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 role of alterations of the MTS1 tumor suppressor gene on chromosome 9p21, which encodes p16, the inhibitor of cyclin-dependent-kinase-4 and 6, in tumorigenesis is not yet clear. Phosphorylation of the retinoblastoma protein by cyclin-dependent kinases 4 and 6 prevents its interaction with the transcription factor E2F, which subsequently promotes the expression of S phase regulated genes, such as thymidine kinase. Although a role of p16 in this regulation has been presumed, there is no proof so far that loss of this tumor suppressor gene really affects E2F-mediated regulations. We investigated the regulation of thymidine kinase in phytohemagglutinin-stimulated normal human lymphocytes and in the p16-negative human acute lymphoblastic leukemia cell lines, MOLT-4 and CEM. Compared to normal lymphocytes, MOLT-4 and CEM cells exhibited an altered cell cycle regulation of thymidine kinase, a much higher intracellular activity of this enzyme, and higher thymidine kinase mRNA expression. Transient expression of p16 in normal human lymphocytes caused arrest in G1, but was without effect on the cell growth of MOLT-4 and CEM cells, although all of them express functional retinoblastoma protein. Nevertheless, in the two leukemia cell lines transient overexpression of p16 reestablished the normal regulation of thymidine kinase, paralleled by an increase of the underphosphorylated form of retinoblastoma protein and decrease of free E2F bound to its motif in the thymidine kinase promoter. We demonstrate that loss of p16 causes upregulation of this DNA precursor pathway enzyme via activation of E2F by a mechanism involving retinoblastoma protein.
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PMID:The role of p16 in the E2F-dependent thymidine kinase regulation. 862 83

To understand how the growth of T-cells transformed by Human T-cell leukemia virus type I (HTLV-I) is deregulated, we analysed the expression of cell-cycle regulatory genes in HTLV-I infected and non-infected T-cell lines. We investigated the gene for 6 cyclins, 4 cyclin-dependent kinases, and 5 cyclin-dependent kinase inhibitors, and found the following: (1) HTLV-I infected T-cell lines preferentially expressed cyclin D2, whereas cyclin D3 was the major D-type cyclin in HTLV-I negative T-cell lines; (2) HTLV-I infected T-cell lines expressed strikingly low levels of p18Ink4 compared with those that were HTLV-I negative; (3) HTLV-I infected T-cell lines expressed high levels of p21Waf1/Cip1/Sdi1, whereas p21Waf1/Cip1/Sdi1 was undetectable in HTLV-I negative T-cell lines. These features were also found in T-cells immortalized by Tax1, which we established. Therefore, it is strongly suggested that Tax1 alters the expression of these cell-cycle regulatory genes.
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PMID:Expression of cell-cycle regulatory genes in HTLV-I infected T-cell lines: possible involvement of Tax1 in the altered expression of cyclin D2, p18Ink4 and p21Waf1/Cip1/Sdi1. 862 84

p16(INK4A) and p18 proteins are highly specific inhibitors of cyclin-dependent serine/threonine kinase activities required for the overcoming of the G1 checkpoint in the eukaryotic cell division cycle. The frequent cytogenetic aberrations occurring in several human neoplasms at the level of their codifying genes along with their molecular function strongly suggest that they might be important tumor suppressor genes. We looked for homozygous deletions of p16(INK4A) and p18 genes in 21 cases of childhood T cell lineage acute lymphoblastic leukemia (ALL). Twenty of 21 patients (95%) had homozygous deletions of p16(INK4A) gene while three out of 21 (14%) showed p18 gene biallelic deletion. Loss of heterozygosity studies were performed in 18 of the T cell ALL investigated by means of two highly polymorphic 9p21 markers. The results obtained demonstrated that genetic deletions of different extension occur on the short arms of the 9 chromosome pair. Karyotypic analyses, performed in 13 cases, failed to demonstrate 9p alterations in 12 samples, (92%) thus demonstrating that p16(INK4A) gene homozygous deletions are not restricted to cases with cytogenetically detectable 9p aberrations. The high incidence of p16(INK4A) gene deletions in pediatric T cell lineage ALL suggests that this genetic alteration could represent an early and key event in the development of such a malignancy but it should not have any prognostic value. Conversely, the inactivation of p18 gene, observed in a lower but significant number of cases, could participate in the progression of acute leukemias towards a more aggressive disease. Finally, our results may suggest that p16(INK4A) protein plays a key role in the control of proliferation and/or differentiation of human T lymphocytes.
Leukemia 1996 Feb
PMID:Homozygous deletions of cyclin-dependent kinase inhibitor genes, p16(INK4A) and p18, in childhood T cell lineage acute lymphoblastic leukemias. 863 34

The Fas/Apo-1 molecule is a member of tumor necrosis factor/nerve growth factor (TNF/NGF) receptor family and is able to induce apoptosis in various type of malignant cells, including most of the human leukemia T-cells. We previously demonstrated that the Fas-resistant variants may exist in highly Fas-sensitive human leukemia T-cell lines. The surface expression of Fas antigen was unchanged in the variant cells, suggesting the requirement of the cytoplasmic mechanism to exert apoptosis. In the present study, we examined the changes in cytoplasmic proteins of the Fas-sensitive and Fas-resistant cells after stimulation with anti-Fas antibody, 2D1. In Western blotting analysis, we found that the stimulation of Fas-sensitive cells with 2D1, but not resistant variants, induced a repression of cyclin-dependent kinases (cdks), p34cdc2 and p33cdk2, along with apoptosis. There was no alteration in the expression of bcl-2, HSP70, HSP90, and cyclin proteins examined. This observation seemed specific to Fas-mediated apoptosis, because calcium ionophore A23187 or sodium azide failed to repress the expression of cdks. These results indicate that the specific depletion of cdks, most likely due to proteolysis, may play a role in Fas-mediated apoptosis.
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PMID:Selective depletion of cyclin-dependent kinases is associated with Fas-mediated apoptosis in human leukemia T-cell lines. 878 21

Cell cycle progression requires activation of different cyclin-dependent kinases (CDKs) which are positively regulated by cyclins and negatively regulated by CDK inhibitors. Growth inhibition of the Calu-1 lung carcinoma cells induced with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA), a potent activator of protein kinase C, is associated with G2/M arrest and induction of expression of a novel, faster-migrating form of p21(WAF1/CIP1/SDI1) (p21) protein, an inhibitor of cyclin-dependent kinases. This faster-migrating p21 protein was also expressed in TPA-treated A549 lung carcinoma cells which also exhibited G2/M arrest but not in TPA-treated U937 leukemia cells, which only expressed a slower-migrating form of p21 protein. However, reverse transcriptase-polymerase chain reaction and Southern analysis demonstrated no evidence of novel splice in TPA-treated Calu-1 cells. On the other hand, immunoblotting analysis demonstrated that the faster-migrating p21 protein could be detected only by peptide antibody directed against the N terminus but not the C terminus, suggestive of truncation of the latter or protein modification that results in the loss of the C-terminal epitope. Correlation of G2/M arrest with expression of the faster-migrating p21 protein suggests that this novel form of p21 protein may be a mediator of G2/M arrest and growth inhibition.
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PMID:Novel form of p21(WAF1/CIP1/SDI1) protein in phorbol ester-induced G2/M arrest. 893 83

In order to better understand the molecular background of differences between the clinical picture of T- and B-lineage ALLs, we studied the expression of several proteins involved in the regulation of cell proliferation in bone marrow blast cells from 30 cases of previously untreated acute lymphoblastic leukaemia (ALL); 14 cases were T- and 16 B-cell lineage ALLs. We studied several cyclin-dependent kinases (cdk1, cdk2, cdk4, cdk6) and cyclins (cyclin A, cyclin B1, cyclin D3 and cyclin E). We also studied proliferating cell nuclear antigen (PCNA) and Bcl-2 expression, the latter protein known to be involved in the prolonged survival of B-lineage ALL blasts. Proteins obtained from cell lysates were resolved on polyacrylamide gel followed by immunodetection and densitometry of specific bands. Expression of cdk1 and PCNA, markers of proliferative activity, was significantly higher in T- than in B-lineage ALL. Cdk6, which was highly correlated to PCNA, was also higher in T-cell ALL. In contrast, B-lineage ALL displayed a higher expression of anti-apoptotic protein Bcl-2. We hypothesize that those particularities may reflect differential roles of cell multiplication and apoptosis in the neoplastic proliferation of B- and T-lineage ALL.
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PMID:Differential expression of cell proliferation regulatory proteins in B- and T-lineage acute lymphoblastic leukaemias. 894 94

In hematological malignancies, structural alterations of genes for G1-specific cyclin-dependent kinases inhibitors (CKIs) have been extensively investigated. G1-CKIs might play an important role not only as tumor suppressor genes but also in cellular differentiation. We examined constitutive and differentiation-induced expression and regulation of the four members of the G1-CKI family p16INK4A, p15INK4B, p18INK4C and p19INK4D in acute myeloid leukemia as well as their expression in normal granulocytes and monocytes. p18INK4C and p19INK4D mRNA were expressed constitutively at high levels in seven myeloid cell lines and 16 AML patient samples, whereas expression of p15INK4B mRNA was very low and only detectable by nested RT-PCR analysis. During phorbol ester-induced monocytic differentiation of leukemic HL-60 cells expression of particular G1-CKIs was disparately regulated. This process was associated with growth arrest of the majority of the cells (> or = 80%) in G1/G0, and in parallel p15INK4B were upregulated whereas p18INK4C and p19INK4D expression was downregulated. In contrast, granulocytic differentiation induced by DMSO was accompanied by an increase of p18INK4C and p19INK4D expression only. PMA treatment of blast cells from two AML patients confirmed these cell line results. Disparate regulation of p15INK4B and p18INK4C mRNA was dependent on intermediary protein synthesis and occurred at the post-transcriptional level as shown by nuclear run-on analysis and mRNA half-life studies. In normal granulocytes and monocytes low constitutive p15INK4B and p18INK4C mRNA expression was detectable by RT-PCR only, but p19INK4D transcripts were noted by Northern blotting in both cell types. Disparate expression of G1-specific cell cycle inhibitors indicates complex and divergent roles of particular CKIs during normal and leukemic myeloid hematopoiesis.
Leukemia 1997 Jan
PMID:Expression and regulation of G1 cell-cycle inhibitors (p16INK4A, p15INK4B, p18INK4C, p19INK4D) in human acute myeloid leukemia and normal myeloid cells. 900 19

The level of various G1 cyclins and cyclin-dependent kinases (cdks) present in the nuclei of synchronized ML-1 human myeloblastic leukemia cells was determined as a function of time after initiation of cell growth with insulin-like growth factor-1 (IGF-1) and transferrin (Tf), and following induction of differentiation with transforming growth factor-beta1 (TGF-beta1). Cyclin E and cdk2 were expressed at relatively high levels in the nuclei of proliferation-stimulated cells, whereas cyclin D1 and cdk5 were expressed at comparably high levels in the nuclei of differentiation-induced cells. In the nuclear extracts from proliferation-stimulated cells, cyclin E complexed specifically with cdk2, whereas in nuclear extracts from differentiation-induced cells, cyclin D1 bound specifically to cdk5. Increased cyclin E/cdk2 expression was accompanied by increased DNA synthesis, whereas increased cyclin D1/cdk5 levels correlated with decreased DNA synthesis. In both growth- and differentiation-induced cells, cyclin D2 expression preceded the expression of cyclin D3, and a significantly larger amount of these cyclins was present in differentiation- as compared to proliferation-induced cells. In contrast, cdk4 and cdk6 were present at similar levels in the nuclear extracts from both growth- and differentiation-induced cells. These data show that, in ML-1 cells, the proliferation-associated progression from G1 to S, as well as the differentiation-associated transit from G1 to maturation is accompanied by the expression of specific cyclin/cdk pairs, comprising cdk2/cyclin E in growth and cdk5/cyclin D1 in differentiation.
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PMID:Differential expression of proteins regulating cell cycle progression in growth vs. differentiation. 915 Feb 73

The retinoblastoma susceptibility gene (Rb) plays a key role in regulating the cell cycle in association with cyclins and cyclin-dependent kinases (CDKs). Alteration of the Rb gene as well as CDK inhibitors (CDKIs) leads to deregulated cellular growth which promotes cancer formation. We examined the genomic configuration of the entire Rb gene in 40 primary adult T cell leukemias/lymphomas (ATL) and two ATL cell lines by Southern blotting and also by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analyses. Homozygous loss of exon 1 was identified in one of 21 acute ATL, one of 15 chronic ATL, and none of four lymphomatous ATL samples. No point mutations were identified. Previously, we found that 10 of these same ATL samples had alterations of either p16(INK4A) (homozygous deletion) or p27(kip1) (homozygous deletion or point mutation). Although the numbers are very low, none of the samples with an aberrant Rb gene had an altered CDKI and vice versa, suggesting that both genes probably operate in a common pathway and alteration of either can provide these cells with a growth advantage.
Leukemia 1997 Jul
PMID:Extensive analysis of the retinoblastoma gene in adult T cell leukemia/lymphoma (ATL). 920 79

Tax, a regulatory protein of HTLV-1, is an oncoprotein which immortalizes human T-cells and induces tumors in transgenic mice. Here, we found that Tax binds to a cyclin-dependent kinase inhibitor, p16Ink4a. p16Ink4a binds to cyclin-dependent kinases, CDK4 and CDK6, and inhibits their activity, resulting in suppression of G1 phase progression. The binding of Tax to p16Ink4a induced a reduction of p16Ink4a/CDK4 complex, with subsequent activation of CDK4 kinase. Tax also suppressed p16Ink4a-mediated inhibition of cell growth. The p16Ink4a gene was frequently deleted in many T-cell lines, but not in HTLV-1-infected T-cell lines. Taking these findings together, the functional inactivation of p16Ink4a by Tax through protein-protein interaction is suggested to contribute to cellular immortalization and transformation by HTLV-1.
Leukemia 1997 Apr
PMID:HTLV-1 Tax protein interacts with cyclin-dependent kinase inhibitor p16Ink4a and counteracts its inhibitory activity to CDK4. 920 82


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