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 p21 protein, a regulator of cyclin-dependent kinases (CDKs), has been thought to be one of the key proteins to function in cell proliferation suppression upon DNA damage. In normal cells but not in many tumor cells, p21 forms a quaternary complex with a cyclin, a CDK and the proliferating cell nuclear antigen (PCNA), one of the DNA replication and repair factors, suggesting that this complex might play an important role in maintaining the integrity of the genome. Here, we have focused on the p21-PCNA interaction in the context of DNA replication or DNA repair, presenting the data from both in vitro and in vivo studies of the p21 function.
Leukemia 1997 Apr
PMID:p53-induced p21 controls DNA replication. 920 78

Mammalian D-type cyclins are differentially expressed during the first gap phase (G1) of the cell cycle in various cell types, and function as regulatory subunits of cyclin-dependent kinases (cdks), cdk4 and cdk6, to form holoenzymes whose activities are both necessary and rate limiting for G1 progression. Mitogenic signals induce the expression of cyclin D and cdk4 proteins, and facilitate their assembly into holoenzymes and their post-translational modification, while anti-proliferative stimuli extinguish the activity of cyclin D-dependent kinases by inducing cdk inhibitors which directly interfere with their catalytic functions and/or inhibit the post-translational activation of cyclin-bound cdks. Therefore, a variety of extracellular signals target and regulate the cyclin D/cdk4 serine/threonine kinases, which execute their critical functions during middle to late G1 phase by phosphorylating key substrates, including the retinoblastoma tumor suppressor gene products (pRb). Although overexpression of cyclin D, or inactivation of Rb or cdk inhibitor gene alone is not sufficient for cell transformation, high frequency of alterations of these genes in cancers suggests that inactivation of this particular pathway is involved in tumor development.
Leukemia 1997 Apr
PMID:Control of G1 progression by D-type cyclins: key event for cell proliferation. 920 86

Many human tumours show perturbations of a pathway that includes the D-cyclins, their associated cyclin-dependent kinases, and specific kinase inhibitors. The focal point of this pathway is the product of the retinoblastoma tumour suppressor gene, pRb, which imposes a block on G1 phase progression. Thus, the major role of the cyclin D-dependent kinases is to overcome this block by initiating the phosphorylation of pRb. Excessive activity of this pathway is likely to lead to excessive cell proliferation. Conversely, accumulation of the inhibitors is associated with the cessation of cell division.
Leukemia 1997 Apr
PMID:Regulation and function of the cyclin-dependent kinase inhibitor p16CDKN2. 920 87

Mantle-cell lymphoma comprises 2%-10% of all non-Hodgkin's lymphomas (NHLs). Patients present with generalized disease, and have a poor prognosis. Three different histologic patterns (mantle zone, nodular, and diffuse) and three different cytological variants (classical, blastic, and pleomorphic) have been described. The phenotype (strong surface IgM, CD5+, CD10-, CD23-, cyclin D1+ and B-cell markers+) is remarkably constant. Dependent on the methods used (PCR, Southern blot analysis, and cytogenetics) a t(11;14) can be detected in approximately 35%-66% of cases. Using FISH analysis, possibly almost all cyclin D1-expressing MCLs carry this translocation, indicating that a substantial part of these translocations are missed by conventional methods. This has been confirmed by DNA fiber FISH analysis by which the breakpoints could be accurately mapped over a 220 kb region centromeric of the cyclin D1 gene. Additional genetic abnormalities involve breakpoints and deletion at the 3' end of the cyclin D1 gene, numerical chromosomal aberrations, mutations in p53, and deletions of p16. These may be associated with tumor progression. Owing to the translocation t(11;14), the cyclin D1 gene is activated. At the RNA level, approximately 90% of MCLs show overexpression. This corroborates immunohistochemistry on paraffin tissue sections. Since expression of cyclin D1 in normal lymphoid cells is very low to undetectable, and only hairy-cell leukemia and very few other B-cell lymphomas show expression, immunohistochemistry for cyclin D1 provides an excellent marker for MCL. In hairy-cell leukemia, expression is moderate and cannot be explained by chromosomal translocation.
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PMID:Bcl-1/cyclin D1 in malignant lymphoma. 920 53

Loss of the p16INK4A gene by homozygous deletions or point mutations is attributed to the development of many types of cancers including leukemia. T cell acute lymphoblastic leukemias (T-ALLs) and B-cell ALLs show a remarkable rate of 75 and 20% homozygous deletion of this gene, respectively. Restoration of p16 expression in p16-deficient solid tumor cell lines results in a dramatic reduction of growth and maligant phenotype. To test the hypothesis that p16INK4A suppresses the growth of p16-deficient leukemias, we utilized a retroviral system to restore wild-type (wt) or mutant p16 protein expression. We tested the efficacy of our system by expressing the wt or mutant p16 genes in the osteosarcoma cell line, U20S, which lacks p16 and retains functional retinoblastoma protein (pRb). The wt p16 protein formed complexes with both cyclin-dependent kinases (CDK) 4 and 6 and inhibited U20S growth by 30-fold. The p16 mutants E120K and R144C formed complexes with CDK4 and CDK6 in cells and inhibited cell growth as effectively as wt p16 (20-fold) while the mutant proteins that did not complex with detectable levels of CDK4 or CDK6 only inhibited growth 0.25- and five-fold (G101W and D141, respectively) or not at all (H83Y and DA4). The COOH-terminal 'tail' of the wt p16 protein (amino acid residues 141-156), missing in mutant D141, enhanced the growth suppressive capability of p16. The amino acid substitutions in mutants G101W and H83Y not only disrupted CDK4 and CDK6 binding, but decreased the protein half-lives by two- and three-fold, respectively, compared to wt p16. The wt, but not mutant p16 genes, effectively inhibited the growth of T cell acute lymphoblastic (CEM) and myeloid leukemia (NB-4 and K562) cell lines that lacked the p16 gene, but retained functional pRb. Growth of the T-ALL cell line, HSB-2, which lacked both p16 and pRb, was not inhibited, indicating the growth suppression involved the pRb pathway. These results define regions critical for the function of p16 and demonstrate that restoration of wt p16 expression in p16-deficient leukemias significantly reverted their transformed phenotype and inhibited their growth.
Leukemia 1997 Oct
PMID:Inhibition of growth of human leukemia cell lines by retrovirally expressed wild-type p16INK4A. 932 88

The human T-cell leukemia/lymphotropic virus type 1 (HTLV-1) induces a malignant lymphocytic disease. The HTLV-1 transactivator protein, Tax, is believed to be crucial for the development of the disease since it is transforming in vitro and induces tumors in transgenic animals. Although the transcriptional modulation of viral and cellular gene expression by Tax has been analyzed thoroughly, it has remained unclear how the Tax functions act on the cell cycle of primary T cells. To investigate the mechanism of Tax-mediated T-cell stimulation, we transduced primary human cord blood T cells with a conditional, tetracycline repressor-based tax expression system. Permanent Tax expression results in an abnormal proliferation of T cells which closely resemble HTLV-1-infected lymphocytes. Suppression of Tax synthesis stopped lymphocyte growth and caused cell cycle arrest in the G1 phase. Upon reinduction of tax expression, the arrested cells entered the S phase. This showed that Tax has mitogenic activity, which is required for stimulating the G1- to S-phase transition of immortalized lymphocytes. In mammalian cells, the G1-phase progression is controlled by the serial activation of several cyclin-dependent kinases (Cdks), starting with Cdk4 and Cdk6. In the presence of Tax, both Cdk4 and Cdk6 were activated. The suppression of Tax synthesis, however, resulted in a significant reduction of the Cdk4 and Cdk6 activities but did not influence the expression of Cdk4, Cdk6, or cognate D-type cyclin proteins. These data suggest that Tax induces Cdk4 and Cdk6 activity in primary human T lymphocytes; this Cdk activation is likely to account for the mitogenic Tax effect and for the abnormal T-cell proliferation of HTLV-1-infected lymphocytes.
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PMID:Stimulation of cyclin-dependent kinase activity and G1- to S-phase transition in human lymphocytes by the human T-cell leukemia/lymphotropic virus type 1 Tax protein. 942 Feb 68

Two dimensional gel electrophoresis of proteins from HL-60 human leukaemia cells treated with bistratene A, a specific activator of protein kinase C (PKC) delta, was performed in conjunction with sequencing in order to identify components of the signal transduction pathway of this isoform of PKC. Stathmin (oncoprotein 18) was identified in this way and the phosphorylation of this protein after treatment with bistratene A, was confirmed by Western blotting of 2D gels. Since stathmin has phosphorylation sites for mitogen activated protein (MAP) kinases, cyclin dependent kinases and calcium/calmodulin dependent protein kinases, it is assumed that one of these enzymes, acting downstream from PKC delta, is responsible for the phosphorylation. Another approach to determining the role of PKC delta involves the identification of interacting proteins using the yeast two hybrid screen. The sequence of nine out of ten independently isolated clones from a two hybrid screen showed perfect homology to human ribosomal protein L8. This protein has previously been shown to exist in complexes with ribosomal RNA, aminoacyl-tRNA and elongation factor-1 alpha, a known substrate of PKC delta, suggesting a role for PKC delta in protein synthesis regulation.
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PMID:Approaches to determine the specific role of the delta isoform of protein kinase C. 950 72

We previously reported that injection of recombinant granulocyte colony-stimulating factor (G-CSF) suppressed the development of leukemia in mice transplanted with C2M-A5 (C2M) myeloid leukemia cells and that the anti-leukemic effect of G-CSF was ascribed to the induction of apoptosis of C2M cells. These observations make a striking contrast with other previous reports on the biological activities of G-CSF. In the present study, in order to further clarify the G-CSF-induced apoptosis of C2M cells, we studied the effects of G-CSF on the cell cycle as well as the molecular events involving D-type cyclines and their cyclin-dependent kinases (cdk) in G-CSF-treated C2M cells. Cell cycle analysis revealed that G-CSF treatment of C2M cells resulted in accelerated entry from the first gap (G1) phase into the DNA synthesis (S) phase. Western blotting disclosed that G-CSF treatment resulted in down-regulation of cyclin D2 and cdk2 and up-regulation of cyclin D1 and cdk4. The reciprocal relationship between the up-regulation of cyclin D1 and down-regulation of cyclin D2 was closely associated with accelerated entry into S phase and subsequent apoptosis of C2M cells. These results suggest that G-CSF-induced apoptosis of C2M cells might be ascribed to imbalanced cell cycle progression due to deregulated expression of D-type cyclins and their cdks.
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PMID:Accelerated entry into S phase associated with up-regulation of cyclin D1 as a mechanism for granulocyte colony-stimulating factor (G-CSF)-induced apoptosis of murine myeloid leukemia cells. 961 17

The cyclin DI/PRAD1 oncogene, a key regulator of the G1 phase of the cell cycle, has been incriminated in the pathogenesis of human neoplasia. Cyclin D1 was also demonstrated to be identical to the long-sought bcl-1 oncogene in B-cell malignancies with the t(11;14)(q13;q32) translocation. We report here a small deletion in the 3'-untranslated portion of the cyclin D1 gene in leukemia cells of a patient diagnosed with B-chronic lymphocytic leukemia (CLL), associated with overexpression of the corresponding cyclin D1 mRNA. During a Northern blot survey of B-cell malignancies, we identified a patient whose CLL cells showed a marked increase in 1.5-1.6 kb cyclin D1 mRNA species. Subsequent Southern blot analysis showed that genomic DNA from the patient's cells contained an extra band in the EcoRI digest, suggesting that one allele of the cyclin D1 gene may be altered. Polymerase chain reaction (PCR) analysis of the genomic DNA and direct DNA sequencing clearly disclosed that one allele of the cyclin D1 gene was deleted in the 3'-untranslated region, which would contribute to an increased stability of its mRNA. Reverse transcription-polymerase chain reaction (RT-PCR) analysis and direct DNA sequencing revealed that the cyclin D1 mRNA was deleted at the corresponding region. This finding provides further evidence for a critical role of cyclin D1 in the pathogenesis of B-cell malignancies and highlights a novel mechanism, a small deletion in the 3'-untranslated region, responsible for deregulation of the cyclin D1 gene in oncogenesis.
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PMID:A small deletion in the 3'-untranslated region of the cyclin D1/PRAD1/bcl-1 oncogene in a patient with chronic lymphocytic leukemia. 962 42

The RB tumor suppressor protein is a cell cycle regulator, where hypophosphorylated RB is associated with G1/0 arrest and its cyclin-dependent phosphorylation in G1 allows progression from G1 to S. The present report shows that in human leukemia cells induced to undergo growth arrest with sodium butyrate or DMSO, hypophosphorylation of the RB protein is not G1 restricted and also occurs in S and G2/M cells as well as in G1 cells when growth is inhibited. While all of the RB protein in G1/0 cells is hypophosphorylated, residual cells in S and G2 have significant detectable amounts of hypophosphorylated RB as well as still hyperphosphorylated RB protein. Thus RB hypophosphorylation can be induced in S and G2 as well as the G1 phase. The results show that growth retardation in other than the G1 phase is associated with occurrence of hypophosphorylated RB. RB may thus have a broader capability to inhibit proliferation than just in G1.
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PMID:Hypophosphorylation of the RB protein in S and G2 as well as G1 during growth arrest. 963 74


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