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 human papillomavirus type 16 (HPV-16) E7 oncoprotein rapidly induces centrosome duplication errors in primary human cells, thereby increasing the propensity for multipolar mitoses, which can lead to chromosome missegregation and aneuploidy. We analyzed a series of HPV-16 E7 mutants and demonstrate that this biological activity of the E7 oncoprotein is mediated by sequences encompassing the core pRB binding site but is independent of its ability to inactivate the retinoblastoma tumor suppressor protein pRB and the related pocket proteins p107 and p130. In addition, interaction of E7 with the S4 subunit of the 26S proteasome and dysregulation of cdc25A transcription are also dispensable for the induction of centrosome duplication errors. Consistent with these results, expression of HPV-16 E7 induces abnormal centrosome duplication in a cell line that lacks functional pRB and in mouse embryo fibroblasts that are deficient for pRB, p107, and p130. These results demonstrate that the molecular mechanism whereby HPV-16 E7 induces centrosome duplication errors is independent of its ability to inactivate pRB, p107, and p130 or to interact with the S4 proteasome subunit.
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PMID:Human papillomavirus type 16 E7 oncoprotein can induce abnormal centrosome duplication through a mechanism independent of inactivation of retinoblastoma protein family members. 1458 69

Cell migration and survival are coordinately regulated through activation of c-Abl (Abl) family tyrosine kinases. Activated Abl phosphorylates tyrosine 221 of c-CrkII (Crk; Crk-Y221-P), which prevents Crk from binding to the docking protein p130(CAS) (CAS). Disruption of CAS-Crk binding blocks downstream effectors of the actin cytoskeleton and focal adhesion assembly, inhibits cell migration, and disrupts survival signals leading to apoptosis. Here we show that inhibition of the 26 S proteasome and ubiquitination facilitates Abl-mediated Crk-Y221-P, leading to disassembly of CAS-Crk complexes in cells. Surprisingly, inhibition of these molecular interactions does not perturb cell migration but rather specifically induces apoptosis. Furthermore, we demonstrate that attachment to an extracellular matrix plays a key role in regulating the apoptotic machinery through caspase-mediated cleavage of Abl and Crk-Y221-P. Our findings indicate that regulated protein degradation by the proteasome specifically controls cell death through regulation of Abl-mediated Crk Tyr221 phosphorylation and assembly of the CAS-Crk signaling scaffold.
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PMID:Deregulation of proteasome function induces Abl-mediated cell death by uncoupling p130CAS and c-CrkII. 1626 43

Despite a number of attempts to improve treatment of ovarian cancer, it remains the most common cause of death from gynecological cancers. Thus, it is very important to identify more effective drugs for treatment and prevention of ovarian cancer. All-trans-retinoic acid (ATRA) has been shown to arrest the growth of ovarian carcinoma cells in G0/G1 and to significantly elevate levels of Rb2/p130 protein, a member of the retinoblastoma family of tumor suppressors. As ATRA treatment leads to a significant increase in the amount of Rb2/p130 protein but not mRNA, the elevated levels of Rb2/p130 protein is likely the result of increased stability. In studies to elucidate the mechanism by which ATRA alters Rb2/p130 stability in ovarian cancer cells, it was determined that PP2A, a serine/threonine phosphatase, binds and dephosphorylates Rb2/p130. Dephosphorylated Rb2/p130 exhibits decreased ubiquitination and thus is not degraded by the proteasome. The sites at which PP2A catalytic subunit (PP2Ac) interacts with Rb2/p130 have been localized to the NLS in the C-terminus of Rb2/p130. These sites are also involved in the interaction of Rb/p130 with importin beta and importin alpha, members of the nuclear transport machinery. It is known that importin alpha recognizes a NLS on a target protein and importin beta binds the nuclear pore complex. Moreover, it has been shown that the binding of importin alpha to NLS significantly decreases with phosphorylation of NLS. In ATRA-treated ovarian carcinoma cells, PP2A binds to Rb2/p130 and dephosphorylates the NLS of Rb2/p130 leading to the interaction of importin alpha with Rb2/p130. Importin beta then binds to the importin alpha-Rb2/p130 complex, leading to the translocation of the Rb2/p130 to the nucleus where it acts to arrest ovarian cancer cells in G1 and suppress proliferation.
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PMID:Rb2/p130 and protein phosphatase 2A: key mediators of ovarian carcinoma cell growth suppression by all-trans retinoic acid. 1693 53

Cellular levels of products from both oncogenes and tumor suppressor genes in normal cells need to be critically regulated to avoid malignant transformation. These products are often controlled by the ubiquitin proteasome pathway, the specific degradation mechanism in the cell. E3 ubiquitin ligases polyubiquitylate their specific substrates by collaborating with E1 and E2, and then the modified substrates are degraded in the proteasome. Mdm2 targets p53 and retinoblastoma protein, two major tumor suppressor gene products, for ubiquitin-dependent degradation. SCF(Skp2) targets other tumor suppressor gene products and CDK inhibitors such as p130, Tob1, p27(Kip1), p57(Kip2), and p21(Cip1). Therefore, both E3 ligases act like oncogene products. In contrast, degradation of several oncogene products, such as Cyclin E, Notch, c-Myc, c-Jun, and c-Myb, are mediated by SCF(Fbw7). Fbw7 is often deleted or mutated in human cancers and acts like a tumor suppressor. As well as growth factor receptors and signal transduction regulators, DNA repair-related proteins are also regulated via the ubiquitin-proteasome pathway mediated by their specific E3 ligases. The stabilization of oncogene products and enhanced degradation of tumor suppressor gene products or DNA repair proteins might be associated with carcinogenesis and malignant progression, due to defects or the abnormal expression of their E3 ligases.
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PMID:Ubiquitin-mediated control of oncogene and tumor suppressor gene products. 1945 46

Not only does 5-aza-2'-deoxycytidine (5-aza-CdR) induce the reexpression of silenced genes through the demethylation of CpG islands, but it increases the expression of unmethylated genes. However, the mechanism by which 5-aza-CdR activates the expression of genes is not completely understood. Here, we report that the pRb pocket proteins pRb, p107, and p130 were degraded in various cancer cell lines in response to 5-aza-CdR treatment, and this effect was dependent on the proteasome pathway. Mouse double minute 2 (MDM2) played a critical role in this 5-aza-CdR-induced degradation of pRb. Furthermore, PP2A phosphatase-induced MDM2 dephosphorylation at S260 was found to be essential for MDM2 binding to pRb in the presence of 5-aza-CdR. pRb degradation resulted in the significant reexpression of several genes, including methylated CDKN2A, RASFF1A, and unmethylated CDKN2D. Finally, knockdown of pRb pocket proteins by either RNAi or 5-aza-CdR treatment induced a significant decrease in the recruitment of SUV39H1 and an increase in the enrichment of KDM3B and KDM4A to histones around the promoter of RASFF1A and thus reduced H3K9 di- and trimethylation, by which RASFF1A expression is activated. Our data reveal a novel mechanism by which 5-aza-CdR induces the expression of both methylated and unmethylated genes by degrading pRb pocket proteins.
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PMID:5-Aza-2'-deoxycytidine reactivates gene expression via degradation of pRb pocket proteins. 2199 Mar 74

Cell cycle progression is dependent on two major waves of gene expression. Early cell cycle gene expression occurs during G1/S to generate factors required for DNA replication, while late cell cycle gene expression begins during G2 to prepare for mitosis. Here we demonstrate that the MuvB complex-comprised of LIN9, LIN37, LIN52, LIN54, and RBBP4-serves an essential role in three distinct transcription complexes to regulate cell cycle gene expression. The MuvB complex, together with the Rb-like protein p130, E2F4, and DP1, forms the DREAM complex during quiescence and represses expression of both early and late genes. Upon cell cycle entry, the MuvB complex dissociates from p130/DREAM, binds to B-Myb, and reassociates with the promoters of late genes during S phase. MuvB and B-Myb are required for the subsequent recruitment of FoxM1 to late gene promoters during G2. The MuvB complex remains bound to FoxM1 during peak late cell cycle gene expression, while B-Myb binding is lost when it undergoes phosphorylation-dependent, proteasome-mediated degradation during late S phase. Our results reveal a novel role for the MuvB complex in recruiting B-Myb and FoxM1 to promote late cell cycle gene expression and in regulating cell cycle gene expression from quiescence through mitosis.
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PMID:The MuvB complex sequentially recruits B-Myb and FoxM1 to promote mitotic gene expression. 2239 50

The E2F family of transcription factors contributes to oncogenesis through activation of multiple genes involved in cellular proliferation, a process that is opposed by the Retinoblastoma tumor suppressor protein (RB). RB also increases E2F1 stability by inhibiting its proteasome-mediated degradation, but the consequences of this post-translational regulation of E2F1 remain unknown. To better understand the mechanism of E2F stabilization and its physiological relevance, we examined the streamlined Rbf1-dE2F1 network in Drosophila. During embryonic development, Rbf1 is insulated from ubiquitin-mediated turnover by the COP9 signalosome, a multi-protein complex that modulates E3 ubiquitin ligase activity. Here, we report that the COP9 signalosome also protects the Cullin4-E3 ligase that is responsible for dE2F1 proteasome-mediated destruction. This dual role of the COP9 signalosome may serve to buffer E2F levels, enhancing its turnover via Cul4 protection and its stabilization through protection of Rbf1. We further show that Rbf1-mediated stabilization of dE2F1 and repression of dE2F1 cell cycle-target genes are distinct properties. Removal of an evolutionarily conserved Rbf1 C terminal degron disabled Rbf1 repression without affecting dE2F1 stabilization. This mutant form of Rbf1 also enhanced G(1)-to-S phase progression when expressed in Rbf1-containing S2 embryonic cells, suggesting that such mutations may generate gain-of-function properties relevant to cellular transformation. Consistent with this idea, several studies have identified mutations in the homologous C terminal domains of RB and p130 in human cancer.
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PMID:Rbf1 degron dysfunction enhances cellular DNA replication. 2289 52

Inorganic arsenic exerts toxic effect on multiple systems including the immune system. We previously showed in a study on mouse thymocytes and B-cell lymphoma A20 cells that arsenite induces cell cycle arrest at G0/G1 by suppressing expression of E2F-target genes. In this study, we furthermore investigated the involvement of retinoblastoma (RB) family proteins in E2F-dependent cell cycle arrest by arsenite. Arsenite exposure of A20 cells was showed to increase the protein level of p130, a RB family member, without changing the mRNA level. Suppression of arsenite-induced p130 by siRNA reduced the G0/G1 phase, indicating that p130 accumulation is responsible for arsenite-induced G0/G1 arrest. The accumulated p130 was shown to increase the p130 complex with E2F4, a transcription-suppressing E2F. Comparison by Western blotting of arsenite-induced p130 and p130 accumulated by a proteasome inhibitor suggested that arsenite-induced p130 is hypophosphorylated and hypoubiquitinated and refractory to proteasome-dependent degradation. We also showed that arsenite increases mRNA and protein of p16(INK4a), an inhibitor of CDK4/6 that phosphorylates p130. Down-regulation of arsenite-induced p16(INK4a) by siRNA suppressed the p130 accumulation. We propose a novel mechanism in which arsenite inhibits phosphorylation/ubiquitin-dependent proteasome degradation of p130 by inducing p16(INK4a) and the accumulated p130 causes cell cycle arrest with E2F4.
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PMID:Inorganic arsenic exposure induces E2F-dependent G0/G1 arrest via an increase in retinoblastoma family protein p130 in B-cell lymphoma A20 cells. 2389 Jan 98

The study of the small DNA tumor viruses continues to provide valuable new insights into oncogenesis and fundamental biological processes. Although much has already been revealed about how the human papillomaviruses (HPVs) can transform cells and contribute to cervical and oropharyngeal cancer, there clearly is much more to learn. In this issue of Oncogene, Pang et al., doi:10.1038/onc.2013.426, demonstrate that the high-risk HPV16 E7 oncogene can promote cellular proliferation by interacting with the DREAM (DP, RB-like, E2F and MuvB) complex at two distinct phases of the cell cycle. Consistent with earlier work, HPV16 E7 can bind to the retinoblastoma tumor suppressor (RB) family member p130 (RBL2) protein and promote its proteasome-mediated destruction thereby disrupting the DREAM complex and can prevent exit from the cell cycle into quiescence. In addition, they demonstrate that HPV16 E7 can bind to MuvB core complex in association with BMYB and FOXM1 and activate gene expression during the G2 and M phase of the cell cycle. Thus, HPV16 E7 acts to prevent exit from the cell cycle entry and promotes mitotic proliferation and may account for the high levels of FOXM1 often observed in poor-risk cervical cancers.
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PMID:Human papillomavirus type 16 E7 perturbs DREAM to promote cellular proliferation and mitotic gene expression. 2414 69

The retinoblastoma (RB) tumor suppressor and related family of proteins play critical roles in development through their regulation of genes involved in cell fate. Multiple regulatory pathways impact RB function, including the ubiquitin-proteasome system with deregulated RB destruction frequently associated with pathogenesis. With the current study we explored the mechanisms connecting proteasome-mediated turnover of the RB family to the regulation of repressor activity. We find that steady state levels of all RB family members, RB, p107, and p130, were diminished during embryonic stem cell differentiation concomitant with their target gene acquisition. Proteasome-dependent turnover of the RB family is mediated by distinct and autonomously acting instability elements (IE) located in their C-terminal regulatory domains in a process that is sensitive to cyclin-dependent kinase (CDK4) perturbation. The IE regions include motifs that contribute to E2F-DP transcription factor interaction, and consistently, p107 and p130 repressor potency was reduced by IE deletion. The juxtaposition of degron sequences and E2F interaction motifs appears to be a conserved feature across the RB family, suggesting the potential for repressor ubiquitination and specific target gene regulation. These findings establish a mechanistic link between regulation of RB family repressor potency and the ubiquitin-proteasome system.
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PMID:The Evolutionarily Conserved C-terminal Domains in the Mammalian Retinoblastoma Tumor Suppressor Family Serve as Dual Regulators of Protein Stability and Transcriptional Potency. 2590 25


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