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)

Bile acids have been implicated in biliary tract carcinogenesis, in part, by activating the epidermal growth factor receptor (EGFR). Overexpression of Mcl-1, a potent antiapoptotic protein of the Bcl-2 family, has also been reported in cholangiocarcinomas. Because receptor tyrosine kinases like EGFR may modulate antiapoptotic protein expression, we examined the hypothesis that bile acids modulate Mcl-1 expression levels via EGFR. Deoxycholate increased cellular Mcl-1 protein in a concentration-dependent manner. The deoxycholate-mediated increase of cellular Mcl-1 protein was blocked equally by EGFR tyrosine kinase inhibitors or an EGFR-neutralizing antibody. Although inhibition of mitogen-activated protein kinases did not attenuate the deoxycholate-associated increase in Mcl-1 protein, the Raf-1 inhibitor, BAY 37-9751, effectively blocked the cellular increase of this protein. Neither Mcl-1 transcriptional activity nor its mRNA stability was altered by deoxycholate treatment. However, Mcl-1 protein stability was increased by bile acid treatment, an effect duplicated by proteasome inhibition. Deoxycholate prolongation of Mcl-1 turnover was blocked by either EGFR inhibitors or the Raf-1 inhibitor. Whereas the deoxycholate-induced increase in Mcl-1 reduced Fas-mediated apoptosis, the Raf-1 inhibitor potentiated Fas apoptosis. Our results demonstrate that bile acids block Mcl-1 protein degradation via activation of an EGFR/Raf-1 cascade resulting in its cellular accumulation. Raf-1 inhibitors block this increase of Mcl-1 and render the cells more susceptible to apoptosis, a potential therapeutic strategy for cholangiocarcinomas.
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PMID:Bile acids inhibit Mcl-1 protein turnover via an epidermal growth factor receptor/Raf-1-dependent mechanism. 1243 43

Enzyme inducers such as 3H-1,2-dithiole-3-thione (D3T) enhance the detoxication of environmental carcinogens and protect against neoplasia. The putative molecular sensor for inducers is Keap1, a sulfhydryl-rich protein that sequesters the transcription factor Nrf2 in the cytoplasm. Expression of these detoxication enzymes is blunted in nrf2-deficient mice; moreover, these mice are more sensitive to carcinogenesis, and the protective actions of dithiolethiones are lost with nrf2 disruption. Hepatic gene expression profiles were examined by oligonucleotide microarray analysis in vehicle- or D3T-treated wild-type mice as well as in nrf2 single and keap1-nrf2 double knockout mice to identify those genes regulated by the Keap1-Nrf2 pathway. Transcript levels of 292 genes were elevated in wild-type mice 24 h after treatment with D3T; 79% of these genes were induced in wild-type, but not nrf2-deficient mice. These nrf2-dependent, D3T-inducible genes included known detoxication and antioxidative enzymes. Unexpected clusters included genes for chaperones, protein trafficking, ubiquitin/26 S proteasome subunits, and signaling molecules. Gene expression patterns in keap1-nrf2 double knockout mice were similar to those in nrf2-single knockout mice. D3T also led to nrf2-dependent repression of 31 genes at 24 h; principally genes related to cholesterol/lipid biosynthesis. Collectively, D3T increases the expression of genes through the Keap1-Nrf2 signaling pathway that directly detoxify toxins and generate essential cofactors such as glutathione and reducing equivalents. Induction of nrf2-dependent genes involved in the recognition and repair/removal of damaged proteins expands the role of this pathway beyond primary control of electrophilic and oxidative stresses into secondary protective actions that enhance cell survival.
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PMID:Modulation of gene expression by cancer chemopreventive dithiolethiones through the Keap1-Nrf2 pathway. Identification of novel gene clusters for cell survival. 1250 15

Certain types of human papillomaviruses have been etiologically associated with malignant lesions, most notably with cervical cancer. The major oncoproteins of these cancer-associated viruses are encoded by the viral E6 and E7 genes. Thorough characterization of these oncoproteins and their interaction with cellular proteins has shown that both E6 and E7 exploit the ubiquitin-proteasome system to degrade and, thus, to functionally inactivate negative cell-regulatory proteins including members of the p110(RB) family and p53. This act of piracy is assumed to contribute to both the efficient propagation of HPVs and HPV-induced carcinogenesis.
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PMID:Human papillomavirus-induced carcinogenesis and the ubiquitin-proteasome system. 1250 57

The oncoproteins of the DNA tumor viruses, adenovirus E1A, simian virus 40 T antigen, and papillomavirus E7, each interact with the retinoblastoma family of tumor suppressors, leading to cell cycle stimulation, apoptosis induction, and cellular transformation. These proteins utilize a conserved LXCXE motif, which is also found in cellular proteins, to target the retinoblastoma family. Here, we describe a herpesvirus protein that shares a subset of the properties of the DNA tumor virus oncoproteins but maintains important differences as well. The human cytomegalovirus pp71 protein employs an LXCXD motif to attack the retinoblastoma family members and induce DNA synthesis in quiescent cells. pp71 binds to and induces the degradation of the hypophosphorylated forms of the retinoblastoma protein and its family members p107 and p130 in a proteasome-dependent manner. However, pp71 does not induce apoptosis and fails to transform cells. Thus, the similarities and differences in comparison to E1A, T antigen, and E7 make pp71 an interesting new tool with which to further dissect the role of the retinoblastoma/E2F pathway in cellular growth control and carcinogenesis.
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PMID:Human cytomegalovirus pp71 stimulates cell cycle progression by inducing the proteasome-dependent degradation of the retinoblastoma family of tumor suppressors. 1261 64

Human papillomavirus (HPV) E6 viral oncoprotein plays an important role during cervical carcinogenesis. This oncoprotein binds the tumor suppressor protein p53, leading to its degradation via the ubiquitin-proteasome pathway. Therefore, it is generally assumed that in HPV-positive cancer cells p53 function is completely abolished. Nevertheless, recent findings suggest that p53 activity can be recovered in cells expressing endogenous E6 protein. To investigate whether p53-dependent functions controlling genome integrity, cell proliferation, and apoptosis can be reactivated in cervical cancer cells, we examined the capacity of HeLa, INBL, CaSki, C33A, and ViBo cell lines to respond to neocarzinostatin (NCS), a natural product which induces single- and double-strand breaks in DNA. We found that NCS treatment inhibits cellular proliferation through G2 cell cycle arrest and apoptosis induction. This effect was preceded by nuclear accumulation of p53 protein and by an increase of p21 transcripts. Although apoptosis was blocked in ViBo cells (HPV-negative), nuclear accumulation of transcriptionally active p53 and inhibition of cell proliferation are observed after NCS treatment. These results suggest that HPV-positive cervical cancer cells are capable of responding efficiently to DNA damage provoked by NCS treatment through a p53-dependent pathway in spite of the presence of E6 protein.
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PMID:Neocarzinostatin induces an effective p53-dependent response in human papillomavirus-positive cervical cancer cells. 1275 Apr 35

Hepatitis B virus (HBV) X protein (HBx) plays an essential role in viral replication and in the development of hepatocellular carcinoma. HBx has the ability to transactivate the expression of all HBV proteins, including the viral core protein HBc. Consistent with its regulatory role, HBx is relatively unstable and is present at low levels in the cell. We report here that the level of HBx was significantly reduced by the coexpression of HBc in cultured human hepatoma cells, whereas the level of HBx mRNA was unaffected. The repression of HBx by HBc was relieved by treating cells with the proteasome inhibitor MG132, indicating that HBc acts by stimulating the proteasome-mediated degradation of HBx. Moreover, the inhibitory effect of HBc was specific to HBx and did not affect other proteins, including p53, a known target of the proteasome. Although no direct physical interaction between HBc and HBx could be demonstrated, mutational analysis indicated that the C-terminal half of HBc is responsible for its inhibitory effect. These results suggest that HBc functions as a novel regulator of the HBV life cycle and of hepatocellular carcinogenesis through control of the HBx level via an inhibitory feedback type of mechanism.
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PMID:Hepatitis B virus core protein stimulates the proteasome-mediated degradation of viral X protein. 1280 15

Reversible down-regulation of gap junctional intercellular communication (GJIC) is proposed to be an important cellular mechanism in tumor promotion. Gap junction function is modified by a variety of tumor promoters, including the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA). Treatment of cells with TPA results in the activation and subsequent depletion of the TPA-responsive protein kinase C (PKC) isoforms. TPA-induced degradation of the PKC isoforms alpha, delta and epsilon was recently shown to occur via the ubiquitin-proteasome pathway. In the present study we investigated the role of the proteasome in the TPA-induced modification of GJIC in IAR20 rat liver epithelial cells. TPA exposure of IAR20 cells induced hyperphosphorylation of gap junction protein connexin43 and inhibition of GJIC. Prolonged TPA treatment induced down-regulation of PKCalpha, delta and epsilon and a reduction in the total PKC activity, which was associated with recovery of GJIC. Co-treatment of IAR20 cells with TPA and the proteasomal inhibitor MG132 suppressed down-regulation of PKCalpha, delta and epsilon and caused prolonged PKC activity. Under these conditions, the recovery of GJIC was blocked. The general PKC inhibitor GF109203X reversed the effect of MG132, indicating that the prolonged TPA-induced inhibition of GJIC caused by MG132 was due to the prolonged PKC activity. These results indicate that proteasomal degradation of PKC is one mechanism by which the recovery of GJIC after TPA treatment is regulated.
Carcinogenesis 2003 Jul
PMID:Recovery of gap junctional intercellular communication after phorbol ester treatment requires proteasomal degradation of protein kinase C. 1280 62

Lung cancer is the leading cause of cancer mortality. Chemoprevention is an attractive strategy to combat this major public health problem. Pre-clinical and clinical studies have identified diverse candidate chemopreventive agents that affect cellular proliferation, differentiation, apoptosis and tumor angiogenesis, among other pathways. These pharmacological agents are undergoing testing through use of pre-clinical models and clinical trials. These studies have uncovered cyclin D1 as a chemoprevention target and a surrogate marker of chemopreventive response in the lung. Chemoprevention of tobacco-carcinogen transformed human bronchial epithelial (HBE) cells appears to be due at least partly to degradation of cyclin D1. These studies of cultured HBE cells were extended to the in vivo setting by examination of preneoplastic bronchial lesions that established the frequent aberrant expression of cyclin D1 in lung carcinogenesis. Certain retinoids, natural and synthetic derivatives of vitamin A, repress cyclin D1, but activation of the epidermal growth factor receptor (EGFR) induces cyclin D1. Retinoids and specific chemopreventive agents can activate the proteasome-dependent degradation of cyclin D1 and also repress EGFR expression, thereby reducing cyclin D1 levels. These actions oppose the mitogenic effects of cyclin D1. This is hypothesized to trigger G1 arrest and thereby permit repair of carcinogenic damage of genomic DNA. These and other pre-clinical and clinical studies that will be reviewed here indicate that cyclin D1 and perhaps other cyclins are attractive pharmacological targets for lung cancer chemoprevention.
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PMID:Cyclin D1 as a target for chemoprevention. 1286 74

Helicobacter pylori infection is associated with increased gastric epithelial cell turnover and is a risk factor for noncardia gastric cancer. H. pylori reduces the expression of p27 protein, a cyclin-dependent kinase inhibitor of the G(1) to S-phase cell cycle transition and gastric tumor suppressor gene. Although cell cycle dysregulation associated with decreased p27 may contribute to gastric carcinogenesis, how H. pylori reduces p27 in gastric epithelial cells remains unknown. In the present study, we investigated the mechanisms of the p27 decrease, using AGS and MKN28 gastric epithelial cells cocultured with H. pylori strains under conditions of defined cell cycle distribution. The expression of p27 protein was reduced by H. pylori in a dose- and time-dependent manner. Northern blot and pulse-chase analyses revealed that this reduction was not regulated at a transcriptional level but by accelerated p27 degradation via a proteasome-dependent pathway. Despite up-regulation of the proteasome-dependent degradation of p27 protein, neither threonine 187-phosphorylated p27 nor skp2 (the ubiquitin ligase for p27) were increased. Furthermore, H. pylori impaired p27 ubiquitination and did not increase global proteasomal function. These results indicate that H. pylori increases the degradation of p27 through a proteasomal pathway distinct from the physiological pathway that degrades p27 during cell cycle progression. Putative virulence genes of H. pylori (cagA, cagE, or vacA) played no role in reducing p27 expression. Increased degradation of p27 by H. pylori through a proteasome-dependent, ubiquitin-independent pathway may contribute to the increased risk of gastric cancer associated with chronic H. pylori infection.
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PMID:Helicobacter pylori increases proteasome-mediated degradation of p27(kip1) in gastric epithelial cells. 1290 57

Peroxisome proliferator-activated receptor gamma (PPARgamma) is a member of the nuclear hormonal receptor superfamily expressed in a large number of human cancers. Here, we demonstrate that PPARgamma is expressed and transcriptionally active in breast cancer cells independent of their p53, estrogen receptor, or human epidermal growth factor receptor 2 status. 2-Cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO), a novel synthetic triterpenoid, is a ligand for PPARgamma. We investigated the molecular mechanisms of CDDO on proliferation and apoptosis in breast cancer cells. In all breast cancer cell lines studied, CDDO transactivated PPARgamma, induced dose- and time-dependent cell growth inhibition, cell cycle arrest in G(1)-S and G(2)-M, and apoptosis. We then used differential cDNA array analysis to investigate the molecular changes induced by CDDO. After 16-h exposure of MCF-7 and MDA-MB-435 cells to CDDO, we found genes encoding the following proteins to be up-regulated in both cell lines: p21(Waf1/CIP1); GADD153; CAAT/enhancer binding protein transcription factor family members; and proteins involved in the ubiquitin-proteasome pathway. Among the down-regulated genes, we focused on the genes encoding cyclin D1, proliferating cell nuclear antigen, and the insulin receptor substrate 1. Using Western blot analysis and/or real-time PCR, we confirmed that CDDO regulated the expression of cyclin D1, p21(Waf1/CIP1), and Bcl-2. Cyclin D1 and p21(Waf1/CIP1) were additionally confirmed as important mediators of CDDO growth inhibition in genetically modified breast cancer cell lines. CDDO was able to significantly reduce the growth of MDA-MB-435 tumor cells in immunodeficient mice in vivo. The finding that CDDO can target genes critical for the regulation of cell cycle, apoptosis, and breast carcinogenesis suggests usage of CDDO as novel targeted therapy in breast cancer.
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PMID:Activation of peroxisome proliferator-activated receptor gamma by a novel synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid induces growth arrest and apoptosis in breast cancer cells. 1452 19


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