Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The expression of certain cell cycle regulatory proteins: cdk1, cdk2, cdk4, cyclin A, cyclin B, cyclin E, Bcl2 and PCNA was examined in peripheral blood lymphocytes (PBL) from 25 cases of chronic lymphocytic leukemias (CLL) in order to analyze a possible cell cycle involvement of CLL lymphocytes. For comparison, we also studied the expression of these proteins in: 23 samples of non-Hodgkin's lymphoma (NHL) tissue of different histological types, 10 samples of non-neoplastic lymphoid tissue (NLT), non-stimulated PBL (NS-PBL) and PHA-stimulated PBL (PHA-PBL) from three healthy donors. Samples were lysed and proteins were resolved on polyacrylamide gel followed by Western blot. The expression of cdk4 and cyclin E, both known to act in early cell cycle stage, was approximately on the same level in all groups of lymphoid pathology examined. In particular, we found that that 19 out of 24 CLL cases were cyclin E positive and all but one were cdk4 positive, ie they expressed these markers over twice the level of non-stimulated healthy PBL. The cdk1 expression was above the level seen in NS-PBL in 14 (56%) cases, but the average expression was significantly lower than in the other tissues examined, including low-grade lymphomas. Cdk2 expression was comparable in CLL and in low malignancy grade NHL, but weaker than in other NHL and in NLT. Cyclins A and B, normally observed in advanced cell cycle phases, were not seen in any CLL case. The presence of cdk4 and cyclin E in the blood cells of the majority of CLL cases studied, as well as cdk1 and cdk2 in some cases, indicate that the CLL cells are not quiescent, but are blocked in an early stage of the G1 cell cycle phase, and/or that the expression of these proteins is pathologically deregulated.
Leukemia 1995 Aug
PMID:Expression of cell cycle regulatory proteins in chronic lymphocytic leukemias. Comparison with non-Hodgkin's lymphomas and non-neoplastic lymphoid tissue. 764 28

Cyclins are regulatory subunits of the cyclin dependent kinases (CDKs), the enzymes that drive the cell through the respective phases and check-points of the cell cycle. The expression of cyclins in non-tumor cells, regulated by timely induction of their synthesis and proteolysis, is scheduled, occurring at discrete periods of the cell cycle. Using multiparameter flow cytometry we have recently observed that expression of cyclins B1 and E in individual normal lymphocytes mitogenically stimulated by phytohemagglutinin (PHA) and lymphocytic leukemic MOLT-4 cells was similar, restricted to particular phases of the cycle: cyclin B1 was detected only in G2+M- and cyclin E in late G1 and early S-phase cells. In the present study we have measured the expression of cyclins A, D2 and D3 in these cells. The presence of cyclin A was restricted to late S and G2 phases, both in the case of lymphocytes and of MOLT-4 cells. Over 95% of the non-stimulated lymphocytes were both cyclin D2 and D3 negative. Mitogenic stimulation with PHA-induced expression of cyclins D2 and D3 in over 50% cells, which corresponds to the percentage of cells that respond to this mitogen in cultures. Expression of these proteins peaked between 8 and 24 h after addition of PHA, and then decreased at the time of cell entrance to S. During exponential growth (48-72 h after stimulation with PHA) expression of the D-type cyclins was diminished: only between 5-10% of the lymphocytes had levels of cyclin D3 as high as G1 cells between 8-24 h after PHA stimulation. Populations of proliferating lymphocytes and MOLT-4 cells were very heterogeneous in terms of expression of D-type cyclins by individual cells. While expression of cyclin D2 in exponentially growing MOLT-4 cells was similar to that of proliferating lymphocytes, the percent of cells expressing cyclin D3 as well as the degree of expression, was higher in MOLT-4 cells, regardless of the phase of the cycle. These results, with our earlier observations of the untimely expression of cyclins B1 and E in several other tumor lines, suggest that altered expression of cyclins may be a frequent feature of malignancy.
Leukemia 1995 May
PMID:Expression of cyclins A, D2 and D3 in individual normal mitogen stimulated lymphocytes and in MOLT-4 leukemic cells analyzed by multiparameter flow cytometry. 776 53

The p27Kip1 gene codes for a cyclin-dependent kinase inhibitor implicated in G1 arrest by transforming growth factor beta, cell-cell contact, agents that elevate cyclic AMP, and the growth-inhibitory drug rapamycin. p27 binds to and inhibits complexes formed by cyclin E-cdk2, cyclin A-cdk2, and cyclin D-cdk4. The involvement of p27 in the negative regulation of cell proliferation suggests that it may also function as a tumor suppressor gene. Using a combination of somatic cell hybrid panels and fluorescence in situ hybridization p27Kip1 has been mapped to the short arm of chromosome 12 at the 12p12-12p13.1 boundary, reported to harbor deletions and rearrangements in leukemia and mesotheliomas. In order to assess potential p27Kip1 gene alterations, we have screened a total of 147 human primary solid tumors and found no detectable cancer-specific mutations. These results argue that the often observed loss of antimitogenic transforming growth factor beta responsiveness in human cancer cells is not due to structural defects in p27Kip1.
 ...
PMID:p27Kip1: chromosomal mapping to 12p12-12p13.1 and absence of mutations in human tumors. 788 10

To study the involvement of cyclins in cell-cycle progression, changes of mRNA levels for three G1 cyclins (cyclin C, D1 and E) and cyclin A were studied in a leukemia cell line, HEL cells, before and after incubation with 12-O-tetradecanoylphorbol-13-acetate (TPA). Unexpectedly, the cyclin D1 mRNA level markedly increased in the HEL cells when the cells were growth-arrested by TPA, while the amounts of cyclin E and A mRNAs decreased to an almost undetectable level in HEL cells after incubation with TPA. The similar marked increment of the cyclin D1 mRNA level was observed in other leukemia cell lines, CMK and HL-60 cells, after incubation with TPA. The cyclin C mRNA was not detected in HEL cells before and after incubation with TPA.
 ...
PMID:Increment of the cyclin D1 mRNA level in TPA-treated three human myeloid leukemia cell lines: HEL, CMK and HL-60 cells. 837 83

The expression of E and D-type cyclins, Cyclin-Dependent Kinase (CDK) 2 and 4, as well as CDK inhibitors p21Cip1 and p27Kip1 were examined during in vitro differentiation of mouse embryonic stem (ES) cells. ES cells cultured in presence of Differentiation Inhibitory Activity/Leukemia Inhibitory Factor (DIA/LIF) express very low levels of cyclin E/CDK2 complexes, p21Cip1 and p27Kip1 CDK inhibitors, while cyclin D/CDK4-associated kinase activity is undetectable. Withdrawal of DIA/LIF, which induces differentiation, results in the progressive up-regulation of all. Up-regulation of D cyclins occurs through an increase in the steady-state levels of mRNA, concomitantly with the activation of Brachyury and Goosecoid, two early markers of mesoderm differentiation. Similarly, cells from the epiblast of the early postimplantation mouse embryo do not express any cyclin D/CDK4 complexes. These are progressively upregulated at gastrulation and early organogenesis. DIA/LIF-stimulated ES cells are not growth-arrested by overexpression of p16Ink4a, a specific inhibitor of CDK4 and CDK6. We propose that the G1/S transition may be regulated by a minimal mechanism in mouse embryonic stem cells. Induction of differentiation triggers the establishment of a more sophisticated mechanism involving both cyclin D/CDK4- and CDK inhibitor-associated control of G1-phase progression.
 ...
PMID:Withdrawal of differentiation inhibitory activity/leukemia inhibitory factor up-regulates D-type cyclins and cyclin-dependent kinase inhibitors in mouse embryonic stem cells. 857 Feb 8

The v-Abl tyrosine kinase encoded by the Abelson murine leukemia virus (A-MuLV) can either stimulate or inhibit cell proliferation, depending on the cell context. In a NIH-3T3-derived cell line, N3T3, v-Abl blocks the serum-induced entry into S phase. In these G1-arrested cells v-Abl does not interfere with the activation of cyclin D1 or cyclin E-dependent kinases. As a result, v-Abl does not block the hyperphosphorylation and inactivation of the retinoblastoma protein RB. However, activation of cyclin A-dependent kinase is inhibited due to a v-Abl-induced block in the accumulation of cyclin A mRNA and protein. Ectopic expression of cyclin A enabled the v-Abl-arrested cells to enter S phase, whereas cyclins E and D1, or E2Fs 1 and 4 could not overcome the v-Abl arrest. Taken together, these results suggest that v-Abl tyrosine kinase arrests cell cycle progression in G1 by inhibiting the expression of cyclin A.
 ...
PMID:Cells arrested in G1 by the v-Abl tyrosine kinase do not express cyclin A despite the hyperphosphorylation of RB. 870 61

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.
 ...
PMID:Differential expression of cell proliferation regulatory proteins in B- and T-lineage acute lymphoblastic leukaemias. 894 94

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.
 ...
PMID:Differential expression of proteins regulating cell cycle progression in growth vs. differentiation. 915 Feb 73

Cyclin E is one of the G1 cyclins that play an important role in cell proliferation. Overexpression of cyclin E protein has been reported in several solid tumors, but little is known about the involvement of cyclin E in leukemia. In this study, we analyzed the expression of cyclin E gene product in 85 patients with acute myelogenous leukemia (AML) by Western blot analysis. In 23 of 85 AML samples (27%), cyclin E expression was enhanced in blasts. Among the French-American-British classification of AML, the ratio of the samples with enhanced cyclin E expression was high in M5 and low in M2 and M3. No rearrangements were observed by Southern blot analysis in these AML blasts with enhanced cyclin E expression. Flow cytometric analysis showed no correlation between overexpression of cyclin E and cell cycle distribution. Immunoblot analysis of cyclin D1 showed no correlation between overexpression of cyclin E and that of cyclin D1. Interestingly, p27 expression detected by Western blotting was apparently enhanced in 18 of 23 AML cells with enhanced cyclin E expression but none of 14 AML cells without enhanced cyclin E exhibited enhanced p27 expression. The rates of complete remission and of disease-free survival of the patients with M4 or M5 leukemia blasts with overexpressed cyclin E seemed to be low. Therefore, we suggest the necessity of a larger-scale study to elucidate the contribution of cyclin E overexpression to the phenotype and the prognosis of certain AML.
 ...
PMID:Overexpression of cyclin E in acute myelogenous leukemia. 934 56

Onconase is a 12 kDa protein homologous to pancreatic RNase A isolated from amphibian oocytes which shows cytostatic and cytotoxic activity in vitro, inhibits growth of tumors in mice and is in phase III clinical trials. The present study was aimed to reveal mechanisms by which onconase perturbs the cell cycle progression. Human histiocytic lymphoma U937 cells were treated with onconase and expression of cyclins D3 and E, as well as of the cyclin-dependent kinase inhibitors (CKIs) p16INK4A, p21WAF1/CIP1 and p27KIP1 (all detected immunocytochemically) was measured by multiparameter flow cytometry, in relation to the cell cycle position. Also monitored was the status of phosphorylation of retinoblastoma protein (pRb) by a novel method utilizing mAb which specifically detects underphosphorylated pRb in individual cells. Cell incubation with 170 nM onconase for 24 h and longer led to their arrest in G1 which was accompanied by a decrease in expression of cyclin D3, no change in cyclin E, and enhanced expression of all three CKIs. pRb was underphosphorylated in the onconase arrested G1 cells but was phosphorylated in the cells that were still progressing through S and G2/M in the presence of onconase. The cytostatic effect of onconase thus appears to be mediated by downregulation of cyclin D3 combined with upregulation of p27KIP1, p16INK4A and p21WAF1/CIP1, the events which may prevent phosphorylation of pRb during G0/1 and result in cell arrest at the restriction point controlled by Cdk4/6 and D type cyclins.
Leukemia 1998 Aug
PMID:G1 arrest of U937 cells by onconase is associated with suppression of cyclin D3 expression, induction of p16INK4A, p21WAF1/CIP1 and p27KIP and decreased pRb phosphorylation. 969 79


1 2 3 4 5 6 7 8 9 10 Next >>