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: UMLS:C0023418 (leukemia)
93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The modification of proteins with ubiquitin is involved in the regulation of various important biological pathways. A crucial step in this process is the modification of specific substrate proteins with ubiquitin by E3 ligases. The ubiquitylation of proteins can result in altered protein function or degradation by the 26S proteasome. Various proteins playing an important role during hematopoiesis are regulated via ubiquitin modification. Recently, alterations in ubiquitylation and proteasomal degradation have been implicated in hematological cancers. Based on these findings, novel therapies that specifically target ubiquitylation or the proteasome are currently being developed. In this review, we will highlight the role of ubiquitylation in normal and malignant hematopoiesis and discuss novel therapeutical approaches that are now tested in various hematological malignancies.
Leukemia 2006 Sep
PMID:Ubiquitylation in normal and malignant hematopoiesis: novel therapeutic targets. 1692 49

The corepressor BCOR potentiates transcriptional repression by the proto-oncoprotein BCL6 and suppresses the transcriptional activity of a common mixed-lineage leukemia fusion partner, AF9. Mutations in human BCOR cause male lethal, X-linked oculofaciocardiodental syndrome. We identified a BCOR complex containing Polycomb group (PcG) and Skp-Cullin-F-box subcomplexes. The PcG proteins include RING1, RYBP, NSPC1, a Posterior Sex Combs homolog, and RNF2, an E3 ligase for the mono-ubiquitylation of H2A. BCOR complex components and mono-ubiquitylated H2A localize to BCL6 targets, indicating that the BCOR complex employs PcG proteins to expand the repertoire of enzymatic activities that can be recruited by BCL6. This also suggests that BCL6 can target PcG proteins to DNA. In addition, the BCOR complex contains components of a second ubiquitin E3 ligase, namely, SKP1 and FBXL10 (JHDM1B). We show that BCOR coimmunoprecipitates isoforms of FBXL10 which contain a JmjC domain that recently has been determined to have histone H3K36 demethylase activity. The recruitment of two distinct classes of E3 ubiquitin ligases and a histone demethylase by BCOR suggests that BCOR uses a unique combination of epigenetic modifications to direct gene silencing.
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PMID:Polycomb group and SCF ubiquitin ligases are found in a novel BCOR complex that is recruited to BCL6 targets. 1694 29

Human T cell leukemia virus type 1 (HTLV-1) is the etiological agent of adult T cell leukemia. HTLV-1 encodes a trans-activating protein, Tax, which is largely responsible for the oncogenic properties of the virus. Tax promotes T cell transformation by deregulating the activity of various cellular factors, including the transcription factor NF-kappaB. Tax activates the IkappaB kinase (IKK) via physical interaction with the regulatory subunit, IKKgamma, although it is unknown precisely how Tax activates the IKK complex. Here we show that Tax modulates the cellular localization of the IKK complex. The IKKs relocalize from a broad distribution in the cytoplasm to concentrated perinuclear "hot spots" in both HTLV-1-transformed lines and in Tax-expressing Jurkat cells. Relocalization of IKK is not observed with Tax mutants unable to activate NF-kappaB, suggesting that only activated forms of IKK are relocalized. However, relocalization of IKK is strictly dependent on Tax expression because it does not occur in ATL cell lines that lack Tax expression or in Jurkat cells treated with phorbol 12-myristate 13-acetate and ionomycin. Furthermore, IKKgamma is required for redistribution because cells lacking IKKgamma were unable to relocalize IKKalpha upon expression of Tax. We also find that Tax ubiquitination likely regulates IKK relocalization because mutation of three critical lysine residues in Tax renders it unable to relocalize IKK and activate the canonical and noncanonical NF-kappaB pathways. Finally, we have observed that the perinuclear IKK in Tax-expressing cells colocalizes with the Golgi, and disruption of Golgi with either nocodazole or brefeldin A leads to a redistribution of IKK to the cytoplasm. Together, these results demonstrate that Tax induces relocalization of the IKK complex in a ubiquitin-dependent manner, and dynamic changes in the subcellular localization of the IKK complex may be critical for Tax function.
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PMID:Activation of NF-kappa B by the human T cell leukemia virus type I Tax oncoprotein is associated with ubiquitin-dependent relocalization of I kappa B kinase. 1714 47

In an ex vivo mouse model, regulatory transplantation tolerance is not only linked to Foxp3, but also to release of leukaemia inhibitory factor (LIF) and to expression of axotrophin (also known as MARCH-7), a putative ubiquitin E3 ligase associated with feedback control of T cell activation and of T cell-derived LIF. Given this coordinate correlation with tolerance, we now ask if Foxp3 expression is influenced by LIF or by axotrophin. In spleen cells from allo-rejected mice we found that exogenous LIF reduced interferon gamma release in response to donor antigen by 50%, but LIF had no direct effect on levels of Foxp3 protein in allo-primed cells that were either tolerant, or aggressive, for donor antigen. However, we did find an effect of axotrophin on Foxp3: in the axotrophin null mouse, thymic Foxp3 transcripts were reduced compared to axotrophin wildtype littermates. To test whether these findings in the mouse were of potential significance in man we measured transcript levels of axotrophin and LIF in peripheral blood cell samples collected for a recently published clinical study concerning haematopoietic stem cell recipients. In controls, human peripheral blood CD4+CD25+cells contained significantly more FOXP3 and axotrophin than CD4+CD25-cells. In bone marrow autograft recipients, where peripheral blood cell samples directly represent both the grafted tissue and the immune response, both FOXP3 and axotrophin negatively correlated with graft versus host disease (GVHD). These data suggest that (i) thymic Foxp3+T cell development is influenced by axotrophin; and (ii) clinical auto-GVHD inversely correlates with axotrophin transcript expression as has been previously reported for FOXP3.
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PMID:Evidence for functional inter-relationships between FOXP3, leukaemia inhibitory factor, and axotrophin/MARCH-7 in transplantation tolerance. 1716 53

In a previous study, we demonstrated immunoreactivity of a subset of neuronal intranuclear rodlets (INRs) in the human substantia nigra for promyelocytic leukaemia (PML) protein, the signature protein of PML bodies. In the present study, we extend these observations and describe the ultrastructural features, immunohistochemical staining characteristics, and topographical pattern of distribution of PML-immunoreactive intranuclear rodlets (PML-INRs). Consistent with a purported role for PML bodies in nuclear proteolysis and/or transcriptional regulation, PML-INRs are immunoreactive for components of the ubiquitin-proteasome system, the transcriptional regulator CREB-binding protein, acetylated histone H4, and the eukaryotic translation initiation factor eIF4E. Immunoelectron microscopy reveals that they all possess a filamentous core and, in some, this is surrounded by a granular shell. We further demonstrate that a proportion of INRs in extranigral sites also show partial immunoreactivity for PML. These observations indicate an intimate association between two neuronal nuclear bodies, PML bodies and INRs. Because both of these structures have been implicated in neurodegenerative disease, PML-INRs may provide a tool with which to study changes in nuclear substructure in disease.
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PMID:Promyelocytic leukaemia-immunoreactive neuronal intranuclear rodlets in the human brain. 1723 8

Curcumin, a well-known chemopreventive agent, has been shown to suppress the proliferation of a wide variety of tumor cells through a mechanism that is not fully understood. Cyclin E, a proto-oncogene that is overexpressed in many human cancers, mediates the G(1) to S transition, is a potential target of curcumin. We demonstrate in this report a dose- and time-dependent down-regulation of expression of cyclin E by curcumin that correlates with the decrease in the proliferation of human prostate and breast cancer cells. The suppression of cyclin E expression was not cell type dependent as down-regulation occurred in estrogen-positive and -negative breast cancer cells, androgen-dependent and -independent prostate cancer cells, leukemia and lymphoma cells, head and neck carcinoma cells, and lung cancer cells. Curcumin-induced down-regulation of cyclin E was reversed by proteasome inhibitors, lactacystin and N-acetyl-L-leucyl-L-leucyl-L-norleucinal, suggesting the role of ubiquitin-dependent proteasomal pathway. We found that curcumin enhanced the expression of tumor cyclin-dependent kinase (CDK) inhibitors p21 and p27 as well as tumor suppressor protein p53 but suppressed the expression of retinoblastoma protein. Curcumin also induced the accumulation of the cells in G1 phase of the cell cycle. Overall, our results suggest that proteasome-mediated down-regulation of cyclin E and up-regulation of CDK inhibitors may contribute to the antiproliferative effects of curcumin against various tumors.
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PMID:Curcumin induces the degradation of cyclin E expression through ubiquitin-dependent pathway and up-regulates cyclin-dependent kinase inhibitors p21 and p27 in multiple human tumor cell lines. 2698 69

The Tax oncoprotein of human T-cell leukaemia virus type I (HTLV-I) persistently activates nuclear factor-kappaB (NF-kappaB), which is required for HTLV-I-mediated T-cell transformation. Tax activates NF-kappaB by stimulating the activity of IkappaB kinase (IKK), but the underlying mechanism remains elusive. Here, we show that Tax functions as an intracellular stimulator of an IKK-activating kinase, Tak1 (TGF-beta-activating kinase 1). In addition, Tax physically interacts with Tak1 and mediates the recruitment of IKK to Tak1. In HTLV-I-infected T cells, Tak1 is constitutively activated and complexed with both Tax and IKK. We provide genetic evidence that Tak1 is essential for Tax-induced IKK activation. Furthermore, unlike cellular stimuli, the Tax-specific NF-kappaB signalling does not require the ubiquitin-binding function of IKKgamma. These findings show a pathological mechanism of IKK activation by Tax and provide an example for how IKK is persistently activated in cancer cells.
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PMID:Retroviral oncoprotein Tax deregulates NF-kappaB by activating Tak1 and mediating the physical association of Tak1-IKK. 1736 73

To facilitate high-throughput functional genetic screens in embryonic stem cells, a simple and efficient system to construct cDNA-based random RNA interference (RNAi) library was developed in the study. Previous studies have demonstrated that sequence-specific gene silencing could be induced by long double-stranded RNA (dsRNA) in mouse embryos, mouse oocytes, embryonic stem cells, and other mammalian cells. Based on these findings, a dsRNA-expressing RNAi vector system was designed. This study provided evidence that the vector design could induce efficient knockdown of expression of both exogenous egfp gene and endogenous MTM1 gene in mouse embryonic stem cells. A random RNAi library was established by cloning enzyme-digested cDNA of mouse embryonic stem (ES) cells into the BamHI site of the convergent dual promoter RNAi vector. Sequencing of 20 randomly selected clones from the library showed that 17 contained inserts and that all of them were unique sequences. A functional genetic screen of genes involving in self-renewal and differentiation with the random RNAi library identified ubiquitin. The ubiquitin knockdown ES cell line generated 20%-30% of undifferentiated colonies in the absence of leukemia inhibitor factor, whereas parental ES cells and control vector pDCont transfectants produced less than 5% of colonies of undifferentiated cells, suggesting that ubiquitin plays a role in ES cell differentiation. The random RNAi library provides a useful tool for investigation of molecular mechanisms of cellular development and differentiation.
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PMID:A cDNA-based random RNA interference library for functional genetic screens in embryonic stem cells. 1737 69

The PPPY motif in the matrix (MA) domain of human T-cell leukemia virus type 1 (HTLV-1) Gag associates with WWP1, a member of the HECT domain containing family of E3 ubiquitin ligases. Mutation of the PPPY motif arrests particle assembly at an early stage and abolishes ubiquitination of MA. Similar effects are seen when Gag is expressed in the presence of a truncated form of WWP1 that lacks the catalytically active HECT domain (C2WW). To understand the role of ubiquitination in budding, we mutated the four lysines in MA to arginines and identified lysine 74 as the unique site of ubiquitination. Virus-like particles produced by the K74R mutant did not contain ubiquitinated MA and showed a fourfold reduction in the release of infectious particles. Furthermore, the K74R mutation rendered assembly hypersensitive to C2WW inhibition; K74R Gag budding was inhibited at significantly lower levels of expression of C2WW compared with wild-type Gag. This finding indicates that the interaction between Gag and WWP1 is required for functions other than Gag ubiquitination. Additionally, we show that the PPPY(-) mutant Gag exerts a strong dominant-negative effect on the budding of wild-type Gag, further supporting the importance of recruitment of WWP1 to achieve particle assembly.
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PMID:The role of WWP1-Gag interaction and Gag ubiquitination in assembly and release of human T-cell leukemia virus type 1. 1760 63

We have reported that a novel c-Myc-binding protein, MM-1, repressed the E-box-dependent transcription activity of c-Myc by recruiting the HDAC1 complex via TIF1beta/KAP1, a transcriptional corepressor. We have also reported that a mutation of A157R in MM-1, which is often observed in patients with leukemia or lymphoma, abrogated all of the repressive activities of MM-1 toward c-Myc, indicating that MM-1 is a novel tumor suppressor. In this study, we found that MM-1 was bound to a component of proteasome and stimulated degradation of c-Myc in human cells. Knockdown of endogenous MM-1 in human HeLa cells by introduction of siRNA against MM-1 stabilized the endogenous c-Myc. To identify proteins that participate in c-Myc degradation by MM-1, in vivo and in vitro binding assays were carried out. The results showed that MM-1 directly bound to Rpt3, a subunit of 26S proteasome, and that c-Myc directly bound to Skp2, which recruited ElonginC, ElonginB and Cullin2, thereby forming a novel ubiquitin E3 ligase. Knockdown of endogenous Cullin2 stabilized the endogenous c-Myc. Thus, MM-1 is a factor that connects c-Myc to the ubiquitin E3 ligase and the proteasome.
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PMID:MM-1 facilitates degradation of c-Myc by recruiting proteasome and a novel ubiquitin E3 ligase. 1778 14


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