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 mammalian D-type cyclins D1, D2, and D3 activate the cyclin-dependent kinases CDK4 and CDK6 in G1 and thereby promote the cell's commitment to enter S phase. To elucidate the extent of functional overlap among the D-type cyclins, we have examined several aspects of the least characterized member of this subfamily of G cyclin proteins, cyclin D3. Microinjection of cyclin D3-neutralizing antibody inhibited G1/S transition in human (IMR-90) and rat (R12) diploid fibroblasts, indicating that analogous to cyclins D1 and D2, cyclin D3 is essential for timely progression through G1. In contrast to cyclins D1 and D2, cyclin D3 was (i) ubiquitously expressed among a panel of 70 human cultured cell types; (ii) strongly upregulated upon induction of HL-60 leukaemia cells to differentiate; and (iii) accumulated to high levels in a wide range of quiescent cell types in mouse and human differentiated tissues. Complementary analyses of human biopsies and mouse tissues at different stages of foetal and postnatal development revealed lineage-dependent transient or long-term accumulation of the cyclin D3 protein, correlating with initiation/establishment or maintenance of the mature phenotypes, respectively. Our data support the notion that the biological roles of the individual D-type cyclins are not fully redundant, and suggest a possible dual role for cyclin D3 in cell proliferation and induction and/or maintenance of terminal differentiation.
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PMID:Cyclin D3: requirement for G1/S transition and high abundance in quiescent tissues suggest a dual role in proliferation and differentiation. 974 82

Thrombopoietin (TPO) is a recently cloned growth and differentiation factor implicated in megakaryocytopoiesis. Here, we show that TPO, interleukin-3 (IL-3) and, at least in short-term assays, also interferon gamma (IFN gamma) induced proliferation in acute myeloid leukemia (AML-M7)-derived M-07e cells. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway was activated after stimulation with any of the three cytokines. Thus, the TPO-receptor (TPO-R) MPL was tyrosine phosphorylated after a short-term stimulation with TPO, followed by tyrosine phosphorylation of STAT 3 and STAT 5, but not of STAT 1. IL-3 and IFN gamma induced phosphorylation of STAT 5 or STAT 1, respectively, without affecting the other STATs. As STATs are thought to regulate proliferation by modulating expression of inhibitors of cyclin-dependent kinases (Cdk), we analyzed p21 and p27 expression after stimulation with TPO or IL-3. In contrast to the constitutively low p21 expression, p27 mRNA levels were high in synchronized, cytokine-deprived cells in G0/1 phase. Stimulation with TPO or IL-3 induced a rapid decrease of p27 mRNA. The phosphorylation cycle of the retinoblastoma protein (Rb) was inversely correlated with the level of p27 mRNA. Hyperphosphorylation of Rb was detectable 9 h after onset of stimulation, concomitantly with the decrease of p27 mRNA and shortly before transition of the cells into S phase. As phosphorylation of Rb is a key event for transition of cells into S phase, our observations support the notion of p27 being an important regulator during cytokine-induced proliferation. Whether the JAK/STAT pathway is directly involved in p27 expression or not, remains to be elucidated. The JAK inhibitor AG-490 blocked cytokine-induced STAT 5 phosphorylation and proliferation of M-07e cells in a dose-dependent manner. Although these data indicate a role for the JAK/STAT pathway in cytokine-induced proliferation, a direct influence on the p27 mRNA downregulation has to be confirmed. The second major effect of TPO, polypoidization, could not be observed in M-07e cells. Even long-term culture with TPO did not induce endomitosis in these cells. However, polyploidization could be brought about by the kinase inhibitor K-252a. After 3 days of exposure to this reagent, 17% of the originally mononucleated cells contained two to five nuclei. K-252a-induced polykaryon formation was not preceded by STAT 5 phosphorylation. Thus, K-252a did not mimic TPO stimulation at the early steps of the signaling chain. Taken together, our experiments confirm a role for the JAK/STAT pathway in cytokine-induced proliferation; TPO and IL-3 induce downregulation of the Cdk inhibitor p27, hyperphosphorylation of Rb and subsequently transition of the cells into S phase; the kinase inhibitor K-252a induces polyploidization of M-07e cells, but this effect is independent of STAT 5 phosphorylation.
Leukemia 1998 Oct
PMID:Effects of thrombopoietin, interleukin-3 and the kinase inhibitor K-252a on growth and polyploidization of the megakaryocytic cell line M-07e. 976 6

The products of the tumor suppressor genes are considered to function as specific inhibitors of tumor cell growth. In this communication, we present evidence to show that these proteins inhibit tumor cell proliferation by participating in the activation of tumor cell differentiation. The ML-1 human myeloblastic leukemia cells used in this study proliferate when treated with insulin-like growth factor I and transferrin but differentiate to monocytes when exposed to tumor necrosis factor alpha or transforming growth factor beta1, or to macrophage-like cells when treated with both these cytokines. Initiation of proliferation but not of differentiation was followed by a 20- to 25-fold increase in the nuclear level of the DNA polymerase-associated processivity factor PCNA and of the proliferation-specific transcription factor E2F1. In contrast, induction of differentiation but not of proliferation was followed by a 25- to 30-fold increase in the nuclear level of the tumor suppressor proteins p53 (wild type), pRb, and p130/Rb2 and of the p53-dependent cyclin kinase inhibitor p21/Cip1. p53 and p21/Cip1, respectively, inhibit the expression and activation of PCNA, whereas p130 and pRb, respectively, inhibit the expression and activation of E2F1. As a result, G1-S-associated DNA and mRNA synthesis is inhibited, growth uncoupled from differentiation, and maturation enabled to proceed. Where this function of the tumor suppressor proteins is impaired, the capacity for differentiation is lost, which leads to the sustained proliferation that is characteristic of the cancer cell.
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PMID:Tumor suppressor proteins as regulators of cell differentiation. 976 53

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

The mammalian A-type cyclin family consists of two members, cyclin A1 (encoded by Ccna1) and cyclin A2 (encoded by Ccna2). Cyclin A2 promotes both G1/S and G2/M transitions, and targeted deletion of Ccna2 in mouse is embryonic lethal3. Cyclin A1 is expressed in mice exclusively in the germ cell lineage and is expressed in humans at highest levels in the testis and certain myeloid leukaemia cells. To investigate the role of cyclin A1 and possible redundancy among the cyclins in vivo, we generated mice bearing a null mutation of Ccna1. Ccna1-/- males were sterile due to a block of spermatogenesis before the first meiotic division, whereas females were normal. Meiosis arrest in Ccna1-/- males was associated with increased germ cell apoptosis, desynapsis abnormalities and reduction of Cdc2 kinase activation at the end of meiotic prophase. Cyclin A1 is therefore essential for spermatocyte passage into the first meiotic division in male mice, a function that cannot be complemented by the concurrently expressed B-type cyclins.
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PMID:Cyclin A1 is required for meiosis in the male mouse. 984 12

During the last 10 years, multiple signal transduction pathways within cells have been discovered. These pathways have been linked to the regulation of many diverse cellular events such as proliferation, senescence, differentiation and apoptosis. This review will focus upon the many roles of signaling by the p42/p44 mitogen-activated protein (MAP) kinase pathway. Recent evidence suggests that signaling by the MAP kinase pathway can both enhance proliferation by increased expression of molecules such as cyclin D1, but also cause growth arrest by increased expression of molecules such as the cyclin kinase inhibitor protein p21(Cip-1/MDA6/WAF1). These differential effects on growth have been correlated to the amplitude and duration of the MAP kinase activity signal. Furthermore several laboratories are reporting data suggesting that inhibition of the MAP kinase pathway, as well as a family of upstream MAP kinase activators, the protein kinase C family, represent an important route to both radio- and chemo-sensitization of tumor cells. Herein, we describe the historical discovery and characterization of the MAP kinase pathway. In addition we describe potential mechanisms by which inhibition of protein kinase C, the MAP kinase pathway, and potentially of p21(Cip-1/MDA6/WAF1) expression, may alter the sensitivities of leukemic and carcinoma cells to cytotoxic insults, leading to increased apoptosis and loss of clonogenicity.
Leukemia 1998 Dec
PMID:The roles of signaling by the p42/p44 mitogen-activated protein (MAP) kinase pathway; a potential route to radio- and chemo-sensitization of tumor cells resulting in the induction of apoptosis and loss of clonogenicity. 984 14

Human cyclin A1 is a newly cloned, tissue-specific cyclin that is prominently expressed in normal testis. In this study, we showed that cyclin A1 was highly expressed in a subset of leukemia samples from patients. The highest frequency of cyclin A1 overexpression was observed in acute myelocytic leukemias, especially those that were at the promyelocyte (M3) and myeloblast (M2) stages of development. Cyclin A1 expression was also detected in normal CD34(+) progenitor cells. The expression of cyclin A1 increased when these cells were stimulated to undergo myeloid differentiation in vitro. Taken together, our observations suggest that cyclin A1 may have a role in hematopoiesis. High levels of cyclin A1 expression are especially associated with certain leukemias blocked at the myeloblast and promyelocyte stages of differentiation.
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PMID:Cyclin A1 expression in leukemia and normal hematopoietic cells. 1006 80

The p16 gene encoding a specific inhibitor of cyclin-dependent kinases 4 and 6 has been reported to be inactivated at a variety of rates in malignant tumors. We studied frequency and mechanism of inactivation of the p16 gene in various types of childhood acute lymphoblastic leukemia (ALL) using 36 leukemic cell lines established from children (B precursor-ALL, 28; B-ALL/Burkitt's lymphoma, 3; and T-ALL, 5). On Southern blot, homozygous deletions or hemizygous deletions with rearrangement were detected in 14 cell lines. The expression of p16 protein was not observed on Western blot in 18 of 22 cell lines with intact p16 gene, but induced in 16 cell lines after treatment with the demethylating agent, indicating the silencing of the p16 gene by hypermethylation. Of note, the p16 gene was inactivated by hypermethylation of the 5' CpG island in nine of nine cell lines with 11q23 translocation, but was restored with the treatment of the demethylating agent. Partial methylation of the p16 gene was also demonstrated in three of eight primary leukemia samples with this translocation, suggesting that the p16 gene inactivation by hypermethylation might play a role in the leukemogenesis and disease progression of ALL with 11q23 translocation.
Leukemia 1999 Jun
PMID:p16/MTS1/INK4A gene is frequently inactivated by hypermethylation in childhood acute lymphoblastic leukemia with 11q23 translocation. 1036 Mar 77

The function of most cyclin-dependent kinases (Cdks) is to facilitate progression through the checkpoints of the cell cycle, but Cdk5 is known to be involved in differentiation of CNS, muscle, and lens cells, though not in the cell cycle traverse. Here we show an additional role for Cdk5, an enhancement of monocytic differentiation with abrogation of the G1 checkpoint. Human leukemia HL60 cells exposed to 1alpha,25-dihydroxyvitamin D3 (1,25D3) displayed monocytic phenotype and increased Cdk5 kinase activity. An analog of 1,25D3 which does not induce differentiation failed to upregulate Cdk5, and 1,25D3-resistant cells had reduced Cdk5 activity. Active or inactive Cdk5 was associated with cyclin D1, but only active Cdk5 exhibited threonine phosphorylation. Inhibition of Cdk5 expression by an antisense construct reduced the intensity of 1, 25D3-induced expression of CD14, a marker of monocytes, and increased the 1,25D3-induced G1 block. These findings demonstrate a novel aspect of Cdk5 activity-facilitation of the G1- to S-phase transition in cells which are approaching replicative quiescence and a concomitant enhancement of monocytic differentiation.
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PMID:Cyclin-dependent kinase 5 activity enhances monocytic phenotype and cell cycle traverse in 1,25-dihydroxyvitamin D3-treated HL60 cells. 1036 42

Cyclin D1 participates in cell-cycle control, in the progression through the G(1) phase and in the transition from the G(1) to the S phase. The CCND1 locus, located in 11q13, is amplified and cyclin-D1 protein is over-expressed in a wide range of human solid tumors. In some B-lymphoid malignancies, the t(11;14)(q13;q32) translocation joins the Ig heavy-chain locus to the CCND1 locus and leads to cyclin-D1 over-expression. In this study, a series of 127 patients presenting a B-chronic lymphoproliferative disorder (B-CLPD) was analyzed using a competitive RT-PCR designed to detect cyclin-D1-mRNA over-expression. Cyclin-D1 mRNA was expressed in patients with mantle-cell lymphoma (MCL; 10/10), hairy-cell leukemia (HCL; 3/5), B-chronic lymphoid leukemia (B-CLL; 4/111) and B large-cell lymphoma (BLCL; 1/1). Densitometric analysis of RT-PCR products and Western-blot autoradiograms, in addition to cytogenetic data, indicated that activation of the cyclin-D1 gene occurred independently of the t(11;14)(q13;q32) translocation in patients with HCL. Indeed, a normal-sized protein of 36 kDa exhibiting a level incompatible with gene activation by a translocation mechanism was detected in lymphoid cells with a normal karyotype. Moreover, we found a discrepancy between cyclin-D1 mRNA and protein levels in MCL and B-CLL, which suggested that some regulatory mechanisms acting at a post-transcriptional level persist in tumor cells.
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PMID:Transcriptional and post-transcriptional mechanisms induce cyclin-D1 over-expression in B-chronic lymphoproliferative disorders. 1047 32


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