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)

Quinidine inhibits proliferation and promotes cellular differentiation in human breast tumor epithelial cells. Previously we showed quinidine arrested MCF-7 cells in G(1) phase of the cell cycle and led to a G(1) to G(0) transition followed by apoptotic cell death. The present experiments demonstrated that MCF-7, MCF-7ras, T47D, MDA-MB-231, and MDA-MB-435 cells transiently differentiate before undergoing apoptosis in response to quinidine. The cells accumulated lipid droplets, and the cytokeratin 18 cytoskeleton was reorganized. Hyperacetylated histone H4 appeared within 2 h of the addition of quinidine to the medium, and levels were maximal by 24 h. Quinidine-treated MCF-7 cells showed elevated p21(WAF1), hypophosphorylation and suppression of retinoblastoma protein, and down-regulation of cyclin D1, similar to the cell cycle response observed with cells induced to differentiate by histone deacetylase inhibitors, trichostatin A, and trapoxin. Quinidine did not show evidence for direct inhibition of histone deacetylase enzymatic activity in vitro. HDAC1 was undetectable in MCF-7 cells 30 min after addition of quinidine to the growth medium. The proteasome inhibitors MG-132 and lactacystin completely protected HDAC1 from the action of quinidine. We conclude that quinidine is a breast tumor cell differentiating agent that causes the loss of HDAC1 via a proteasomal sensitive mechanism.
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PMID:Rapid induction of histone hyperacetylation and cellular differentiation in human breast tumor cell lines following degradation of histone deacetylase-1. 1093 72

The oncoprotein BCL-3 is a nuclear transcription factor that activates NF-kappaB target genes through formation of heterocomplexes with p50 or p52. BCL-3 is phosphorylated in vivo, but specific BCL-3 kinases have not been identified so far. In this report, we show that BCL-3 is a substrate for the protein kinase GSK3 and that GSK3-mediated BCL-3 phosphorylation, which is inhibited by Akt activation, targets its degradation through the proteasome pathway. This phosphorylation modulates its association with HDAC1, -3, and -6 and attenuates its oncogenicity by selectively controlling the expression of a subset of newly identified target genes such as SLPI and Cxcl1. Our results therefore suggest that constitutive BCL-3 phosphorylation by GSK3 regulates BCL-3 turnover and transcriptional activity.
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PMID:GSK3-mediated BCL-3 phosphorylation modulates its degradation and its oncogenicity. 1546 20

Studies have shown that CCAAT/enhancer-binding protein beta (C/EBP beta) can stimulate adipogenesis in noncommitted fibroblasts by activating expression of peroxisome proliferator-activated receptor-gamma (PPARgamma). Other investigations have established a role for C/EBP alpha as well as PPARgamma in orchestrating the complex program of adipogenic gene expression during terminal preadipocyte differentiation. Consequently, it is important to identify factors regulating transcription of the C/ebp alpha gene. In this study, we demonstrated that inhibition of PPARgamma activity by exposure of 3T3-L1 preadipocytes to a potent and selective PPARgamma antagonist inhibits adipogenesis but also blocks the activation of C/EBP alpha expression at the onset of differentiation. Ectopic expression of C/EBP beta in Swiss 3T3 mouse fibroblasts (Swiss-LAP cells) induces PPARgamma expression without any significant enhancement of C/EBP alpha expression. Treatment of Swiss-LAP cells with a PPARgamma agonist induces adipogenesis, which includes activation of C/EBP alpha expression. To further establish a role for PPARgamma in regulating C/EBP alpha expression, we expressed C/EBP beta in PPARgamma-deficient mouse embryo fibroblasts (MEFs). The data show that C/EBP beta is capable of inducing PPARgamma in Ppar gamma+/- MEFs, which leads to activation of adipogenesis, including C/EBP alpha expression following exposure to a PPARgamma ligand. In contrast, C/EBP beta is not able to induce C/EBP alpha expression or adipogenesis in Ppar gamma-/- MEFs. Chromatin immunoprecipitation analysis reveals that C/EBP beta is bound to the minimal promoter of the C/ebp alpha gene in association with HDAC1 in unstimulated Swiss-LAP cells. Exposure of the cells to a PPARgamma ligand dislodges HDAC1 from the proximal promoter of the C/ebp alpha gene, which involves degradation of HDAC1 in the 26 S proteasome. These data suggest that C/EBP beta activates a single unified pathway of adipogenesis involving its stimulation of PPARgamma expression, which then activates C/EBP alpha expression by dislodging HDAC1 from the promoter for degradation in the proteasome.
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PMID:Activation of CCAAT/enhancer-binding protein (C/EBP) alpha expression by C/EBP beta during adipogenesis requires a peroxisome proliferator-activated receptor-gamma-associated repression of HDAC1 at the C/ebp alpha gene promoter. 1643 20

Prostate cancer cells rely on androgen receptor (AR) for proliferation and survival. Therefore, curing prostate cancer will require elimination of AR. Although androgen is the natural ligand that activates AR, AR activity is also subject to regulation by growth factor/growth factor receptor-stimulated signaling pathways that control the cell cycle. Cell cycle regulatory proteins and protein kinases in signaling pathways affected by growth factors can lead to AR activation in the absence of androgen. While downstream signaling proteins such as cyclins, cyclin-dependent kinases (CDKs), and pRB can modulate AR activity, upstream signaling pathways involving protein kinases such as mitogen-activated protein kinases, protein kinase A, and protein kinase B/Akt can affect post-translational modification of AR to affect not only AR function but also AR stability. Calcium and calmodulin (CaM), essential for proliferation and viability of a number of cells, including prostate cancer cells, play an important role in AR expression, stability, and function. CaM affects AR partly by interacting directly with AR and partly by activating protein kinases such as Akt and DNA-PK that can phosphorylate AR. The ubiquitin/26S proteasome pathway responsible for timely destruction of cell cycle regulatory proteins whose levels impede cell cycle progression also induces AR expression by activating NF-kappaB, and promotes AR activity by participating in the assembly of an AR transcription complex. Maspin, a serine protease inhibitor that is known mostly for its role as a tumor suppressor can also regulate AR intracellular localization and function by competing with AR for binding to the chaperone protein Hsp90 and co-repressor HDAC1, respectively. This perspective reviews the experimental evidence implicating these diverse cellular processes in AR expression, stability, and/or function, and presents a rationale for disrupting these cellular processes as a viable option for the treatment of both the hormone-sensitive and the hormone-insensitive prostate cancer.
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PMID:Regulatory processes affecting androgen receptor expression, stability, and function: potential targets to treat hormone-refractory prostate cancer. 1661 63

We have reported that a novel c-Myc-binding protein, MM-1, repressed the E-box-dependent transcription activity of c-Myc by recruiting the HDAC1 complex via TIF1beta/KAP1, a transcriptional corepressor. We have also reported that a mutation of A157R in MM-1, which is often observed in patients with leukemia or lymphoma, abrogated all of the repressive activities of MM-1 toward c-Myc, indicating that MM-1 is a novel tumor suppressor. In this study, we found that MM-1 was bound to a component of proteasome and stimulated degradation of c-Myc in human cells. Knockdown of endogenous MM-1 in human HeLa cells by introduction of siRNA against MM-1 stabilized the endogenous c-Myc. To identify proteins that participate in c-Myc degradation by MM-1, in vivo and in vitro binding assays were carried out. The results showed that MM-1 directly bound to Rpt3, a subunit of 26S proteasome, and that c-Myc directly bound to Skp2, which recruited ElonginC, ElonginB and Cullin2, thereby forming a novel ubiquitin E3 ligase. Knockdown of endogenous Cullin2 stabilized the endogenous c-Myc. Thus, MM-1 is a factor that connects c-Myc to the ubiquitin E3 ligase and the proteasome.
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PMID:MM-1 facilitates degradation of c-Myc by recruiting proteasome and a novel ubiquitin E3 ligase. 1778 14

IFIXalpha, a member of the interferon-inducible HIN-200 family, has been identified as a putative tumor suppressor. However, the molecular mechanisms underlying IFIXalpha-mediated tumor suppression are poorly understood. In the present study, we demonstrated that the metastasis suppressor maspin acts as the downstream target of IFIXalpha. IFIXalpha suppressed the invasion activity of MDA-MB-468 breast cancer cells, and its inhibitory effect was reversed by the knockdown of maspin. Both Maspin mRNA and protein were upregulated by IFIXalpha. Histone deacetylase (HDAC) inhibitors, but not DNA methyltransferase inhibitor upregulated maspin, and HDAC1 inhibited the transactivation of maspin promoter. Although the HDAC1 protein was downregulated in IFIXalpha-expressing cells, IFIXalpha did not affect HDAC1 mRNA levels. Conversely, a proteasome inhibitor restored the level of HDAC1 protein in IFIXalpha-expressing cells, and the polyubiqutination of HDAC1 was promoted by IFIXalpha, suggesting that HDAC1 is regulated by IFIXalpha through a ubiquitin-proteasome pathway. Together, these data provide novel insights into the tumor-suppressive function of IFIXalpha.
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PMID:Interferon-inducible protein IFIXalpha inhibits cell invasion by upregulating the metastasis suppressor maspin. 1824 78

Histone deacetylases (HDAC) play a critical role in chromatin modification and gene expression. Recent evidence indicates that HDACs can also regulate functions of nonhistone proteins by catalyzing the removal of acetylated lysine residues. Here, we show that the HDAC inhibitor LBH589 down-regulates DNA methyltransferase 1 (DNMT1) protein expression in the nucleus of human breast cancer cells. Cotreatment with the proteasomal inhibitor MG-132 abolishes the ability of LBH589 to reduce DNMT1, suggesting that the proteasomal pathway mediates DNMT1 degradation on HDAC inhibition. Deletion of the NH(2)-terminal 120 amino acids of DNMT1 diminishes LBH589-induced ubiquitination, indicating that this domain is essential for its proteasomal degradation. DNMT1 recruits the molecular chaperone heat shock protein 90 (Hsp90) to form a chaperone complex. Treatment with LBH589 induces hyperacetylation of Hsp90, thereby inhibiting the association of DNMT1 with Hsp90 and promoting ubiquitination of DNMT1. In addition, inactivation of HDAC1 activity by small interfering RNA and MS-275 is associated with Hsp90 acetylation in conjunction with reduction of DNMT1 protein expression. We conclude that the stability of DNMT1 is maintained in part through its association with Hsp90. Disruption of Hsp90 function by HDAC inhibition is a unique mechanism that mediates the ubiquitin-proteasome pathway for DNMT1 degradation. Our studies suggest a new role for HDAC1 and identify a novel mechanism of action for the HDAC inhibitors as down-regulators of DNMT1.
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PMID:Inhibition of histone deacetylases promotes ubiquitin-dependent proteasomal degradation of DNA methyltransferase 1 in human breast cancer cells. 1850 31

Telomerase activity, which has fundamental roles in development and carcinogenesis, strongly depends on the expression of human telomerase reverse transcriptase (hTERT), its catalytic subunit. In this report, we show that the basic helix-loop-helix factor, TAL1 (T-cell acute lymphoblastic leukemia 1), is a negative regulator of the hTERT promoter. Indeed, TAL1 overexpression leads to a decrease in hTERT mRNA abundance and hence to reduced telomerase activity. Conversely, suppression of TAL1 by RNA interference in Jurkat cells increases hTERT expression. Analysis by chromatin immunoprecipitation assays showed that TAL1 binds to the hTERT proximal promoter and recruits HDAC1. Considering the relationship recently established between TAL1 and the human T-cell leukemia virus type 1 (HTLV-1) Tax protein, which was confirmed in T lymphocyte clones derived from adult T-cell leukemia patients, we analyzed the effect of TAL1 with respect to the earlier characterized effects of Tax and HBZ (HTLV-1 basic leucine zipper) on hTERT expression. TAL1 was observed to reinforce the negative effect of Tax, whereas hTERT transactivation by the HBZ-JunD complex was repressed by TAL1 overexpression. Moreover, HBZ was found to induce proteasome-mediated degradation of TAL1. These observations support a model in which Tax and TAL1 by repressing hTERT would initially favor genomic instability, whereas expression of factors such as HBZ allows at a later stage an increase in hTERT production and consequently in telomerase activity.
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PMID:Inhibition of the hTERT promoter by the proto-oncogenic protein TAL1. 1958 3

3,3'-Diindolylmethane (DIM) is an anticancer agent that induces cell cycle arrest and apoptosis through unknown mechanisms. Here, we report that DIM can selectively induce proteasome-mediated degradation of class I histone deacetylases (HDAC1, HDAC2, HDAC3, and HDAC8) without affecting the class II HDAC proteins. DIM induced downregulation of class I HDACs in human colon cancer cells in vitro and in vivo in tumor xenografts. HDAC depletion relieved HDAC-mediated transcriptional inhibition of the cyclin-dependent kinase inhibitors p21WAF1 and p27KIP2, significantly increasing their expression and triggering cell cycle arrest in the G(2) phase of the cell cycle. Additionally, HDAC depletion was associated with an induction of DNA damage that triggered apoptosis. Our findings indicate that DIM acts to selectively target the degradation of class I HDACs.
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PMID:Chemopreventive agent 3,3'-diindolylmethane selectively induces proteasomal degradation of class I histone deacetylases. 2006 55

Polycomb group (PcG) protein-dependent histone methylation and ubiquitination drives chromatin compaction leading to reduced tumor suppressor expression and increased cancer cell survival. Green tea polyphenols and S-adenosylhomocysteine (AdoHcy) hydrolase inhibitors are important candidate chemopreventive agents. Previous studies indicate that (-)-epigallocatechin-3-gallate (EGCG), a potent green tea polyphenol, suppresses PcG protein level and skin cancer cell survival. Inhibition of AdoHcy hydrolase with 3-deazaneplanocin A (DZNep) inhibits methyltransferases by reducing methyl group availability. In the present study, we examine the impact of EGCG and DZNep cotreatment on skin cancer cell function. EGCG and DZNep, independently and in combination, reduce the level of PcG proteins including Ezh2, eed, Suz12, Mel18 and Bmi-1. This is associated with reduced H3K27me3 and H2AK119ub formation, histone modifications associated with closed chromatin. Histone deacetylase 1 level is also reduced and acetylated H3 formation is increased. These changes are associated with increased tumor suppressor expression and reduced cell survival and are partially reversed by vector-mediated maintenance of Bmi-1 level. The reduction in PcG protein level is associated with increased ubiquitination and is reversed by proteasome inhibitors, suggesting proteasome-associated degradation.
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PMID:(-)-Epigallocatechin-3-gallate and DZNep reduce polycomb protein level via a proteasome-dependent mechanism in skin cancer cells. 2179 53


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