Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0598766 (leukemogenesis)
 4,065 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Tax proteins of the oncovirinae viruses are phosphorylated transcriptional activators that exhibit oncogenic potential. The role of phosphorylation in their functional activities remains unknown. As a model for the Human T-cell leukemia virus type I (HTLV-I), Bovine Leukemia Virus (BLV) permits the characterization of viral replication and leukemogenesis in vivo. Here, we show that the BLV Tax protein is phosphorylated on serine residues 106 and 293 both in insect and in mammalian cells. These sites can also be efficiently phosphorylated by the cdc2 and MAP kinases in vitro. Mutation of these residues does not affect the capacity of the Tax protein to function as a transactivator. Indeed, the Tax proteins mutated at one or both serines increase LTR-directed viral transcription at levels similar to those obtained with wild-type Tax in cell culture. Moreover, inhibition of Tax phosphorylation by W7, a calmodulin antagonist, does not alter its transactivation activity. Thus, phosphorylation on serines 106 and 293 is not required for transactivation by Tax. However, simultaneous substitution of both serines into alanine residues destroys the capacity of Tax to cooperate with the Ha-ras oncogene to transform primary rat embryo fibroblasts and induce tumors in nude mice. When the serines were replaced with aspartic acid residues, the oncogenic potential of Tax was maintained indicating that the negative charge rather than the phosphate group itself was required for Tax oncogenicity. Finally, to assess the role of the serine residues in vivo, recombinant viruses which express the Tax mutants were constructed and injected into sheep. It appeared that the mutated proviruses replicate at levels similar to the wild-type virus in vivo. We conclude that Tax phosphorylation is dispensable for transactivation and viral replication in vivo but is required for its oncogenic potential in vitro.
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PMID:Phosphorylation of bovine leukemia virus Tax protein is required for in vitro transformation but not for transactivation. 961 25

The transcription factor C/EBP alpha regulates early steps of normal granulocyte differentiation since mice with a disruption of the C/EBP alpha gene do not express detectable levels of the granulocyte colony-stimulating factor receptor and produce no neutrophils. We have recently shown that C/EBP alpha function is also impaired in acute myeloid leukemias. However, how the transcriptional activity of C/EBP alpha is regulated both in myelopoiesis and leukemogenesis is not fully understood. The current study demonstrates that activated Ras enhances the ability of C/EBP alpha to transactivate the granulocyte colony-stimulating factor receptor promoter and a minimal promoter containing only C/EBP DNA binding sites. Ras signaling activates C/EBP alpha via the transactivation domain because it enhances the transactivation function of a fusion protein containing a Gal4 DNA binding domain and the C/EBP alpha transactivation domain and does not change C/EBP alpha DNA binding. Ras acts on serine 248 of the C/EBP alpha transactivation domain, because it does not enhance the transactivation function of a C/EBP alpha serine 248 to alanine point mutant. Interestingly, serine 248 of C/EBP alpha is a protein kinase C (PKC) consensus site, and a PKC inhibitor blocks the activation of C/EB alpha by Ras. Ras signaling leads to phosphorylation of C/EBP alpha in vivo. Finally, mutation of serine 248 to alanine obviates the ability of C/EBP alpha to induce granulocytic differentiation. These data suggest a model where Ras signaling enhances the activity of C/EBP alpha to induce granulocytic differentiation by phosphorylation of serine 248.
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PMID:Ras signaling enhances the activity of C/EBP alpha to induce granulocytic differentiation by phosphorylation of serine 248. 1197 95

Winged helix factors are important regulators of embryonal development and tissue differentiation. They are also involved in translocations found in acute leukemias and solid tumors. We have detected transcripts from five known and four novel winged helix genes in leukemia cell lines and CD34(+) blood progenitor cells by reverse trancription-polymerase chain reaction with degenerate primers on the highly conserved DNA binding domain. The genomic clones coding for two new winged helix proteins, FOXD4a and FOXD4b were isolated by high-stringency hybridization of a human phage library. FOXD4a and FOXD4b are encoded by a 1319 and 1250 bp single exon coding for a winged helix DNA binding domain, an amino-terminal acidic region and a carboxy-terminal proline- and alanine-rich region which correspond to putative transcriptional regulatory motifs. TATA box, CCAAT box, and transcription factor binding motifs have been identified in the 5' region of the genes. In addition, foxD4a and foxD4b cDNA has been isolated from NB-4 mRNA. The fox genes are transcribed in a tissue-restricted pattern in adult and fetal human tissues. FoxD4a and foxD4b mRNA was expressed in the leukemia cell lines KG-1, Kasumi, NB-4, HL-60, U937, THP-1, HEL, U266, Jurkat, and Raji. It has already been shown that winged helix factors are also involved in carcinogenesis. Based upon these studies, our results suggest that FOXD4a and FOXD4b may play a role in leukemogenesis.
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PMID:FOXD4a and FOXD4b, two new winged helix transcription factors, are expressed in human leukemia cell lines. 1223 74

Nucleophosmin (NPM) is a nucleus-cytoplasmic shuttling protein that is implicated in centrosome duplication, cell cycle progression and stress response. At the steady state, NPM localizes mainly in the nucleolus, where it forms a complex with different cellular proteins. One-third of acute myeloid leukemias (AML) are characterized by aberrant cytoplasmic localization of NPM, due to mutations within its last coding exon (exon 12) that cause a frameshift and the formation of novel C-termini. We report here our investigations on the molecular basis for the aberrant localization of mutated NPM. Alignment of the C-terminus of the various NPM mutants revealed the obligatory presence of four amino-acid residues that match a CRM1-dependent nuclear export signal (NES). Single alanine-substitutions at these sites provoked nuclear re-localization, while fusion of the mutated C-terminus to a heterologous nuclear protein induced CRM1-dependent cytoplasmic localization. Molecular characterization of one exceptional AML carrying cytoplasmic NPM and germ line exon 12 revealed a somatic mutation in the splicing donor site of exon 9 that caused the formation of a functional NES. It appears, therefore, that AMLs are frequently characterized by gain-of-function mutations of NPM that create functional NES, suggesting that alterations of nuclear export might represent a general mechanism of leukemogenesis and a novel target for therapeutic intervention.
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PMID:Cytoplasmic localization of NPM in myeloid leukemias is dictated by gain-of-function mutations that create a functional nuclear export signal. 1650

Studies have documented the potential antitumor activities of oridonin, a compound extracted from medicinal herbs. However, whether oridonin can be used in the selected setting of hematology/oncology remains obscure. Here, we reported that oridonin induced apoptosis of t(8;21) acute myeloid leukemic (AML) cells. Intriguingly, the t(8;21) product AML1-ETO (AE) fusion protein, which plays a critical role in leukemogenesis, was degraded with generation of a catabolic fragment, while the expression pattern of AE target genes investigated could be reprogrammed. The ectopic expression of AE enhanced the apoptotic effect of oridonin in U937 cells. Preincubation with caspase inhibitors blocked oridonin-triggered cleavage of AE, while substitution of Ala for Asp at residues 188 in ETO moiety of the fusion abrogated AE degradation. Furthermore, oridonin prolonged lifespan of C57 mice bearing truncated AE-expressing leukemic cells without suppression of bone marrow or reduction of body weight of animals, and exerted synergic effects while combined with cytosine arabinoside. Oridonin also inhibited tumor growth in nude mice inoculated with t(8;21)-harboring Kasumi-1 cells. These results suggest that oridonin may be a potential antileukemia agent that targets AE oncoprotein at residue D188 with low adverse effect, and may be helpful for the treatment of patients with t(8;21) AML.
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PMID:Oridonin, a diterpenoid extracted from medicinal herbs, targets AML1-ETO fusion protein and shows potent antitumor activity with low adverse effects on t(8;21) leukemia in vitro and in vivo. 1719 33

Ecotropic viral integration site 1 (EVI1) is an important transcription factor for leukemogenesis. EVI1 is a member of a group of transcription factors with C-terminal binding protein (CtBP)-binding motifs that act as transcriptional co-repressors; however, we recently found that EVI1 directly activates GATA2 transcription, which is an important gene for the maintenance of hematopoietic stem cells. We show here that EVI1-activated GATA2 transcripts derive from exon 1S of GATA2, which is specifically activated in neural and hematopoietic cells. EVI1 was acetylated by the histone acetyltransferase p300/CBP association factor (P/CAF) in myeloid leukemia cells and hematopoietic progenitor cells. Acetylation at Lys(564), which is adjacent to the CtBP-binding consensus sequence of EVI1, was found to be important for transcriptional activation of GATA2. Mutation of Lys(564) to alanine (K564A) markedly reduced the ability of EVI1 to bind DNA and activate transcription of GATA2. Furthermore, we confirmed that Lys(564) in EVI1 was specifically acetylated in leukemia and primary hematopoietic cells by using an antibody directed against an acetylated Lys(564) EVI1 peptide. Moreover, co-transfection of P/CAF with EVI1 overcame the suppressive effect of the CtBP co-repressor and resulted in GATA2 transcriptional activation; nonetheless, CtBP2 was still included in the protein complex with EVI1 and P/CAF on the EVI1-binding site in the GATA2 promoter region. Thus, acetylation of EVI1 at Lys(564) by P/CAF enhances the DNA binding capacity of EVI1 and thereby contributes to the activation of GATA2.
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PMID:Acetylation of lysine 564 adjacent to the C-terminal binding protein-binding motif in EVI1 is crucial for transcriptional activation of GATA2. 2036 50