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 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

Recent studies of the Smad family proteins, which are the key signal transducers of the TGF-beta family ligands, have revealed the ability of Smads to interact with various components of the 26S proteasome system. Such interactions are now known to contribute to the regulation of Smad protein levels before and after Smad activation. Most importantly, such interactions are also shown to be an integral part of the signaling functions of Smads. Through a physical interaction with different ubiquitin E3 ligases (HECT family, SCF and APC complex), the TGF-beta/activin responsive Smad3 exhibits the novel ability to regulate the ubiquitination of several key regulators, such as the oncoprotein SnoN and the multi-domain docking protein HEF1. The proteasomal degradation of these two proteins links TGF-beta signaling to multiple signaling pathways involving SnoN and HEF1. Through the interaction with proteasome beta subunit HsN3 and the substrate marker protein ornithine decarboxylase antizyme (AZ), the BMP responsive Smad1 regulates the proteasomal targeting events that contribute to the degradation of Smad1 and its interacting proteins, one of which is SNIP1, a repressor of the transcriptional co-activator CBP/p300. Thus, the novel physical link between Smads and components in the 26S proteasome system allow the intracellular events triggered by the TGF-beta family ligands to connect with those induced by many other extracellular regulators, thereby forming an extremely complex signaling network to regulate a wide range of biological activities.
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PMID:The 26S proteasome system in the signaling pathways of TGF-beta superfamily. 1295 30

While the p53 homologue p73 has been found to be involved in tumorigenesis, the molecular mechanisms involved in this function are still not fully evident. The presence of two distinct promoters allows the formation of two proteins with opposite effects: while TA-p73 shows pro-apoptotic effects, DeltaN-p73 has an evident anti-apoptotic function. The relative expression of the two proteins is in fact related to the prognosis of several cancers. Since both p73 and p63, the other member of the same family, share the ability to interact with each other, it is important to understand the mechanisms that control the degradation and stability of both proteins, and their relative isoforms. p73 and p63 stability is regulated not only by protein modifications (phosphorylation, acetylation) but also by its degradation in the proteasome. To this end, the interaction with Mdm2, p300/CBP, and SUMO-1 are discussed in details.
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PMID:p73 and p63 protein stability: the way to regulate function? 1455 34

Hypoxia-inducible factor (HIF-1) is an oxygen-dependent transcriptional activator, which plays crucial roles in the angiogenesis of tumors and mammalian development. HIF-1 consists of a constitutively expressed HIF-1beta subunit and one of three subunits (HIF-1alpha, HIF-2alpha or HIF-3alpha). The stability and activity of HIF-1alpha are regulated by various post-translational modifications, hydroxylation, acetylation, and phosphorylation. Therefore, HIF-1alpha interacts with several protein factors including PHD, pVHL, ARD-1, and p300/CBP. Under normoxia, the HIF-1alpha subunit is rapidly degraded via the von Hippel-Lindau tumor suppressor gene product (pVHL)- mediated ubiquitin-proteasome pathway. The association of pVHL and HIF-1alpha under normoxic conditions is triggered by the hydroxylation of prolines and the acetylation of lysine within a polypeptide segment known as the oxygen-dependent degradation (ODD) domain. On the contrary, in the hypoxia condition, HIF-1alpha subunit becomes stable and interacts with coactivators such as p300/CBP to modulate its transcriptional activity. Eventually, HIF-1 acts as a master regulator of numerous hypoxia-inducible genes under hypoxic conditions. The target genes of HIF-1 are especially related to angiogenesis, cell proliferation/survival, and glucose/iron metabolism. Moreover, it was reported that the activation of HIF-1alpha is closely associated with a variety of tumors and oncogenic pathways. Hence, the blocking of HIF-1a itself or HIF-1alpha interacting proteins inhibit tumor growth. Based on these findings, HIF-1 can be a prime target for anticancer therapies. This review summarizes the molecular mechanism of HIF-1a stability, the biological functions of HIF-1 and its potential applications of cancer therapies.
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PMID:Hypoxia-inducible factor (HIF-1)alpha: its protein stability and biological functions. 1503 65

Autoimmune regulator (AIRE) is responsible for the development of organ-specific autoimmune disease in a monogenic fashion. Rare and low levels of tissue expression together with the lack of AIRE-expressing cell lines have hampered a detailed analysis of the molecular dynamics of AIRE. Here we have established cell lines stably transfected with AIRE and studied the regulatory mechanisms for its subcellular expression. We found that nuclear body (NB) formation by AIRE was dependent on the cell cycle. Biochemical fractionation revealed that a significant proportion of AIRE is associated with the nuclear matrix, which directs the functional domains of chromatin to provide sites for gene regulation. Upon proteasome inhibition, AIRE NBs were increased with concomitant reduced expression in the cytoplasm, suggesting that subcellular targeting of AIRE is regulated by a ubiquitin-proteasome pathway. We also found that AIRE NBs compete for cAMP-response element-binding protein-binding protein/p300, a common coactivator of transcription, with the promyelocytic leukemia gene product. These results suggest that the transcriptional regulating activities of AIRE within a cell are controlled and organized in a spatiotemporal manner.
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PMID:Subcellular expression of autoimmune regulator is organized in a spatiotemporal manner. 1515 Feb 63

p73 has been identified recently as a structural and functional homologue of the tumor suppressor p53. Here, we report that p73 stability is directly regulated by the ubiquitin-proteasome pathway. Furthermore, we show that the promyelocytic leukemia (PML) protein modulates p73 half-life by inhibiting its degradation in a PML-nuclear body (NB)-dependent manner. p38 mitogen-activated protein kinase-mediated phosphorylation of p73 is required for p73 recruitment into the PML-NB and subsequent PML-dependent p73 stabilization. We find that p300-mediated acetylation of p73 protects it against ubiquitinylation and that PML regulates p73 stability by positively modulating its acetylation levels. As a result, PML potentiates p73 transcriptional and proapoptotic activities that are markedly impaired in Pml-/- primary cells. Our findings demonstrate that PML plays a crucial role in modulating p73 function, thus providing further insights on the molecular network for tumor suppression.
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PMID:Ubiquitin-dependent degradation of p73 is inhibited by PML. 1518 4

Akt/protein kinase B is a downstream target of the phosphatidylinositol 3-kinase (PI3K) pathway and plays a critical role in promotion of cell survival. The function of transcriptional coactivator p300 is required by many transcription factors to either activate or repress gene expression. Here, we show that induction of PI3K enhances the metabolic stability of endogenous p300 protein. On the other hand, repression of PI3K by LY294002 induces p300 degradation through the 26S proteasome pathway and impedes the transcriptional activity of the coactivator. In addition, Akt interacts with the coactivator and the activity of Akt is required to maintain the steady-state level of p300. Our study provides a new insight into the molecular mechanisms by which the critical concentration of p300 protein is regulated and suggests a role for Akt in control of various cellular activities through the transcriptional coactivator p300.
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PMID:Role of Akt/protein kinase B in the activity of transcriptional coactivator p300. 1522 90

Transcriptional coactivator p300 is required for embryonic development and cell proliferation. Valproic acid, a histone deacetylase inhibitor, is widely used in the therapy of epilepsy and bipolar disorder. However, it has intrinsic teratogenic activity through unidentified mechanisms. We report that valproic acid stimulates proteasome-dependent p300 degradation through augmentation of gene expression of the B56gamma regulatory subunits of protein phosphatase 2A. The B56gamma3 regulatory and catalytic subunits of protein phosphatase 2A interact with p300. Overexpression of the B56gamma3 subunit leads to proteasome-mediated p300 degradation and represses p300-dependent transcriptional activation, which requires the B56gamma3 interaction domain of p300. Conversely, silencing of the B56gamma subunit expression by RNA interference increases the stability and transcriptional activity of the coactivator. Our study establishes the functional interaction between protein phosphatase 2A and p300 activity and provides direct evidence for signal-dependent control of p300 function.
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PMID:B56 regulatory subunit of protein phosphatase 2A mediates valproic acid-induced p300 degradation. 1563 55

Muscle wasting during sepsis and other catabolic conditions is, at least in part, mediated by glucocorticoids and is associated with upregulated transcription of multiple genes in the ubiquitin-proteasome proteolytic pathway. In addition to transcription factors, nuclear cofactors, including p300, regulate gene transcription. We tested the hypothesis that glucocorticoids upregulate the expression of p300 in muscle cells. Treatment of cultured L6 myotubes, a rat skeletal muscle cell line, with dexamethasone resulted in a dose- and time-dependent increase in p300 protein and mRNA levels. Surprisingly, the effect of dexamethasone on p300 levels was not inhibited by the glucocorticoid receptor (GR) antagonist RU38486 and RU38486 exerted an agonist effect on p300, increasing its expression. Co-immunoprecipitation showed that treatment of the myotubes with dexamethasone resulted in protein-protein interaction between p300 and C/EBPbeta, but not C/EBPdelta. The present results suggest that glucocorticoids upregulate the expression of p300 and its interaction with C/EBPbeta in skeletal muscle. Increased expression and activity of p300 may be involved in the regulation of gene transcription in glucocorticoid-dependent muscle wasting.
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PMID:Dexamethasone upregulates the expression of the nuclear cofactor p300 and its interaction with C/EBPbeta in cultured myotubes. 1566 15

Huntington's disease can be used as a model to study neurodegenerative disorders caused by aggregation-prone proteins. It has been proposed that the entrapment of transcription factors in aggregates plays an important role in pathogenesis. We now report that the transcriptional activity of CBP is already repressed in the early time points by soluble mutant huntingtin, whereas the histone acetylase activity of CBP/p300 is gradually diminished over time. Mutant huntingtin bound much stronger to CBP than normal huntingtin, possibly contributing to repression. Especially at the later time points, CBP protein level was gradually reduced via the proteasome pathway. In sharp contrast, p300 was unaffected by mutant huntingtin. This selective degradation of CBP was absent in spinocerebellar ataxia 3. Thus, mutant huntingtin specifically affects CBP and not p300 both at the early and later time points, via multiple mechanisms. In addition to the reduction of CBP, also the altered ratio of these closely related histone acetyltransferases may affect chromatin structure and transcription and thus contribute to neurodegeneration.
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PMID:Mutant huntingtin represses CBP, but not p300, by binding and protein degradation. 1645 24


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