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)

Epstein-Barr virus encoded latent membrane protein 1 (LMP1), an oncogenic protein, plays an important role in the carcinogenesis of nasopharyngeal carcinoma. The MDM2 gene is a cellular pro-oncogene that is abnormally up-regulated in human tumors. MDM2 is overexpressed in nasopharyngeal carcinoma, which is associated with the presence of EBV and cervical lymph node metastasis. Because MDM2 is capable of self-ubiquitination, and the ubiquitin proteasome pathway-dependent degradation is an important mechanism for regulating MDM2 levels in cells. Here we show that LMP1 augment MDM2 protein expression in dose-dependent level, and also lead to a drastic accumulation of ubiquitinated MDM2 species, this effect is associated with the stability of MDM2 modulated by LMP1. This is the first time to explain LMP1-regulated MDM2 through a post-ubiquitination mechanism.
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PMID:Ubiquitination of MDM2 modulated by Epstein-Barr virus encoded latent membrane protein 1. 1757 19

Cervical cancer is a virus-induced disease that is caused by the integration of high-risk infecting human papillomaviruses (HPV) in the host genome. For this reason, the carcinogenesis process of cervical cancer is associated to the expression of the viral oncogenic proteins E6 and E7. These proteins are capable of inactivating p53 and pRb, which induces a continuous cell proliferation with the increasing risk of accumulation of DNA damage that eventually leads to cancer. Moreover, cervical cancer can be prevented by prophylactic HPV vaccines; their molecular characteristics and mechanism of action are reviewed. Ultimately, new molecular targets for cervical cancer like proteasome, the EGFR family and IGF family are exposed.
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PMID:Molecular biology of cervical cancer. 1759 48

The Wnt signaling pathway is essential for embryonic development and carcinogenesis. Upon Wnt stimulation, beta-catenin is stabilized and associates with T-cell factor or lymphoid enhancing factor, thereby activating transcription of target genes. In the absence of Wnt stimulation, the level of beta-catenin is reduced via glycogen synthase kinase (GSK)-3beta-mediated phosphorylation and subsequent proteasome-dependent degradation. Here, we report the identification of Ajuba as a negative regulator of the Wnt signaling pathway. Ajuba is a member of LIM domain-containing proteins that contribute to cell fate determination and regulate cell proliferation and differentiation. We found that enforced expression of Ajuba destabilized beta-catenin and suppressed target gene expression. Ajuba promoted GSK-3beta-mediated phosphorylation of beta-catenin by reinforcing the association between beta-catenin and GSK-3beta. Furthermore, Wnt stimulation induced both accumulation of beta-catenin and destabilization of Ajuba. Our findings suggest that Ajuba is important for regulation of the Wnt signaling pathway.
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PMID:Ajuba negatively regulates the Wnt signaling pathway by promoting GSK-3beta-mediated phosphorylation of beta-catenin. 1762 Dec 69

Abnormal accumulation of beta-catenin is considered to be a strong driving force in hepatocellular carcinogenesis; however, the mechanism of beta-catenin accumulation in tumours is unclear. Here, it was demonstrated that hepatitis B virus X protein (HBx) differentially regulates the level of beta-catenin through two ubiquitin-dependent proteasome pathways depending on p53 status. In the presence of p53, HBx downregulated beta-catenin through the activation of a p53-Siah-1 proteasome pathway. For this purpose, HBx upregulated Siah-1 expression at the transcriptional level via activation of p53. In the absence of p53, however, HBx stabilized beta-catenin through the inhibition of a glycogen synthase kinase-3beta-dependent pathway. Interestingly, HBx variants with a Pro-101 to Ser substitution were unable to activate p53 and thus could stabilize beta-catenin irrespective of p53 status. Based on these findings, a model of beta-catenin regulation by HBx is proposed whereby the balance between the two opposite activities of HBx determines the overall expression level of beta-catenin. Differential regulation of beta-catenin by HBx depending on host (p53 status) and viral factors (HBx sequence variation) helps not only to explain the observation that cancers accumulating beta-catenin also exhibit a high frequency of p53 mutations but also to understand the contradictory reports on the roles of HBx during hepatocellular carcinogenesis.
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PMID:Hepatitis B virus X protein differentially affects the ubiquitin-mediated proteasomal degradation of beta-catenin depending on the status of cellular p53. 1762 16

Dietary components that are capable of inhibiting the growth of cancer cells without affecting the growth of normal cells are receiving considerable attention in developing novel cancer-preventive approaches. Tea, made from young leaves and leaf buds of the tea plant, 'Camellia sinensis', and the world's second most consumed beverage, has received a great deal of attention both from the general public and the scientific community because tea polyphenols are strong antioxidants, and tea preparations have inhibitory activity against tumorigenesis. Besides this, the wide spread consumption of tea throughout the world evoked the interest of the scientific community in the possibility of its use in cancer prevention. There are three main types of tea, all coming from the tea plant viz. black tea (fermented,) green tea (unfermented), or oolong tea (semi-fermented), classified based on the methods of brewing and processing. Inhibition of tumorigenesis by green or black tea preparations has been demonstrated in various animal models in different organs. Various epidemiological studies substantiate the correlation between tea consumption and cancer prevention; however, they have not yielded clear conclusions pertaining to the protective effects of tea consumption against cancer development in humans. Many mechanisms have been proposed for the inhibition of carcinogenesis by tea, including the modulation of signal transduction pathways (including growth factor-mediated, mitogen-activated protein kinase (MAPK)-dependent, and ubiquitin/proteasome degradation pathways ) that lead to the inhibition of cell proliferation and transformation; induction of apoptosis of preneoplastic and neoplastic cells, and inhibition of tumor invasion as well as angiogenesis. These mechanisms need to be evaluated, verified and corroborated in animal models and humans in order to gain more understanding on the effects of tea consumption on human cancer. Because the causative factors are different for different populations, tea consumption may affect carcinogenesis only in selected situations rather than having the general effect on all cancers. Although, on the basis of many epidemiological observations and numerous laboratory studies, it can be concluded that tea consumption is likely to have beneficial effects in reducing cancer risk in different populations, yet there is a need to define the population that could benefit from tea consumption. After careful evaluation of additional studies, it may be possible to recommend consumption of tea polyphenols by humans. Although considerable accumulating information provides a compelling body of evidence for the preventive potential of tea against cancer, naturally occurring tea polyphenols have yet to be evaluated in clinical intervention in human trials.
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PMID:Tea and cancer chemoprevention: a comprehensive review. 1769 25

The E7 protein encoded by the oncogenic human papillomavirus type 16 has been shown to bind and inactivate insulin-like growth factor-binding protein-3 (IGFBP-3), the pro-apoptotic product of a tumour suppressor gene; however, the molecular mechanism underlying E7-induced inactivation of IGFBP-3 remained uncertain. In this study, we map the IGFBP-3-binding domain for E7 to the nuclear localization signal in the conserved C-terminal domain of IGFBP-3. Moreover, we demonstrate that both proteins interact in the nucleus and that E7 induces polyubiquitination and proteasome-dependent proteolysis of nuclear IGFBP-3 in cervical cancer cells. This leads to a dramatic shortening of the half-life of nuclear IGFBP-3, whereas the stability of an E7-non-binding IGFBP-3 mutant is not affected by E7. Finally, we show that E7-mediated destruction of nuclear IGFBP-3 correlates with the inhibition of IGFBP-3-induced apoptotic cell death. These data are consistent with E7-induced ubiquitin/proteasome-dependent inactivation of nuclear IGFBP-3.
Carcinogenesis 2007 Dec
PMID:Human papillomavirus type 16 E7 oncoprotein inhibits apoptosis mediated by nuclear insulin-like growth factor-binding protein-3 by enhancing its ubiquitin/proteasome-dependent degradation. 1782 6

Human papillomavirus (HPV) is the necessary cause for cervical cancer development, and the interaction of HPV-E6 with p53 is known as the most important event in HPV-associated carcinogenesis. In vitro studies have suggested that HPV-E6 interacts more efficiently with the arginine (Arg) p53 variant at position 72 as it appears to be more susceptible to degradation through the ubiquitin proteasome pathway. However, few reports have corroborated this data, and the role of the p53 codon 72 polymorphism in the development of cervical cancer requires further elucidation. We performed a meta-analysis review of all studies published within European populations to summarize the overall risk of this polymorphism considering the influence of the geographical/ethnic location as an important factor in defining a genetic profile and the susceptibility for cervical cancer development. Our analysis revealed that the p53 Arg/Arg genotype does not seem to represent a risk marker for the development of cervical lesions in the majority of the European countries analysed. However, in countries with low incidence rates of cervical cancer, this polymorphism might represent a significant genetic marker.
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PMID:Is the p53 codon 72 polymorphism a key biomarker for cervical cancer development? A meta-analysis review within European populations. 1791 68

The hepatitis B virus (HBV) large surface antigen (LHBS) mutant with deletion at the pre-S(2) region accumulates in endoplasmic reticulum (ER) and is associated with HBV-induced hepatocellular carcinogenesis. In this study, we found that the pre-S(2) LHBS mutant directly interacts with the Jun activation domain-binding protein 1 (JAB1). Association of pre-S(2) LHBS with JAB1 dissociated JAB1 from the JAB1/IRE1 complex in ER. The free (active) JAB1 then translocated into cell nuclei and rendered the Cdk inhibitor p27(Kip1) to cytosolic proteasome for degradation. The pre-S(2) LHBS mutant induced hyperphosphorylation of tumor suppressor retinoblastoma (RB) via cyclin-dependent kinase 2 (Cdk2), a downstream molecule regulated by p27(Kip1). This effect is independent of the ER stress signaling pathway. The transgenic mice carrying the pre-S(2) mutant LHBS gene also exhibited Cdk2 activation, p27(Kip1) degradation, as well as RB hyperphosphorylation. The mouse hepatocytes exhibited morphologic abnormalities such as chromatin condensation, multinucleation, and dysplasia of hepatocytes. In summary, the pre-S(2) LHBS mutant causes p27(Kip1) degradation through direct interaction with JAB1. The pre-S(2) mutant LHBS is suggested to be a potential oncoprotein for HBV-related hepatocellular carcinoma.
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PMID:Hepatitis B virus pre-S2 mutant surface antigen induces degradation of cyclin-dependent kinase inhibitor p27Kip1 through c-Jun activation domain-binding protein 1. 1795 6

TP63, a member of the TP53 gene family, encodes two groups of three isoforms (alpha, beta and gamma). The TAp63 isoforms act as transcription factors. The DeltaNp63 isoforms lack the main transcription activation domain and act as dominant-negative inhibitors of transactivation (TA) isoforms. To clarify the role of these isoforms and to better understand their functional overlap with p53, we ectopically expressed each p63 isoform in the p53-null hepatocellular carcinoma cell line Hep3B. All TA isoforms, as well as DeltaNp63alpha, had a half-life of <1 h when transiently expressed and were degraded by the proteasome pathway. The most stable form was DeltaNp63gamma, with a half-life of >8 h. As expected, TA isoforms differed in their transcriptional activities toward genes regulated by p53, TAp63gamma being the most active form. In contrast, DeltaNp63 isoforms were transcriptionally inactive on genes studied and inhibited TA isoforms in a dose-dependent manner. When stably expressed in polyclonal cell populations, TAp63beta and gamma isoforms were undetectable. However, when treated with doxorubicin (DOX), p63 proteins rapidly accumulated in the cells. This stabilization was associated with an increase in phosphorylation. Strikingly, in DOX-treated polyclonal populations, increase in TAp63 levels was accompanied by overexpression of DeltaNp73. This observation suggests complex regulatory cross talks between the different isoforms of the p53 family. In conclusion, p63 exhibits several transcriptional and stress-response properties similar to those of p53, suggesting that p63 activities should be taken into consideration in approaches to improve cancer therapies based on genotoxic agents.
Carcinogenesis 2008 Feb
PMID:Properties of the six isoforms of p63: p53-like regulation in response to genotoxic stress and cross talk with DeltaNp73. 1804 90

Proteasome inhibitor is a novel class of cancer therapeutics, of which the mechanism of action is not fully understood. It is reported that proteasome inhibitor enhances bone morphogenetic protein (BMP) signaling in osteoblasts to stimulate bone formation. BMP signaling is also an important tumor-suppressing pathway in gastric carcinogenesis. We therefore sought to determine the anti-mitogenic effect of proteasome inhibition in relation to BMP signaling in gastric cancer cells. Results showed that proteasome inhibitor MG-132 significantly suppressed the proliferation and the colony-forming ability of gastric cancer TMK1 cells. In this connection, MG-132 activated BMP signaling, manifested as an increase in Smad1/5/8 phosphorylation and up-regulation of p21(Waf1/Cip1) mRNA and protein expression. Knockdown of BMP receptor II by RNA interference abolished Smad1/5/8 phosphorylation, p21(Waf1/Cip1) induction, and the inhibition of cell proliferation induced by MG-132. Further analysis revealed that MG-132 up-regulated the expression of BMP1 and BMP4 and suppressed the expression of Smad6. Knockdown of Smad6 also mimicked the effect of MG-132 on BMP signaling. Collectively, these findings suggest that inhibition of proteasome suppresses gastric cancer cell proliferation via activation of BMP signaling. This discovery may open up a novel therapeutic avenue to proteasome inhibitors for the management of gastric cancer.
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PMID:Proteasome inhibitor MG-132 lowers gastric adenocarcinoma TMK1 cell proliferation via bone morphogenetic protein signaling. 1843 11


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