID:Inhibition of the peptidyl-prolyl-isomerase Pin1 enhances the responses of acute myeloid leukemia cells to retinoic acid via stabilization of RARalpha and PML-RARalpha. 1915 6


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