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)

While cloning breakpoint sequences of a leukemia patient exhibiting a t(5; 14) translocation, we identified a pseudogenic variant of a novel multigene family in proximity to the breakpoint. Chromosomal in situ hybridization suggested that the gene family is clustered on human chromosome 5q33-q34. The gene family is evolutionarily conserved. Northern blot analysis of mouse tissues revealed low-level expression of a functional member of this gene family in almost all samples. Marked levels of transcripts were detected by in situ hybridization in the retina, the olfactory epithelium, the peripheral neuronal ganglia, and distinct areas of the gut. The predicted protein displays striking similarity to a hypothetical protein of Caenorhabditis elegans (R10E11.3.) and to two yeast deubiquitinating enzymes, Ubp9 and Ubp13, albeit to a lesser extent. We expressed the putative coding region of the human gene in Escherichia coli and demonstrated that it indeed bears deubiquitinating activity based on its ability to cleave ubiquitin from a ubiquitin-beta-galactosidase fusion protein. This new deubiquitinating enzyme has been named UBH1, for ubiquitin hydrolyzing enzyme 1.
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PMID:An evolutionarily conserved gene on human chromosome 5q33-q34, UBH1, encodes a novel deubiquitinating enzyme. 961 26

The transition from metaphase to anaphase and exit from mitosis involve the degradation of active cyclin B-CDC2 complexes by ubiquitin-mediated proteolysis. The anaphase-promoting complex (APC) catalyzes the formation of cyclin B-ubiquitin conjugates, thereby targeting cyclin B for degradation. The APC is composed of eight proteins, including four members of a family characterized by multiple tetratricopeptide repeats (TPR). We mapped two overlapping expressed sequence tag clones within a genomic contig on human chromosome 5, band q31. A search revealed high homology to Saccharomyces cerevisiae CDC23, a TPR protein component of the APC. We have isolated the human CDC23 cDNA containing the full-length predicted open reading frame. The approximately 3.3-kb message is ubiquitously expressed and encodes a protein with 591 amino acids (MW = 68,293 Da) and 9 TPR units. The protein has 30% identity and 51% similarity to the S. cerevisiae protein. The human CDC23 gene contains 16 exons and spans approximately 31 kb. CDC23 maps within the smallest commonly deleted segment in myeloid leukemias characterized by a deletion of 5q; however, we detected no mutations of CDC23 in leukemia cells with loss of 5q. Thus, CDC23 is unlikely to be involved in the pathogenesis of myeloid leukemias characterized by abnormalities of chromosome 5.
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PMID:Human CDC23: cDNA cloning, mapping to 5q31, genomic structure, and evaluation as a candidate tumor suppressor gene in myeloid leukemias. 979 Jul 67

A major problem in assessing the role of calpains in apoptosis induction concerns the fact that calpain inhibitors can also impair the activity of the proteasome, also reported to be involved in apoptosis. Herein we showed that apoptosis induced by calphostin C in U937 human promonocytic leukemia cells was associated, at its onset, with enhanced protein (poly)ubiquitination. This observation prompted us to study whether protein degradation through the ubiquitin/proteasome pathway was involved in apoptosis induction. We found that N-acetyl-Leu-Leu-norleucinal (50 microM), a proteasome as well as a calpain inhibitor, was able to reduce calphostin C-induced apoptosis by approximately 60%, whereas lactacystin (10 microM), a specific proteasome inhibitor, was ineffective. These results suggest that calphostin C-induced apoptosis is partly calpain-mediated, but does not require protein degradation through the ubiquitin/proteasome pathway.
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PMID:Calpain involvement in calphostin C-induced apoptosis. 982 82

Intravenous administration of different cytokines caused important changes in the expression of ubiquitin genes in skeletal muscle. Tumour necrosis factor-alpha caused a 2.2- and 1.9-fold increase in the expression of the 2.4 and 1.2 kb transcripts, respectively. Administration of interferon-gamma also caused a 2.2- and 1.8-fold increase in the 2.4 and 1.2 kb transcripts, respectively. While administration of leukaemia inhibitory factor and interleukin-6 resulted in no changes in ubiquitin gene expression, interleukin-1 administration also caused an increase in both ubiquitin gene transcripts (2.8- and 1.9-fold for the 2.4 and 1.2 kb transcripts, respectively). The results suggest that some of the cytokine effects on the ubiquitin system gene expression could be related to the enhanced skeletal muscle proteolysis found during cancer cachexia and other pathological states.
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PMID:Different cytokines modulate ubiquitin gene expression in rat skeletal muscle. 992 64

The c-myb oncogene has been a target of retroviral insertional mutagenesis in murine monocytic leukemias. One mechanism by which c-myb can be activated is through the integration of a retroviral provirus into the central portion of the locus, causing premature termination of c-myb transcription and translation. We had previously shown that a leukemia-specific c-Myb protein, truncated at the site of proviral integration by 248 amino acids, had approximately a fourfold-increased half-life compared to the normal c-Myb protein, due to its ability to escape rapid degradation by the ubiquitin-26S proteasome pathway. Here we provide evidence for the existence of more than one instability determinant in the carboxy-terminal region of the wild-type protein, which appear to act independently of each other. The data were derived from examination of premature termination mutants and deletion mutants of the normal protein, as well as analysis of another carboxy-terminally truncated protein expressed in leukemia. Evidence is provided that one instability determinant is located in the terminal 87 amino acids of the protein and another is located in the vicinity of the internal region that has leucine zipper homology. In leukemias, different degrees of protein stability are attained following proviral integration depending upon how many determinants are removed. Interestingly, although PEST sequences (rich in proline, glutamine, serine, and threonine), often associated with degradation, are found in c-Myb, deletion of PEST-containing regions had no effect on protein turnover. This study provides further insight into how inappropriate expression of c-Myb may contribute to leukemogenesis. In addition, it will facilitate further studies aimed at characterizing the specific role of individual regions of the normal protein in targeting to the 26S proteasome.
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PMID:Identification of protein instability determinants in the carboxy-terminal region of c-Myb removed as a result of retroviral integration in murine monocytic leukemias. 997 84

PML nuclear bodies (NBs) are subnuclear structures whose integrity is compromised in certain human diseases, including leukemia and neurodegenerative disorders. Infection by a number of DNA viruses similarly triggers the reorganization of these structures, suggesting an important role for the NBs in the viral infection process. While expression of the adenovirus E4 ORF3 protein leads to only a moderate redistribution of PML to filamentous structures, the herpes simplex virus (HSV) ICP0 protein and the cytomegalovirus (CMV) IE1 protein both induce a complete disruption of the NB structure. Recently, we and others have shown that the NB proteins PML and Sp100 are posttranslationally modified by covalent linkage with the ubiquitin-related SUMO-1 protein and that this modification may promote the assembly of these structures. Here we show that the HSV ICP0 and CMV IE1 proteins specifically abrogate the SUMO-1 modification of PML and Sp100, whereas the adenovirus E4 ORF3 protein does not affect this process. The potential of ICP0 and IE1 to alter SUMO-1 modification is directly linked to their capacity to disassemble NBs, thus strengthening the role for SUMO-1 conjugation in maintenance of the structural integrity of the NBs. This observation supports a model in which ICP0 and IE1 disrupt the NBs either by preventing the formation or by degrading of the SUMO-1-modified PML and Sp100 protein species. Finally, we show that the IE1 protein itself is a substrate for SUMO-1 modification, thus representing the first viral protein found to undergo this new type of posttranslational modification.
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PMID:Viral immediate-early proteins abrogate the modification by SUMO-1 of PML and Sp100 proteins, correlating with nuclear body disruption. 1023 77

The E-26 transforming specific (ETS)-related gene TEL, also known as ETV6, is involved in a large number of chromosomal rearrangements associated with leukemia and congenital fibrosarcoma. The encoded protein contains two functional domains: a helix-loop-helix (HLH) domain (also known as pointed domain) located at the N terminus and a DNA-binding domain located at the C terminus. The HLH domain is involved in protein-protein interaction with itself and other members of the ETS family of transcription factors such as FLI1. TEL is a transcription factor, and we and others have shown that it is a repressor of gene expression. To understand further the role of TEL in the cell, we have used an in vivo interaction system to identify proteins that interact with TEL. We show that a protein, UBC9, interacts specifically with TEL in vitro and in vivo. UBC9 is a member of the family of ubiquitin-conjugating enzymes. These enzymes usually are involved in proteosome-mediated degradation; however, our data suggest that interaction of TEL with UBC9 does not lead to TEL degradation. Our studies show that UBC9 binds to TEL exclusively through the HLH domain of TEL. We also show that TEL expressed as fusion to the DNA-binding domain of Gal4 completely represses a Gal4-responsive promoter, but that the coexpression of UBC9 in the same system restores the activity of the promoter. Targeted point mutation of conserved amino acids in UBC9 essential for enzymatic ubiquitination of proteins does not affect interaction nor transcriptional activity. Based on our data, we conclude that UBC9 physically interacts with TEL through the HLH domain and that the interaction leads to modulation of the transcription activity of TEL.
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PMID:Modulation of TEL transcription activity by interaction with the ubiquitin-conjugating enzyme UBC9. 1037 38

Murine acquired immunodeficiency syndrome (MAIDS) is a complex immunopathology caused by a defective murine leukemia virus (LP-BM5) that mainly targets B-lymphocytes. Lymphadenophathy, splenomegaly, hypergammaglobulinemia and progressive immunodeficiency are prominent features of MAIDS. Previously, we showed that the ubiquitin proteolytic system was upregulated in infected lymph nodes [Crinelli, R., Fraternale, A., Casabianca, A. & Magnani, M. (1997) Eur. J. Biochem. 247, 91-97]. In this report, we demonstrate that increased 26S proteasome activity is responsible for accelerated turnover of the IkappaBalpha inhibitor in lymph node extracts derived from animals with MAIDS. The molecular mechanisms mediating IkappaBalpha proteolysis involved constitutive phosphorylation of IkappaBalpha at Ser32 and Ser36 and subsequent ubiquitination, suggesting persistent activation of an NF-kappaB inducing pathway. Interestingly, enhanced IkappaBalpha degradation did not result in enhanced NF-kappaB DNA binding activity, but rather in a different subunit composition. The modulation of NF-kappaB/IkappaB system may affect multiple immunoregulatory pathways and may in part explain the mechanisms leading to the profound immune dysregulation involved in MAIDS pathogenesis.
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PMID:Activation of the ubiquitin proteolytic system in murine acquired immunodeficiency syndrome affects IkappaBalpha turnover. 1042 5

c-MycS proteins are truncated forms of the transcription factor which have been shown to be produced by translation initiation at internal methionines (101, 121, and 134) and to be functional in the regulation of gene expression, cell proliferation, and apoptosis. Treatment of human leukemia HL60 cells with lactacystin, a specific inhibitor of the proteasome, increased the steady-state levels of endogenous c-MycS proteins. The half-life of endogenous [(35)S]MycS was similar to that of c-Myc ( approximately 23 min) in HL60 cells. c-Myc(Delta2-143), which lacks the transcription regulatory domain, had a half-life which was similar to that of endogenous c-Myc in 293 and HL60 cells. Treatment of the cells with lactacystin stabilized [(35)S]Myc(Delta2-143) and [(35)S]Myc and caused multi-ubiquitin conjugates of c-Myc, c-MycS, and Myc(Delta2-143) to accumulate. These findings indicate that the Myc homology boxes and the rest of the transcription regulatory domain (the first 144 amino acids) are dispensable for ubiquitylation and rapid destruction of c-MycS and c-Myc by the proteasome.
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PMID:Ubiquitylation and destruction of endogenous c-mycS by the proteasome: are myc boxes dispensable? 1066 12

Members of the cdc25 family are protein phosphatases that play pivotal roles in cell cycle progression. Cdc25A has been shown to be a critical regulator of the G1/S transition of mammalian cells and to be a myc-target gene with oncongenic properties. We investigated the regulation of cdc25A during terminal differentiation using myeloblastic leukemia M1 cells, that can be induced to undergo differentiation into macrophages by interleukin-6 (IL-6) treatment. In this report it is shown that cdc25A protein is degraded by the ubiquitin-proteasome machinery in both terminally differentiating and cycling cells. Cdc25A was found to have two major peaks of accumulation during cell cycle progression, one in G1 and the other in S/G2. Evidence was obtained that degradation of cdc25A by the ubiquitin-proteasome machinery in terminally differentiating myeloid cells is accelerated compared to cycling cells. Moreover, deregulated expression of c-myc in M1 cells, which had been previously shown to block terminal differentiation, was also found to block IL-6 induced degradation of cdc25A.
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PMID:Cdc25A stability is controlled by the ubiquitin-proteasome pathway during cell cycle progression and terminal differentiation. 1082 87


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