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

Recent advances in cancer biology have clearly demonstrated that the development of neoplasms as well as their progression are strictly linked to the alteration of molecular mechanisms controlling the cell division cycle. Among these mechanisms the functional inactivation of two important tumor suppressor genes, namely RB1 and p53, has been widely recognized as a pivotal step in human cancerogenesis. In addition to such well-known genes, a new tumor suppressor gene, mapping on chromosome 9p21, has recently been identified and cloned. Several findings suggest that its loss of function is involved in the initiation and/or progression of an enormous number of different malignancies. This gene, named p16INK4, codifies for a small protein capable of binding to, and thus of inhibiting, some specific cyclin-dependent threonine-serine kinases that represent key enzymatic activities essential for the G1-S transition in mammalian cells. This review will summarize some aspects of the cell cycle control mechanisms, with major emphasis devoted to the role played by this recently characterized inhibitor and to the possible linkage between its inactivation and cancer formation. In particular, we will discuss these aspects in the light of the role of p16INK4 gene inactivation in the development of human acute lymphoblastic leukemias. Indeed this gene seems to be the first, and so far the only tumor suppressor gene consistently altered in specific acute hematological malignancies. Finally, future trends in the investigation of cell cycle control and leukemogenesis will be analyzed.
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PMID:Cell cycle regulation and human leukemias: the role of p16INK4 gene inactivation in the development of human acute lymphoblastic leukemia. 864 24

MTG8 is a counterpart gene of AML1 in acute myeloid leukemia with t(8:21) translocation. Most of the coding region of the MTG8 is fused with AML1 runt domain. In normal tissues, the MTG8 is highly expressed in brain, but not in hematopoietic tissues. MTG8 may be important in leukemogenesis as well as in AML1 truncation. The function of MTG8 is assumed to be as a transcription factor, because it possesses several features common to transcription factors; putative zinc finger motifs, serine/threonine/proline-rich sequences and a region similar to TAF110. In this paper, we report on the protein properties of the MTG8.
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PMID:Significance of MTG8 in leukemogenesis. 920 71

Chemically-induced rodent tumor models help us to understand a series of genetic changes during carcinogenesis. In this study, we present N-nitroso-N-butylurea (NBU)-induced rat leukemia and compare it with the genetic alterations found in 7,12-dimethylbenz[a]anthracene (DMBA)-induced erythroblastic leukemias which consistently have an A to T transversion at the second base of codon 61 in N-ras. By continuous NBU treatment for 120-150 days, 14 primary leukemias were induced in Long-Evans rats. Myeloblastic leukemia cells predominantly increased in all rats except in one case which predominantly had erythroblastic leukemia cells. Point mutations of Ha-, Ki-, N-ras and p53 were determined after RNA was transcribed into cDNA and this cDNA was used as a substrate for polymerase chain reaction (PCR) which was eventually sequenced. No abnormalities in exons 1 and 2 of Ha-, Ki- and N-ras were detected in all leukemias. In the p53 gene, an A to C transition was found at the second base of codon 198 (Asn-Thr) in one leukemia, but others had no mutation. These results suggest that ras and p53 genes are infrequently involved in NBU-induced leukemias. The genetic target of NBU during leukemogenesis seemed to be different from that of DMBA.
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PMID:ras and p53 genes are infrequently involved in N-nitroso-N-butylurea (NBU)-induced rat leukemia. 950 Feb 11

Transforming growth factor beta (TGF-beta) is a highly conserved peptide with growth-inhibitory activity in multiple normal and transformed cell types. Signal transduction is mediated through the receptor complex, consisting of two active seronine or threonine kinases (TGF-beta-receptor I and II) and the receptor-associated proteins betaglycan (TGF-beta-receptor III) and endoglin. In this study, we assessed the analysis of the role of TGF-beta and the transcription of the genes for TGF-beta and its receptor in highly purified leukemic B-cell precursors (BCPs) of patients with common acute lymphoblastic leukemia (cALL). Leukemic BCPs were positive for gene transcription of TGF-beta (9/9), the TGF-beta-receptor I (9/9), the TGF-beta-receptor II (6/6), betaglycan (5/6), and endoglin (6/6). Incubation with TGF-beta significantly reduced the cell viability of leukemic BCPs by a mean of 45% (p = 0.0009). The reduction of cell viability was associated with the induction of apoptosis by a mean of 31%. TGF-beta caused significant suppression of the S phase (p = 0.002) and accumulation in the G0/G1 phase (p = 0.0005). It also reduced expression of the adhesion surface receptor CD18 and the Fas antigen CD95 from 58% to 40% and from 48% to 27%, respectively. The data indicate that TGF-beta is a negative growth signal in leukemic BCPs and point to an additional role of TGF-beta as an immunomodulatory cytokine, suggesting a complex role of TGF-beta in the leukemogenesis of cALL.
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PMID:TGF-beta and its receptor complex in leukemic B-cell precursors. 980 55

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

A proto-oncogene, MTG8 (ETO/CDR), is disrupted in the t(8;21) translocation associated with acute myeloid leukemia, and the gene product, MTG8, is a phosphoprotein capable of cell transformation in concert with v-H-ras. To obtain insight into functional regulation of MTG8 by phosphorylation, we studied protein kinases that interact with, and phosphorylate, MTG8 in vitro. Recombinant MTG8 protein was first found to be associated with two serine/threonine protein kinases in cell extracts from both HEL cells and a leukemic cell line carrying t(8;21). A cytoplasmic protein kinase of 61 kDa (MTG8N-kinase) phosphorylated the amino-terminal of MTG8, and another of 52 kDa (MTG8C-kinase) phosphorylated the carboxyl-terminal domain. In addition, we demonstrated that heat shock protein 90 (HSP90) specifically binds to the amino-terminal domain of MTG8 in vitro and in vivo. Thus, our results shed new light on post-translational regulation of MTG8, perturbation of which, in AML1-MTG8 protein, probably contributes to leukemogenesis.
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PMID:Association of MTG8 (ETO/CDR), a leukemia-related protein, with serine/threonine protein kinases and heat shock protein HSP90 in human hematopoietic cell lines. 1007 66

The Evi-1 transcriptional repressor protein has two distinct zinc finger DNA binding domains designated ZF1 and ZF2 and is implicated in the progression of human and murine leukemias, in which it is abnormally expressed. In this report, we show that Evi-1-expressing Rat1 fibroblasts are anchorage independent, have an abbreviated G1 phase of the cell cycle, and have a reduced requirement for serum mitogens for S-phase entry. These biological changes are accompanied by a moderately increased production of cell cycle-regulatory proteins cyclin A and cyclin-dependent kinase (Cdk) 2, a dramatic deregulation of Cdk2 kinase activity, and a corresponding increase in the levels of hyperphosphorylated retinoblastoma protein (pRb). We show that the elevated cyclin A-Cdk2 activity is due to the combination of increased accumulation and stabilization of cyclin A bound to a faster-migrating species of Cdk2 believed to be the active threonine 160 phosphorylated form and a substantial reduction in complexed p27. Cyclin E kinase activity is also elevated due to a reduction in p27. A significant reduction in total cellular p27 protein levels and a moderate reduction in p27 mRNA are observed, but no changes in Cdk regulatory kinases and phosphatases occur. The Evi-1 transcriptional repressor domain and the ZF1 DNA binding domain are required for both cell transformation and induction of Cdk2 catalytic activity. We propose that one consequence of Evi-1 expression is to repress the transcription of target genes, which may include p27, that deregulate the normal control of the G1 phase of the cell cycle, providing a cellular proliferative advantage that contributes to transformation in vitro and leukemogenesis in vivo.
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PMID:Loss of cell cycle control by deregulation of cyclin-dependent kinase 2 kinase activity in Evi-1 transformed fibroblasts. 1051 10

In the past three years, a novel signal transduction pathway downstream of the transforming growth factor-beta (TGF-beta) superfamily receptor serine-threonine kinases has been shown to be mediated by a family of latent transcription factors called 'Smads'. These proteins mediate a short-circuited pathway in which a set of receptor-activated Smads are phosphorylated directly by the receptor kinase and then translocate to the nucleus complexed to the common mediator, Smad4, to participate in transcriptional complexes. Smads 2 and 3 mediate signals predominantly from the TGF-beta receptors. Of these, specific roles have been ascribed to Smad3 in control of chemotaxis of neutrophils and macrophages and the inhibition of Smad3 activity by the oncogene Evi-1 suggests that it may play a role in leukemogenesis. Other data, such as the induction by the inflammatory cytokine interferon-gamma of an inhibitory Smad, Smad7, which blocks the actions of Smad3, suggest that identification of the specific gene targets of Smad proteins in immune cells will provide new insight into the mechanisms of TGF-beta action on these cells.
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PMID:TGF-beta signaling from receptors to the nucleus. 1061 54

The protooncogene Pim-1 encodes serine/threonine protein kinases that are involved in cytokine-mediated cell proliferation and in lymphoma- and leukemogenesis. It is largely unknown how Pim-1 executes its biological effects. Here we show that Pim-1 physically interacts with heat shock protein 90 alpha and beta (Hsp90alpha and beta). The Hsp90-specific inhibitor geldanamycin (GA) induced a rapid degradation of Pim-1 and reduced its kinase activity. The expression of Hsp90alpha was regulated by a signal from the cytokine receptor gp130, as is Pim-1's expression. These results indicate that Hsp90 is coordinately regulated with Pim-1 and is involved in the stabilization and function of Pim-1.
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PMID:Regulation of Pim-1 by Hsp90. 1123 9

Certain cell lines like HL 60 and K 562 are utilised as leukemic cell models for leukemogenesis research, which differentiate along the granulocytic and/or monocytic pathway when treated with certain inducer molecules. High dose methylprednisolone treatment has been shown to induce in vivo and in vitro differentiation of myeloid leukemia cells to mature granulocytes in patients with acute promyelocytic leukemia (APL) and other subtypes of acute myeloid leukemia (AML). Arsenic trioxide (As(2)O(3)) has been confirmed to have remission induction effects on APL. However, there are conflicting results on the effects with other AML subtypes. Also, it has been well established that the reversible phosphorylation of proteins is a major regulatory mechanism in the signal transduction pathways that control cell growth and differentiation. Serine/threonine protein phosphatases (PP) are major components of phosphorylation. In this study, we investigated the effect of As(2)O(3) on HL 60 and K 562 myeloid leukemic differentiation and compared the signalling cascades of the two inducers with respect to serine/threonine PP 1 and 2A. We utilised PP1 and PP2A inhibitors okadaic acid and calyculin A. In contrast to methylprednisolone, there was no effect of phosphatase inhibitors on As(2)O(3)-induced leukemic differentiation. Incomplete leukemic differentiation occurred with lower As(2)O(3) concentration as 10(-6)M. Unlike As(2)O(3), methylprednisolone induced complete granulocytic and/or monocytic differentiation of HL 60 and K 562 cells via upregulation of PP2A regulatory subunits. Therefore, As(2)O(3) and methylprednisolone are promising agents that have the potential to be used together in myeloid leukemic differentiation therapy.
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PMID:Arsenic trioxide and methylprednisolone use different signal transduction pathways in leukemic differentiation. 1183 83


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