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)

UV irradiation has been reported to induce p21(WAF1/CIP1) protein degradation through a ubiquitin-proteasome pathway, but the underlying biochemical mechanism remains to be elucidated. Here, we show that ser-114 phosphorylation of p21 protein by glycogen synthase kinase 3beta (GSK-3beta) is required for its degradation in response to UV irradiation and that GSK-3beta activation is a downstream event in the ATR signaling pathway triggered by UV. UV transiently increased GSK-3beta activity, and this increase could be blocked by caffeine or by ATR small interfering RNA, indicating ATR-dependent activation of GSK-3beta. ser-114, located within the putative GSK-3beta target sequence, was phosphorylated by GSK-3beta upon UV exposure. The nonphosphorylatable S114A mutant of p21 was protected from UV-induced destabilization. Degradation of p21 protein by UV irradiation was independent of p53 status and prevented by proteasome inhibitors. In contrast to the previous report, the proteasomal degradation of p21 appeared to be ubiquitination independent. These data show that GSK-3beta is activated by UV irradiation through the ATR signaling pathway and phosphorylates p21 at ser-114 for its degradation by the proteasome. To our knowledge, this is the first demonstration of GSK-3beta as the missing link between UV-induced ATR activation and p21 degradation.
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PMID:Glycogen synthase kinase 3beta phosphorylates p21WAF1/CIP1 for proteasomal degradation after UV irradiation. 1728 49

TWEAK cytokine has been implicated in several biological responses including inflammation, angiogenesis, and osteoclastogenesis. We have investigated the role of TWEAK in regulating skeletal muscle mass. Addition of soluble TWEAK protein to cultured myotubes reduced the mean myotube diameter and enhanced the degradation of specific muscle proteins such as CK and MyHCf. The effect of TWEAK on degradation of MyHCf was stronger than its structural homologue, TNF-alpha. TWEAK increased the ubiquitination of MyHCf and the transcript levels of atrogin-1 and MuRF1 ubiquitin ligases. TWEAK inhibited phosphorylation of Akt kinase and its downstream targets GSK-3beta, FOXO1, mTOR, and p70S6K. Furthermore, TWEAK increased the activation of NF-kappaB transcription factor in myotubes. Adenoviral-mediated overexpression of IkappaB alpha deltaN (a degradation-resistant mutant of NF-kappaB inhibitory protein IkappaB alpha) in myotubes blocked the TWEAK-induced degradation of MyHCf. Chronic administration of TWEAK in mice resulted in reduced body and skeletal muscle weight with an associated increase in the activity of ubiquitin-proteasome system and NF-kappaB. Finally, muscle-specific transgenic overexpression of TWEAK decreased the body and skeletal muscle weight in mice. Collectively, our data suggest that TWEAK induces skeletal muscle atrophy through inhibition of the PI3K/Akt signaling pathway and activation of the ubiquitin-proteasome and NF-kappaB systems.
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PMID:TNF-related weak inducer of apoptosis (TWEAK) is a potent skeletal muscle-wasting cytokine. 1731 37

For over fifty years lithium has been a fundamental component of therapy for patients with bipolar disorders. Lithium has been considered recently for its potential to alleviate neuronal loss and other neurodegeneration processes. For instance, lithium reduces the severity of some behavioral complications of Alzheimer's disease (AD). And there are growing indications that lithium may be of benefit to the underlying pathology of AD, as well as an array of other common CNS disorders, including stroke, Parkinson's disease, and Huntington's disease. Despite these demonstrated and prospective therapeutic benefits, lithium's mechanism of action remains elusive, and opinions differ regarding the most relevant molecular targets. Lithium inhibits several enzymes; significant among these are inositol monophosphatase (IMPase), glycogen synthase kinase-3 (GSK-3), and the proteasome. Most recent publications discussing the medical application of lithium have converged on GSK-3, so this article reviews data and discussions regarding the roles and interactions of GSK-3 with other proteins and its proposed role in the pathogenesis of Alzheimer's disease.
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PMID:Glycogen synthase kinase-3 in neurodegeneration and neuroprotection: lessons from lithium. 1731 63

Hypoxia-inducible transcription factor 1alpha (HIF-1alpha) is a key player in the response to hypoxia. Additionally, HIF-1alpha responds to growth factors and hormones which can act via protein kinase B (Akt). However, HIF-1alpha is not a direct substrate for this kinase. Therefore, we investigated whether the protein kinase B target glycogen synthase kinase 3 (GSK-3) may have an impact on HIF-1alpha. We found that the inhibition or depletion of GSK-3 induced HIF-1alpha whereas the overexpression of GSK-3beta reduced HIF-1alpha. These effects were mediated via three amino acid residues in the oxygen-dependent degradation domain of HIF-1alpha. In addition, mutation analyses and experiments with von Hippel-Lindau (VHL)-defective cells indicated that GSK-3 mediates HIF-1alpha degradation in a VHL-independent manner. In line with these observations, the inhibition of the proteasome reversed the GSK-3 effects, indicating that GSK-3 may target HIF-1alpha to the proteasome by phosphorylation. Thus, the direct regulation of HIF-1alpha stability by GSK-3 may influence physiological processes or pathophysiological situations such as metabolic diseases or tumors.
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PMID:Glycogen synthase kinase 3 phosphorylates hypoxia-inducible factor 1alpha and mediates its destabilization in a VHL-independent manner. 1732 32

Apoptosis is critical for embryonic development, tissue homeostasis, and tumorigenesis and is determined largely by the Bcl-2 family of antiapoptotic and prosurvival regulators. Here, we report that glycogen synthase kinase 3 (GSK-3) was required for Mcl-1 degradation, and we identified a novel mechanism for proteasome-mediated Mcl-1 turnover in which GSK-3beta associates with and phosphorylates Mcl-1 at one consensus motif ((155)STDG(159)SLPS(163)T; phosphorylation sites are in italics), which will lead to the association of Mcl-1 with the E3 ligase beta-TrCP, and beta-TrCP then facilitates the ubiquitination and degradation of phosphorylated Mcl-1. A variant of Mcl-1 (Mcl-1-3A), which abolishes the phosphorylations by GSK-3beta and then cannot be ubiquitinated by beta-TrCP, is much more stable than wild-type Mcl-1 and able to block the proapoptotic function of GSK-3beta and enhance chemoresistance. Our results indicate that the turnover of Mcl-1 by beta-TrCP is an essential mechanism for GSK-3beta-induced apoptosis and contributes to GSK-3beta-mediated tumor suppression and chemosensitization.
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PMID:Degradation of Mcl-1 by beta-TrCP mediates glycogen synthase kinase 3-induced tumor suppression and chemosensitization. 1738 46

The activity of protein phosphatase-2A (PP-2A) is significantly suppressed in the brain of Alzheimer's disease (AD) patients, but the mechanism is not understood. Here, we found an in vivo association of glycogen synthase kinase 3beta (GSK-3beta) with inhibitor-2 of PP-2A (I(2)(PP-2A)). The activation of GSK-3 resulted in accumulation of I(2)(PP-2A) with concomitant suppression of PP-2A activity and increases of tau phosphorylation in HEK293, N2a and PC12 cells, while inhibition of GSK-3 caused decreases of I(2)(PP-2A) with increased PP-2A activity and decreased tau phosphorylation. A positive correlation between GSK-3beta and I(2)(PP-2A) (R=0.9158) and a negative correlation between GSK-3beta and PP-2A (R=-0.9166) were detected. GSK-3 activation did not affect I(2)(PP-2A) mRNA level, while it increased the mRNA level of a heterogeneous ribonucleoprotein A18 (hnRNP A18). The activation of GSK-3 increased the expression and the activity of proteasome system. It suggests that activation of GSK-3 inhibits PP-2A through up-regulation of I(2)(PP-2A) with hnRNP A18-involved mechanism.
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PMID:Activation of glycogen synthase kinase-3 inhibits protein phosphatase-2A and the underlying mechanisms. 1743 4

Myeloid cell leukemia-1 (Mcl-1), an antiapoptotic Bcl-2 family member, is overexpressed in many types of human cancer and associates with cell immortalization, malignant transformation, and chemoresistance. Glycogen synthase kinase-3beta (GSK-3beta), a key component of the Wnt signaling pathway, is involved in multiple physiologic processes such as protein synthesis, tumorigenesis, and apoptosis. Here, we report that expression of Mcl-1 was correlated with phosphorylated GSK-3beta (p-GSK-3beta) at Ser(9) (an inactivated form of GSK-3beta) in multiple cancer cell lines and primary human cancer samples. In addition, Mcl-1 was strikingly linked with poor prognosis of human breast cancer, in which the high level of Mcl-1 was related to high tumor grade and poor survival of breast cancer patients. Furthermore, we found that activation of GSK-3beta could down-regulate Mcl-1 and was required for proteasome-mediated Mcl-1 degradation. Under some physiologic conditions, such as UV irradiation, anticancer drug treatment, and inhibition of growth factor pathways, Mcl-1 was down-regulated through activation of GSK-3beta. Our results indicate that Mcl-1 stabilization by GSK-3beta inactivation could be involved in tumorigenesis and serve as a useful prognostic marker for human breast cancer.
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PMID:Myeloid cell leukemia-1 inversely correlates with glycogen synthase kinase-3beta activity and associates with poor prognosis in human breast cancer. 1749 24

D-type cyclins are direct targets of extracellular signals and critical regulators of G(1) progression. Our previous data demonstrated that IGF-I and FGF-2 synergize to enhance cyclin D1 expression, cyclin E/cdk2 complex activation, and S-phase entry in OP cells. Here, we provide a mechanistic explanation for how two growth factor signaling pathways converge on a major cell cycle regulator. IGF-I and FGF-2 differentially activate signaling pathways to coordinately promote cyclin D1 expression. We show that the p44/p42 MAPK signaling pathway is essential for FGF-2 induction of cyclin D1 mRNA. In contrast, blocking the PI3-Kinase pathway results in loss of IGF-I/FGF-2 synergistic induction of cyclin D1 protein levels. Moreover, the presence of IGF-I significantly enhances nuclear localization of cyclin D1, which also requires PI3K signaling. GSK-3beta, a downstream target of the PI3K/Akt pathway, is phosphorylated in the presence of IGF-I in OPs. Consistent with a known role for GSK-3beta in cyclin D1 degradation, we show that proteasome inhibition in OPs exposed to FGF-2 increased cyclin D1 levels, equivalent to levels seen in IGF-I/FGF-2 treated cells. Thus, we provide a model for cyclin D1 coordinate regulation where FGF-2 stimulation of the MAPK pathway promotes cyclin D1 mRNA expression while IGF-I activation of the PI3K pathway inhibits proteasome degradation of cyclin D1 and enhances nuclear localization of cyclin D1.
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PMID:Synergistic induction of cyclin D1 in oligodendrocyte progenitor cells by IGF-I and FGF-2 requires differential stimulation of multiple signaling pathways. 1750 24

Beta-catenin is the central signalling molecule of the canonical Wnt pathway, where it activates target genes in a complex with lymphoid enhancer factor/T-cell factor transcription factors in the nucleus. The regulation of beta-catenin activity is thought to occur via a cytoplasmatic multiprotein complex that includes the serine/threonine kinase glycogen synthase kinase-3beta (GSK-3beta) that phosphorylates beta-catenin, marking it for degradation by the proteasome. Here, we provide evidence showing that GSK-3beta has a nuclear function in downregulating the activity of beta-catenin. Using colorectal cell lines that express a mutant form of beta-catenin, which cannot be phosphorylated by GSK-3beta and ectopically expressed mutant beta-catenin protein, we show that nuclear GSK-3beta functions in a mechanism that does not involve beta-catenin phosphorylation to reduce the levels of Wnt signalling. We show that GSK-3beta enters the nucleus, forms a complex with beta-catenin and lowers the levels of beta-catenin/TCF-dependent transcription in a mechanism that involves GSK-3beta-Axin binding.
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PMID:Nuclear GSK-3beta inhibits the canonical Wnt signalling pathway in a beta-catenin phosphorylation-independent manner. 1822 84

Functional characterization of signaling pathways that critically control mantle cell lymphoma (MCL) cell growth and survival is relevant to designing new therapies for this lymphoma. We herein demonstrate that the constitutive activation of Akt correlates with the expression of the phosphorylated, inactive form of PTEN. Phosphatidyl-inositol-3 kinase (PI3-K)/Akt or mammalian target of rapamycin (mTOR) inhibition decreased the growth of both primary MCL cultures and established cell lines and antagonizes the growth-promoting activity of CD40 triggering and IL-4. These effects are mediated by nuclear accumulation of the p27(Kip1) inhibitor induced by down-regulation of the p45(Skp2) and Cks1 proteins, which target p27(Kip1) for degradation. Moreover, Akt inhibition down-regulated cyclin D1 by promoting its proteasome-dependent degradation driven by GSK-3. Intriguingly, mTOR inhibition affected cyclin D1 proteolysis only in MCL cells in which GSK-3 is under the direct control of mTOR, suggesting that different MCL subsets could be differently responsive to mTOR inhibition. Finally, PI3-K/Akt inhibitors, but not rapamycin, induced variable levels of caspase-dependent apoptosis and reduced telomerase activity. These results indicate that Akt and mTOR activation have distinct functional relevance in MCL and suggest that targeting Akt may result in more effective therapeutic effects compared with mTOR inhibition.
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PMID:Distinct functional significance of Akt and mTOR constitutive activation in mantle cell lymphoma. 1833 99


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