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 protein p53 is ubiquitinated and neddylated by MDM2 and then degraded by 26S proteasome. However, p53 is stabilized by the HAUSP (Herpes-virus-associated ubiquitin-specific protease) deubiquitinating enzyme. In this study, we discovered that rat HAUSP (rHAUSP) is polyubiquitinated, polyneddylated, and dimerized using co-immunoprecipitation assays. This suggests that rHAUSP may function as a dimer or multimer and is also degraded through the proteasome-mediated degradation. Transfection of rHAUSP into RGC-Lac-Z cell line with the integrated p53 response element revealed that rHAUSP contributed to p53 stabilization, and a rHAUSP (C224S) mutant contributed to p53 destabilization in a dose-dependent manner.
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PMID:HAUSP, a deubiquitinating enzyme for p53, is polyubiquitinated, polyneddylated, and dimerized. 1611 84

Ubiquitin-dependent proteolysis mediates selective destruction of various cell cycle regulators, transcription factors and tumor suppressors. Gankyrin, a seven ankyrin-repeat protein, was originally identified as an oncoprotein commonly overexpressed in hepatocellular carcinomas and independently as a protein associated with the 19S regulatory complex of the 26S proteasome. Gankyrin also binds to CDK4 and the tumor suppressor RB, and accelerates phosphorylation and proteasomal degradation of RB. Recently, we have shown that gankyrin has an anti-apoptotic activity in cells exposed to DNA-damaging agents. Gankyrin binds to MDM2, a major E3 ubiquitin ligase for p53, and increases ubiquitylation and degradation of p53. Gankyrin increases activities of CDK4 and MDM2, and facilitates targeting of polyubiquitylated proteins to the 26S proteasome. Furthermore, inhibition of gankyrin induces apoptosis in cancer cells. Therefore, gankyrin is a promising target for potential anticancer therapeutic agents.
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PMID:The oncoprotein gankyrin negatively regulates both p53 and RB by enhancing proteasomal degradation. 1617 71

The promyelocytic leukemia (PML) can selectively and dynamically recruit a number of proteins including p53 to form a sub-nuclear multiprotein chamber named PML-NBs. In DNA damage response, p53 is recruited into PML-NBs and modified by phosphorylations and acetylations, which in turn potentiate its transcriptional and pro-apoptotic activities. In contrast, in carcinoma cells, the role of PML in the irradiation induced p53-mediated apoptosis is not precisely understood. In this study, we have used the breast carcinoma cell line, MCF-7, and stably suppressed the expression of PML. Inhibition of PML expression had no detectable effect on the expression of endogenous p53 at the mRNA level; however, a significant decrease of p53 protein was observed. There was also an increase in the p53-MDM2 complexes, which may facilitate p53 protein degradation by the ubiquitin-proteasome pathway, also in irradiation treated cells. The p53 transcriptional activity was attenuated both in unstressed and 10 Gy irradiation treated cells. Moreover, inhibition of PML expression in MCF-7 cells significantly reduced p53 downstream genes, cell cycle arrest gene p21(WAF/cip-1) and pro-apoptotic gene Bax expression, then irradiation-induced apoptosis. These results suggest that PML is a key regulator in the irradiation activated p53 apoptotic pathway in breast carcinoma cells.
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PMID:Knocking down PML impairs p53 signaling transduction pathway and suppresses irradiation induced apoptosis in breast carcinoma cell MCF-7. 1621 89

The selectivity of the ubiquitin-26 S proteasome system (UPS) for a particular substrate protein relies on the interaction between a ubiquitin-conjugating enzyme (E2, of which a cell contains relatively few) and a ubiquitin-protein ligase (E3, of which there are possibly hundreds). Post-translational modifications of the protein substrate, such as phosphorylation or hydroxylation, are often required prior to its selection. In this way, the precise spatio-temporal targeting and degradation of a given substrate can be achieved. The E3s are a large, diverse group of proteins, characterized by one of several defining motifs. These include a HECT (homologous to E6-associated protein C-terminus), RING (really interesting new gene) or U-box (a modified RING motif without the full complement of Zn2+-binding ligands) domain. Whereas HECT E3s have a direct role in catalysis during ubiquitination, RING and U-box E3s facilitate protein ubiquitination. These latter two E3 types act as adaptor-like molecules. They bring an E2 and a substrate into sufficiently close proximity to promote the substrate's ubiquitination. Although many RING-type E3s, such as MDM2 (murine double minute clone 2 oncoprotein) and c-Cbl, can apparently act alone, others are found as components of much larger multi-protein complexes, such as the anaphase-promoting complex. Taken together, these multifaceted properties and interactions enable E3s to provide a powerful, and specific, mechanism for protein clearance within all cells of eukaryotic organisms. The importance of E3s is highlighted by the number of normal cellular processes they regulate, and the number of diseases associated with their loss of function or inappropriate targeting.
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PMID:E3 ubiquitin ligases. 1625 Aug 95

Inactivation of retinoblastoma protein (Rb) plays a critical role in the development of human malignancies. It has been shown that Rb is degraded through a proteasome-dependent pathway, yet the mechanism is largely unclear. MDM2 is frequently found amplified and overexpressed in a variety of human tumors. In this study, we find that MDM2 promotes Rb degradation in a proteasome-dependent and ubiquitin-independent manner. We show that Rb, MDM2, and the C8 subunit of the 20S proteasome interact in vitro and in vivo and that MDM2 promotes Rb-C8 interaction. Expression of wild-type MDM2, but not the mutant MDM2 defective either in Rb interaction or in RING finger domain, promotes cell cycle S phase entry independent of p53. Furthermore, MDM2 ablation results in Rb accumulation and inhibition of DNA synthesis. Taken together, these findings demonstrate that MDM2 is a critical negative regulator for Rb and suggest that MDM2 overexpression contributes to cancer development by destabilizing Rb.
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PMID:MDM2 promotes proteasome-dependent ubiquitin-independent degradation of retinoblastoma protein. 1633 94

ARF encodes a potent tumor suppressor that antagonizes MDM2, a negative regulator of p53. ARF also suppresses the proliferation of cells lacking p53, and loss of ARF in p53-null mice, compared with ARF or p53 singly null mice, results in a broadened tumor spectrum and decreased tumor latency. To investigate the mechanism of p53-independent tumor suppression by ARF, potential interacting proteins were identified by yeast two-hybrid screen. The antiapoptotic transcriptional corepressor C-terminal binding protein 2 (CtBP2) was identified, and ARF interactions with both CtBP1 and CtBP2 were confirmed in vitro and in vivo. Interaction with ARF resulted in proteasome-dependent CtBP degradation. Both ARF-induced CtBP degradation and CtBP small interfering RNA led to p53-independent apoptosis in colon cancer cells. ARF induction of apoptosis was dependent on its ability to interact with CtBP, and reversal of ARF-induced CtBP depletion by CtBP overexpression abrogated ARF-induced apoptosis. CtBP proteins represent putative targets for p53-independent tumor suppression by ARF.
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PMID:Targeting of C-terminal binding protein (CtBP) by ARF results in p53-independent apoptosis. 1650 11

Inactivation of retinoblastoma protein (Rb) plays a key role in human tumorigenesis. Although the regulation of Rb by phosphorylation has been extensively studied, the regulation of proteasome-mediated Rb protein degradation is largely unknown. Viral oncoprotein E7, Epstein-Barr virus nuclear antigen 3C (EBNA3C), human cytomegalovirus pp71 and cellular oncoprotein gankyrin all contain the L-x-C-x-E Rb-binding motif and target Rb protein for degradation in either ubiquitin-dependent or ubiquitin-independent proteasome pathways. The molecular mechanisms, however, remain elusive. The MDM2 oncoprotein is overexpressed in a variety of human cancers. MDM2 functions as an ubiquitin E3 ligase and induces p53 protein degradation through ubiquitination-proteasome pathway. Both MDM2 central acidic domain and the C-terminal RING domain are critical for p53 degradation. MDM2 also interacts with Rb through its central acidic domain and inhibits Rb function in part by blocking Rb-E2F-DNA complex formation. Recently, we showed that MDM2 binds to C8 subunit of 20S proteasome and promotes Rb-C8 interaction, leading to a proteasome-dependent ubiquitin-independent degradation of Rb. Knockdown of MDM2 results in accumulation of hypophosphorylated Rb and inhibition of DNA synthesis. Taken together, we suggest that targeting Rb protein for degradation by proteasomes may represent a common neoplastic strategy during human cancer development.
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PMID:Targeting retinoblastoma protein for degradation by proteasomes. 1655 88

Gankyrin is a new oncoprotein with potent cell cycle and apoptotic properties that is overexpressed early in hepatocarcinogenesis and in hepatocellular carcinomas. Gankyrin regulates the phosphorylation of the retinoblastoma protein (pRb) by CDK4 and enhances the ubiquitylation of p53 by the RING ubiquitin ligase MDM2. Purified preparations of the 26S proteasome contain gankyrin, which specifically interacts with the S6b (Rpt3) ATPase of the 19S regulator. In conclusion, gankyrin is a small versatile cell cycle regulator that illustrates the essential interplay between the ubiquitin proteasome system and gene expression in the cell. Here, we discuss the activities of gankyrin and present a model for its function in the regulation of pRb and p53.
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PMID:Gankyrin: a new oncoprotein and regulator of pRb and p53. 1658 Dec 49

A number of proteins are activated by stress stimuli but none so spectacularly or with the degree of complexity as the tumour suppressor p53 (human p53 gene or protein). Once stabilized, p53 is responsible for the transcriptional activation of a series of proteins involved in cell cycle control, apoptosis and senescence. This protein is present at low levels in resting cells but after exposure to DNA-damaging agents and other stress stimuli it is stabilized and activated by a series of post-translational modifications that free it from MDM2 (mouse double minute 2 but used interchangeably to denote human also), a ubiquination ligase that ubiquitinates it prior to proteasome degradation. The stability of p53 is also influenced by a series of other interacting proteins. In this review, we discuss the post-translational modifications to p53 in response to different stresses and the consequences of these changes.
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PMID:The complexity of p53 stabilization and activation. 1660 50

Inhibition of the MDM2-p53 feedback loop is critical for p53 activation in response to cellular stresses. The ribosomal proteins L5, L11, and L23 can block this loop by inhibiting MDM2-mediated p53 ubiquitination and degradation in response to ribosomal stress. Here, we show that L11, but not L5 and L23, leads to a drastic accumulation of ubiquitinated and native MDM2. This effect is dependent on the ubiquitin ligase activity of MDM2, but not p53, and requires the central MDM2 binding domain (residues 51-108) of L11. We further show that L11 inhibited 26 S proteasome-mediated degradation of ubiquitinated MDM2 in vitro and consistently prolonged the half-life of MDM2 in cells. These results suggest that L11, unlike L5 and L23, differentially regulates the levels of ubiquitinated p53 and MDM2 and inhibits the turnover and activity of MDM2 through a post-ubiquitination mechanism.
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PMID:Regulation of the MDM2-p53 pathway by ribosomal protein L11 involves a post-ubiquitination mechanism. 1680 2


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