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 tumor suppressor phosphatase PTEN regulates cell migration, growth, and survival by dephosphorylating phosphatidylinositol second messengers and signaling phosphoproteins. PTEN possesses a C-terminal noncatalytic regulatory domain that contains multiple putative phosphorylation sites, which could play an important role in the control of its biological activity. The protein kinase CK2 phosphorylated, in a constitutive manner, a cluster of Ser/Thr residues located at the PTEN C terminus. PTEN-phosphorylated defective mutants showed decreased stability in comparison with wild type PTEN and were more rapidly degraded by the proteasome. Inhibition of PTEN phosphorylation by the CK2 inhibitor 5,6-dichloro-1-beta-d-ribofuranosyl-benzimidazole also diminished the PTEN protein content. Our results support the notion that proper phosphorylation of PTEN by CK2 is important for PTEN protein stability to proteasome-mediated degradation.
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PMID:The tumor suppressor PTEN is phosphorylated by the protein kinase CK2 at its C terminus. Implications for PTEN stability to proteasome-mediated degradation. 1103 45

The Nuclear Factor (NF)-kappaB family of transcription factors controls expression of genes which promote cell growth, survival, and neoplastic transformation. Recently we demonstrated aberrant constitutive activation of NF-kappaB in primary human and rat breast cancer specimens and in cell lines. Overexpression of the epidermal growth factor receptor (EGFR) family member Her-2/neu, seen in approximately 30% of breast cancers, is associated with poor prognosis. Previously, Her-2/neu has been shown to signal via a phosphatidylinositol 3 (PI3)-kinase to Akt/protein kinase B (PKB) pathway. Since this signaling pathway was recently shown to activate NF-kappaB, here we have tested the hypothesis that Her-2/neu can activate NF-kappaB in breast cancer. Overexpression of Her-2/neu and EGFR-4 in Ba/F3 cells led to constitutive PI3- and Akt kinase activities, and induction of classical NF-kappaB (p50/p65). Similarly, a tumor cell line and tumors derived from MMTV-Her-2/neu transgenic mice displayed elevated levels of classical NF-kappaB. Engagement of Her-2/neu receptor downregulated the level of NF-kappaB. NF-kappaB binding and activity in the cultured cells was reduced upon inhibition of the PI3- to Akt kinase signaling pathway via ectopic expression of kinase inactive mutants, incubation with wortmannin, or expression of the tumor suppressor phosphatase PTEN. Inhibitors of calpain, but not the proteasome, blocked IkappaB-alpha degradation. Inhibition of Akt did not affect IKK activity. These results indicate that Her-2/neu activates NF-kappaB via a PI3- to Akt kinase signaling pathway that can be inhibited via the tumor suppressor PTEN, and is mediated by calpain rather than the IkappaB kinase complex.
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PMID:Her-2/neu overexpression induces NF-kappaB via a PI3-kinase/Akt pathway involving calpain-mediated degradation of IkappaB-alpha that can be inhibited by the tumor suppressor PTEN. 1131 73

Disruption of the gene for the cyclin dependent kinase inhibitor (CDKI) p27/kip1 results in pituitary corticotroph hyperplasia while diminished expression of this protein has been described in aggressive human pituitary tumors. We have previously shown that 1,25-vitamin D3 (VD) hypophosphorylates p27 and interferes with the degradation of this CDKI in thyroid carcinoma cells. In this study we investigated whether VD/EB1089 can induce p27 accumulation and cause growth arrest of pituitary corticotroph cells. VD and EB1089 exhibited a significant reduction in AtT20 corticotroph but not PRL235 lactotroph cell growth. These changes were accompanied by selective accumulation of p27 in AtT20 but not in PRL235 cells. As p27 levels are highly dependent on protein degradation, we examined the effect of VD/EB1089 on p27 association with factors that target this CDKI to the proteasome. VD/EB1089 significantly restricted the association of p27 with Skp2 as well as with cyclin dependent kinase 2 (CDK2). As the tumor suppressor and phosphatase PTEN has been implicated in p27 regulation, we tested whether the effects of VD/EB1089 on p27 accumulation in corticotrophs could be mediated through this pathway. VD/EB1089 did not appreciably alter PTEN expression. Moreover, transfection of PTEN did not influence the effect of VD on p27 accumulation in corticotrophs. We conclude that VD/EB1089 can selectively arrest pituitary corticotroph growth and induce p27 accumulation.This effect is mediated at least partially through diminished p27 association with Skp2 and with CDK2. In contrast to other cell systems, PTEN does not participate in the regulation of corticotroph p27 and is not involved in mediating the effect of VD on p27 in these cells. Our findings highlight p27 and VD analogs as targets for manipulation and drug development respectively in the treatment of inoperable corticotroph adenomas.
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PMID:Vitamin D and its analog EB1089 induce p27 accumulation and diminish association of p27 with Skp2 independent of PTEN in pituitary corticotroph cells. 1240 27

The tumor suppressor PTEN is a putative negative regulator of the phosphatidylinositol 3-kinase/Akt pathway. Exposure to Zn2+ ions induces Akt activation, suggesting that PTEN may be modulated in this process. Therefore, the effects of Zn2+ on PTEN were studied in human airway epithelial cells and rat lungs. Treatment with Zn2+ resulted in a significant reduction in levels of PTEN protein in a dose- and time-dependent fashion in a human airway epithelial cell line. This effect of Zn2+was also observed in normal human airway epithelial cells in primary culture and in rat airway epithelium in vivo. Concomitantly, levels of PTEN mRNA were also significantly reduced by Zn2+ exposure. PTEN phosphatase activity evaluated by measuring Akt phosphorylation decreased after Zn2+ treatment. Pretreatment of the cells with a proteasome inhibitor significantly blocked zinc-induced reduction of PTEN protein as well as the increase in Akt phosphorylation, implicating the involvement of proteasome-mediated PTEN degradation. Further study revealed that Zn2+-induced ubiquitination of PTEN protein may mediate this process. A phosphatidylinositol 3-kinase inhibitor blocked PTEN degradation induced by Zn2+, suggesting that phosphatidylinositol 3-kinase may participate in the regulation of PTEN. However, both the proteasome inhibitor and phosphatidylinositol 3-kinase inhibitor failed to prevent significant down-regulation of PTEN mRNA expression in response to Zn2+. In summary, exposure to Zn2+ ions causes PTEN degradation and loss of function, which is mediated by an ubiquitin-associated proteolytic process in the airway epithelium.
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PMID:Zinc-induced PTEN protein degradation through the proteasome pathway in human airway epithelial cells. 1274 24

The stability of p53 tumor suppressor is regulated by Mdm2 via the ubiquitination and proteasome-mediated proteolysis pathway. The c-Abl and PTEN tumor suppressors are known to stabilize p53 by blocking the Mdm2-mediated p53 degradation. This study investigated the correlation between p53 and merlin, a neurofibromatosis 2 (NF2)-related tumor suppressor, in association with the Mdm2 function. The results showed that merlin increased the p53 stability by inhibiting the Mdm2-mediated degradation of p53, which accompanied the increase in the p53-dependent transcriptional activity. The stabilization of p53 by merlin appeared to be accomplished through Mdm2 degradation, and the N-terminal region of merlin was responsible for this novel activity. This study also showed that overexpression of merlin-induced apoptosis of cells depending preferentially on p53 in response to the serum starvation or a chemotherapeutic agent. These results suggest that merlin could be a positive regulator of p53 in terms of tumor suppressor activity, and provide the promising therapeutic means for treating tumors with non-functional merlin or Mdm2 overexpression.
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PMID:Merlin neutralizes the inhibitory effect of Mdm2 on p53. 1467 3

Geldanamycin (GA) binds to heat shock protein 90 (Hsp90) and interferes with its function which is to protect various cellular proteins involved in signaling, growth control, and survival from ubiquitination and subsequent degradation by the proteasome. Recently, we demonstrated that GA inhibited migration of glioma cells in vitro associated with downregulation of hypoxia-inducible factor (HIF-1 alpha) and phosphorylation of focal adhesion kinase (FAK) (Zagzag et al., 2003, J Cell Physiol 196:394-402). Here, we have investigated the mechanisms through which GA treatment of the T98G glioma cell line induces apoptosis. We found that GA treatment induced cell death in a caspase-dependent manner through activation of caspase-3 and PARP cleavage together with release of cytochrome c and apoptosis inducing factor (AIF) from the mitochondria. Use of synchronized T98G cells showed that GA treatment of glioma cells during S-phase enhanced cytotoxicity followed by M-phase arrest, resulting in mitotic catastrophe. In addition, apoptosis was associated with the downregulation of the survival protein, phosphorylated Akt (pAkt), an important signaling protein in the PI3K pathway, that is overexpressed in many cancers including gliomas. Given that many glioma tumors show deregulation of the PI3K signaling pathway, either through loss of the tumor suppressor protein PTEN or overexpression of the growth factor EGFR, the ability to identify different subsets of patients using simple immunohistochemistry for the presence of absence of pAkt could enable selection of the appropriate kinase inhibitor, such as GA, for drug therapy. Based on our data presented here, GA or its analogs may have potential in the treatment of glioma.
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PMID:Geldanamycin induces mitotic catastrophe and subsequent apoptosis in human glioma cells. 1538 45

Clozapine (CZP), a dibenzodiazepine derivative with a piperazinyl side chain, is in clinical use as an antipsychotic drug. This study investigated the effect of CZP on the modulation of the PI3K/Akt/GSK-3beta pathway in PTEN-negative U-87MG glioblastoma cells. Treatment with CZP rapidly inhibited the basal and EGF-induced phosphorylation of Akt. The inhibition of Akt resulted in the dephosphorylation of GSK-3beta and increased GSK-3beta kinase activity. A voltage-sensitive Ca(2+) channel blocker and calmodulin (CaM) antagonists inhibited Akt phosphorylation, whereas elevation of the intracellular Ca(2+) concentration prevented CZP-induced dephosphorylation of Akt and GSK-3beta, suggesting that Ca(2+)/CaM participates in the inhibition of Akt by CZP in U-87MG cells. In addition, similar to LY294002, CZP arrested cell cycle progression at G0/G1 phase, which was accompanied by decreased expression of cyclin D1. The reduction in the cyclin D1 level induced by CZP was abrogated by the inhibition of GSK-3beta, the inhibition of proteasome-dependent proteolysis, or an increase in the intracellular Ca(2+) concentration. These results suggest that the antipsychotic drug CZP modulates the PI3K/Akt/GSK-3beta pathway by counteracting Ca(2+)/CaM in PTEN-negative U-87MG glioblastoma cells.
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PMID:Clozapine, a neuroleptic agent, inhibits Akt by counteracting Ca2+/calmodulin in PTEN-negative U-87MG human glioblastoma cells. 1654 21

PTEN (phosphatase and tension homolog deleted on chromosome 10) has been shown to be inactivated in a wide range of cancers and the role of this gene product is associated with the suppression of the phosphatidylinositol-3-kinase (PI3K)/Akt pathway in many cancers. Recently, some reports demonstrated that the degree of PTEN expression could predict trastuzumab chemosensitivity in ErbB2-overexpressing breast cancer. Here, we demonstrate the possible involvement of a proteasome inhibitor (PS341) in PTEN expression and elucidate the influence of PI3K/Akt, one of the main cascades of the ErbB2 downstream pathway, and discuss the role of the proteasome inhibitors in trastuzumab resistance. ErbB2-overexpressing SKBR3 human breast cancer cells and trastuzumab-resistant SKBR3/R cells were analyzed in this study. We show that the expression of phosphorylated Akt was highly increased in trastuzumab-resistant cells, although the expression of PI3K, phosphorylated PI3K and non-phosphorylated Akt was unchanged in comparison with wild-type SKBR3 cells. However, following treatment with PS341, the level of phosphorylated Akt was decreased in a dose-dependent manner. Conversely, the level of PTEN was increased in the same fashion. PS341 showed sufficient cytotoxicity in resistant cells in combination with trastuzumab and the efficacy of trastuzumab was inclined to be better in resistant cells under PS341 treatment. Remarkable activity of Akt was observed in trastuzumab-resistant SKBR3 breast cancer cells and this phenomenon could be associated with the decreased expression of PTEN. The proteasome inhibitor PS341 could increase the level of PTEN and inhibit the downstream pathway of ErbB2, interfering with phosphorylation of Akt.
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PMID:Proteasome inhibitor bortezomib increases PTEN expression and enhances trastuzumab-induced growth inhibition in trastuzumab-resistant cells. 1655 4

Angiogenesis is a hallmark of melanoma progression. Antiangiogenic agents have been infrequently tested in patients with advanced melanoma. Experience with most other cancers suggests that single-agent application of angiogenic inhibitors is unlikely to have substantial clinical antitumor activity in melanoma. It is more likely that combinations of antiangiogenic agents with either chemotherapy or other targeted therapy will be needed to produce significant clinical benefit. In melanoma, numerous cellular pathways important to cell proliferation, apoptosis, or metastases have recently been shown to be activated. Activation occurs through specific mutations (B-RAF, N-RAS, and PTEN) or changes in expression levels of various proteins (PTEN, BCL-2, NF-kappaB, CDK2, and cyclin D1). Agents that block these pathways are rapidly entering the clinical setting, including RAF inhibitors (sorafenib), mitogen-activated protein kinase inhibitors (PD0325901), mammalian target of rapamycin inhibitors (CCI-779), and farnesyl transferase inhibitors (R115777) that inhibit N-RAS and proteasome inhibitors (PS-341) that block activation of nuclear factor-kappaB (NF-kappaB). It will be a challenge to evaluate these agents alone, in combination with each other, or with chemotherapy in patients with melanoma. Trials with large populations of biologically ill-defined tumors run the risk of missing clinical antitumor activity that is important for a particular yet-to-be-defined subset of patients. To rationally and optimally develop these targeted agents, it will be critical to adequately test for the presence of the presumed cellular target in tumor specimens and the effect of therapy on the proposed target (biological response). Investigators in this field will need to carefully plan these trials so that at the end of the day, we learn from both the failures and successes of targeted therapy.
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PMID:Molecular targets in melanoma from angiogenesis to apoptosis. 1660 62

Following our identification of PTEN-induced putative kinase 1 (PINK1) gene mutations in PARK6-linked Parkinson's disease (PD), we have recently reported that PINK1 protein localizes to Lewy bodies (LBs) in PD brains. We have used a cellular model system of LBs, namely induction of aggresomes, to determine how a mitochondrial protein, such as PINK1, can localize to aggregates. Using specific polyclonal antibodies, we firstly demonstrated that human PINK1 was cleaved and localized to mitochondria. We demonstrated that, on proteasome inhibition with MG-132, PINK1 and other mitochondrial proteins localized to aggresomes. Ultrastructural studies revealed that the mechanism was linked to the recruitment of intact mitochondria to the aggresome. Fractionation studies of lysates showed that PINK1 cleavage was enhanced by proteasomal stress in vitro and correlated with increased expression of the processed PINK1 protein in PD brain. These observations provide valuable insights into the mechanisms of LB formation in PD that should lead to a better understanding of PD pathogenesis.
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PMID:Altered cleavage and localization of PINK1 to aggresomes in the presence of proteasomal stress. 1680 5


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