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 p53 family of proteins play instrumental roles in mediating the cellular response to stress. The p53-related gene product, p73, occurs as two distinct protein isoforms, referred to as alpha and beta, which differ in the length of the C-terminal region and arise through alternative splicing of the p73 RNA. Here, we describe an analysis of the transcription properties of p73 and show that although there are certain similarities between transcriptional activation mediated by p73 and p53, such as in their sensitivity to adenovirus E1A and the requirement for p300/CBP co-activator proteins, significant differences are apparent in the response mechanisms. Thus, we find that p73 shows a degree of specificity for the promoters of target genes that is quantitatively distinct from the response mediated by p53. For example, p73 activates the GADD45 gene more efficiently than p53, whereas the reverse situation was apparent for the p21 gene. These effects are, in part, due to the influence of a regulatory domain present in the extended C-terminal of the alpha isoform. Moreover, we provide evidence that this domain regulates protein abundance by influencing the proteasome-dependent degradation of p73. These data define a novel level of isoform-specific control in regulating p73 activity, and thereby highlight a significant difference between the mechanisms that govern the transcriptional activity of p53 and p73.
...
PMID:Promoter specificity and stability control of the p53-related protein p73. 1043 30

Control of proliferation and differentiation by the retinoblastoma tumor suppressor protein (pRB) and related family members depends upon their interactions with key cellular substrates. Efforts to identify such cellular targets led to the isolation of a novel protein, EID-1 (for E1A-like inhibitor of differentiation 1). Here, we show that EID-1 is a potent inhibitor of differentiation and link this activity to its ability to inhibit p300 (and the highly related molecule, CREB-binding protein, or CBP) histone acetylation activity. EID-1 is rapidly degraded by the proteasome as cells exit the cell cycle. Ubiquitination of EID-1 requires an intact C-terminal region that is also necessary for stable binding to p300 and pRB, two proteins that bind to the ubiquitin ligase MDM2. A pRB variant that can bind to EID1, but not MDM2, stabilizes EID-1 in cells. Thus, EID-1 may act at a nodal point that couples cell cycle exit to the transcriptional activation of genes required for differentiation.
...
PMID:Cells degrade a novel inhibitor of differentiation with E1A-like properties upon exiting the cell cycle. 1107 89

A hallmark of neurodegenerative diseases caused by polyglutamine expansion is the abnormal accumulation of mutant proteins into ubiquitin-positive inclusions. The local build-up of these ubiquitinated proteins suggests that the proteasome machinery inadequately clears misfolded proteins, resulting in their increase to potentially toxic levels. Inclusions may disrupt normal cell homeostasis by sequestering vital cellular factors, such as chaperones, proteasomes and transcription components. Here, we used fluorescence recovery after photobleaching (FRAP) to examine the intranuclear dynamics of polyglutamine-expanded ataxin1 and inclusion-associated proteins. These experiments demonstrated that at least two types of ataxin1 inclusions exist; those that undergo rapid and complete exchange with a nucleoplasmic pool and those that contain varying levels of slow-exchanging ataxin1. Slow-exchanging inclusions contain high ubiquitin levels, but surprisingly low proteasome levels, suggesting an impairment in the ability of proteasomes to recognize ubiquitinated substrates. Proteasomes and CBP remained highly dynamic components of inclusions, indicating that although enriched with ataxin1, they are not irreversibly trapped. These results redefine our perception of polyglutamine inclusions and demonstrate the usefulness of FRAP and live cell imaging to study factors that modulate their behaviour.
...
PMID:Intranuclear ataxin1 inclusions contain both fast- and slow-exchanging components. 1236 Feb 91

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.
...
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.
...
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.
...
PMID:p73 and p63 protein stability: the way to regulate function? 1455 34

Proteasome-mediated protein degradation has been implicated in playing a role in nuclear receptor-mediated gene expression; inhibition of the proteasome impairs the transcriptional activity of estrogen receptor alpha (ERalpha) and most other nuclear receptors. This coincides with blockage of agonist-dependent degradation of the receptor and elevation of the steady-state levels of SRC family coactivators and CBP. Here, we examined the effects that different ERalpha ligands have on coactivator protein steady-state levels and demonstrate that the selective ER modulators (SERMs) 4-hydroxytamoxifen (4HT) and raloxifene are able to elevate SRC-1 and SRC-3 protein levels. Using the HeLa cell line, we show that this effect is ERalpha dependent. Consistent with the observed increase in coactivator protein levels, we were also able to observe an increase in the transcriptional activity of other nuclear receptors in SERM-treated cells. Information presented here demonstrates an unexpected consequence of SERM treatment, which could help further define the complex tissue responses to 4HT and raloxifene, and suggests that these ligands can have a broad biological action, stimulating the transcriptional activity of other nuclear receptors.
...
PMID:Selective estrogen receptor modulators 4-hydroxytamoxifen and raloxifene impact the stability and function of SRC-1 and SRC-3 coactivator proteins. 1467 39

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.
...
PMID:Hypoxia-inducible factor (HIF-1)alpha: its protein stability and biological functions. 1503 65

Peroxisome proliferator-activated receptor alpha (PPARalpha) is a ligand-activated transcription factor. PPARalpha regulates lipid and glucose metabolism and controls the inflammatory response. Recently, we have shown that PPARalpha is a short-lived protein degraded by the ubiquitin-proteasome system. In this study, we have analysed the effects of interaction with RXRalpha, CBP, and N-CoR and also the implication of phosphorylation on ubiquitination and stability of PPARalpha. Our results show that interaction of PPARalpha with RXRalpha or CBP leads to an increase in the turnover of the protein. In contrast, interaction with the corepressor N-CoR, which inhibits its transcriptional activity, leads to a stabilization of the protein. Interestingly, treatment of cells with an inhibitor of Ser/Thr phosphatases known to lead to hyperphosphorylation of PPARalpha induces its transcriptional activity which is accompanied by a stabilization of the protein. These data indicate that heterodimerization, recruitment of cofactors, and post-translational modifications can modulate the stability of PPARalpha.
...
PMID:Different ways to regulate the PPARalpha stability. 1517 57

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.
...
PMID:Mutant huntingtin represses CBP, but not p300, by binding and protein degradation. 1645 24


1 2 3 4 5 Next >>

---