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

---

Query: EC:3.4.25.1 (proteasome)
28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Auxin mediates numerous plant responses, some of which have been shown to require transcriptional regulation. One auxin response pathway, which depends on the relief of transcriptional repression, is mediated by TIR1 (transport inhibitor response protein 1). TIR1 is an auxin receptor and also a subunit of an SCF-type ubiquitin ligase. In the presence of a low concentration of auxin in the nucleus, members of the Aux/IAA family of transcriptional repressors bind to ARF proteins and inhibit the transcription of specific auxin response genes. Increased nuclear concentrations of auxin promote auxin binding to TIR1, causing the Aux/IAA proteins to associate with TIR1 and leading to their degradation by a proteasome-mediated pathway. This decreases the concentration of Aux/IAA proteins in the nucleus and thereby enables the expression of certain auxin response genes.
...
PMID:Teaching resources. Model of the TIR1 pathway for auxin-mediated gene expression. 1647 40

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.
...
PMID:Targeting of C-terminal binding protein (CtBP) by ARF results in p53-independent apoptosis. 1650 11

The INK4a/ARF locus, encoding two tumor suppressor proteins, p16(INK4a) and p14(ARF) (ARF), plays key roles in many cellular processes including cell proliferation, apoptosis, cellular senescence and differentiation. Inactivation of INK4a/ARF is one of the most frequent events during human cancer development. Although p16(INK4a) is a critical component in retinoblastoma protein (Rb)-mediated growth regulatory pathway, p14(ARF) plays a pivotal role in the activation of p53 upon oncogenic stress signals. A body of evidence indicates that ARF also possesses growth suppression functions independent of p53, the mechanism of which is not well understood. We have recently shown that MDM2 interacts with Rb and promotes proteasome-dependent Rb degradation. In this study, we show that ARF disrupts MDM2-Rb interaction resulting in Rb accumulation. Wild-type ARF, but not ARF mutant defective in MDM2 interaction, stabilizes Rb and inhibits colony foci formation independent of p53. In addition, ablation of Rb impairs ARF function in growth suppression. Thus, this study demonstrates that ARF plays a direct role in regulation of Rb and suggests that inactivation of ARF may lead to defects in both p53 and Rb pathways in human cancer development.
...
PMID:ARF promotes accumulation of retinoblastoma protein through inhibition of MDM2. 1729 63

The INK4a locus (chromosome 9p21) encodes two structurally distinct tumor-suppressor proteins, p16(INK4a) and the alternative reading frame protein, ARF (p19(ARF) in mouse and p14(ARF) in human). Each of these proteins has a major role in cell cycle control and senescence pathways. We originally identified a novel collaborator of ARF, CARF, from a two-hybrid interactive screen using p19(ARF) as bait and found that CARF interacts with ARF in the perinucleolar region and activates p53 function. In the absence of ARF, it interacts with p53 directly leading to ARF-independent enhancement of p53 function and in turn undergoes a negative feedback regulation. Very recently, we found that CARF interacts with HDM2 and undergoes degradation by an HDM2-dependent proteasome pathway. CARF may exert a vital control on p53-HDM2-p21(WAF1) pathway that is central to the cell cycle control, senescence, and DNA damage response of human cells.
...
PMID:CARF binds to three members (ARF, p53, and HDM2) of the p53 tumor-suppressor pathway. 1746 Jan 93

Leaf morphogenesis requires the establishment of adaxial-abaxial polarity after primordium initiation from the shoot apical meristem (SAM). Several families of transcription factors are known to play critical roles in promoting adaxial or abaxial leaf fate. Recently, post-transcriptional gene silencing pathways have been shown to regulate the establishment of leaf polarity, providing novel and exciting insights into leaf development. For example, microRNAs (miR165/166) and a trans-acting siRNA (TAS3-derived tasiR-ARF) have been shown to repress the expression of several key transcription factor genes. In addition, yet another level of regulation, post-translational regulation, has been revealed recently by studies on the role of the 26S proteasome in leaf polarity. Although our understanding regarding the molecular mechanisms underlying establishment of adaxial-abaxial polarity has greatly improved, there is still much that remains elusive. This review aims to discuss recent progress, as well as the remaining questions, regarding the molecular mechanisms underlying leaf polarity formation.
...
PMID:Transcriptional, post-transcriptional and post-translational regulations of gene expression during leaf polarity formation. 1754 70

Alterations in the ARF tumor suppressor protein (also known as p14ARF in humans and p19ARF in the mouse) occur frequently in cancer and are associated with susceptibility to melanoma, pancreatic cancer and nervous system tumors. ARF proteins interact with the E2F-1, -2 and -3 transcription activators to inhibit their transcriptional activity and induce their degradation via the 26S proteasome pathway. The impact of ARF on the E2F proteins may provide a mechanism for p53-independent ARF activity on cell cycle progression and tumor susceptibility. In this report we explored the effects of ARF on E2F ubiquitination and degradation in relationship to cell cycle effects and p53 status. We now show that ARF induced the rapid ubiquitination and degradation of E2F-1 only in the presence of functional p53. E2F-1 continued to be ubiquitinated following ARF induction in cycling p53-wild-type, p21-null cells, showing that effects of ARF were not simply a result of p14ARF induced cell-cycle arrest. Importantly, these data establish that the ARF-E2F-1 pathway is an extension of the p53-mdm2-ARF tumor suppressor network and is unlikely to constitute a p53-independent pathway for ARF function.
...
PMID:p14ARF regulates E2F-1 ubiquitination and degradation via a p53-dependent mechanism. 1763 May 9

We initially cloned CARF (collaborator of ARF), as a novel ARF-binding protein by a yeast interaction screen. It also interacts with p53 directly leading to ARF-independent enhancement of p53 function and in turn undergoes a negative feedback regulation. Herein we report that i) CARF interacts with HDM2 and undergoes degradation by an HDM2-dependent proteasome pathway, and ii) it acts as a transcriptional repressor of HDM2. By overexpression and silencing studies, we demonstrated that CARF exerts a vital control on the p53-HDM2-p21WAF1 pathway that is frequently altered in cancer cells.
...
PMID:CARF (collaborator of ARF) interacts with HDM2: evidence for a novel regulatory feedback regulation of CARF-p53-HDM2-p21WAF1 pathway. 1829 44

Although the tumor suppressor ARF is generally accepted for its essential role in activating the p53 pathway, its p53-independent function has also been proposed. Here, we report that ARF associates with COMMD1 and promotes Lys(63)-mediated polyubiquitination of COMMD1 in a p53-independent manner. We found that ARF interacts with COMMD1 in vivo. Deletion analysis of ARF suggested that the N-terminal amino acids 15-45 are important for its interaction with COMMD1. In addition, we found that endogenous ARF redistributes from the nucleolus to the nucleoplasm and interacts with COMMD1 when DNA is damaged by actinomycin D. Interestingly, we found that ARF promotes the polyubiquitination of COMMD1 through Lys(63) of ubiquitin but not the polyubiquitination of Lys(48), which does not target COMMD1 for proteasome-dependent proteolysis. Moreover, ARF mutants lacking the domain interacting with COMMD1 did not promote COMMD1 polyubiquitination, indicating that physical association is a prerequisite condition for the polyubiquitination process. Together, these data suggest that the ability to promote Lys(63)-mediated polyubiquitination of COMMD1 is a novel property of ARF independent of p53.
...
PMID:Tumor suppressor ARF promotes non-classic proteasome-independent polyubiquitination of COMMD1. 1830 12

The tumor suppressor ARF is one of the most important oncogenic stress sensors in mammalian cells. Its effect is exerted through the interaction with different cellular partners, often resulting in their functional inactivation. This review focuses on the role played by the proteasome in ARF regulation of protein turnover and the function of most of its interacting partners. Specific proteasome components appear to be involved in the regulation of ARF turnover, bringing to light a complex network of interactions between ARF and the proteasome.
...
PMID:The promiscuity of ARF interactions with the proteasome. 1880 16

The tumor suppressor ARF plays an essential role in the cellular response to oncogenic stress mainly through activation of p53. Nucleophosmin (NPM), a multifunctional protein, forms a stable protein complex with ARF in the nucleolus and protects ARF from the proteasome-mediated degradation. Notably, NPM is mutated in about one third of acute myeloid leukaemia (AML) patients and these mutations lead to aberrant cytoplasmic dislocation of nucleophosmin (NPM-c). Cytoplasmic NPM mutants lose their abilities to retain ARF in the nucleolus and fail to stabilize ARF. Thus, activation of the ARF-p53 axis is significantly compromised in these AML cells. We have recently identified the ubiquitin ligase of ARF (ULF) as a key factor that controls ARF turnover in human cells. Here, we found that the steady levels of both ARF and p53 are very low in human acute myeloid leukaemia OCI-AML3 cells expressing cytoplamsic dislocated nucleophosmin (NPM-c). As expected, ARF is very unstable and rapidly degraded by proteasome. Nevertheless, ULF knockdown stabilizes ARF and reactivates p53 responses in these AML cells. These results further demonstrate that ULF is a bona fide E3 ligase for ARF and also suggest that ULF is an important target for activating the ARF-p53 axis in human AML cells.
...
PMID:Reactivating the ARF-p53 axis in AML cells by targeting ULF. 2069 39


<< Previous 1 2 3 4 Next >>

---