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)

Tax oncoprotein of human T-cell leukemia virus type 1 (HTLV-1) affects multiple regulatory processes of infected cells through activation and repression of specific transcription and also through modulation of functions of cell cycle regulators. Previously, we found that Tax binds to p16ink4a, a member of the INK4 family of cyclin-dependent kinase inhibitors, and counteracts its inhibitory activity, resulting in cell cycle progression. In this study, we examined the effects of Tax on other members of the INK4 family and found that Tax can bind to p15ink4b similarly to p16ink4a, but not to p18ink4c and p19ink4d. Tax binding to p15ink4b inactivated its function and restored CDK4 kinase activity. Accordingly, Tax-expressing cells became resistant to p15ink4b-mediated growth arrest induced by TGFbeta. On the other hand, expression of p18ink4c was transcriptionally repressed by Tax through the E-box element of the promoter, which may contribute to the marked reduction of p18ink4c mRNA in HTLV-1-infected T-cells. These observations indicate that Tax suppresses the inhibitory activities of INK4 family members through two independent mechanisms: functional inhibition of two INK4 proteins and repression of expression of another INK4 protein. These effects may play roles in HTLV-1-induced deregulation of the cell cycle, possibly promoting cellular transformation.
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PMID:Down-regulation of the INK4 family of cyclin-dependent kinase inhibitors by tax protein of HTLV-1 through two distinct mechanisms. 1038 62

Flt3-ligand (FL) is a cytokine that is of paramount importance in the proliferation of primitive hematopoietic progenitors. In this study, we show that endothelial cells (EC) produce large amounts of soluble FL and express a membrane-bound form of the molecule. Bone marrow microvascular EC also produce FL, suggesting that EC are an important source of FL in the bone marrow. High concentrations of FL in EC supernatants contrast with its undetectable levels in long-term bone marrow cultures. A single mRNA for FL is detected, suggesting that soluble FL derives from the membrane-bound species by proteolytic release. FL mRNA is stable with a half-life of about 3 h. II-1alpha increases FL mRNA levels and membrane and soluble FL expression. Glucocorticoids, known inhibitors for many hematopoietic growth factors do not down-regulate the expression of FL. On the contrary, GC increase the expression of both species of FL. The neutralization of FL in cocultures EC/ hematopoietic progenitors results in an acceleration of the maturation of the progenitors. IFN-alpha, MIP-1 alpha and TGF-beta stimulate production of membrane-bound and soluble FL. This stimulation is essential to explain their modulatory effect on the generation of clonogenic cells in cocultures EC/hematopoietic progenitors. Leukemia (2000) 14, 153-162.
Leukemia 2000 Jan
PMID:Expression of Flt3-ligand by the endothelial cell. 1063 91

The objective of this study was to assess the influence of specific factors on post-thaw development of mouse cryopreserved morulae. Thawed morulae (n = 206) were randomly distributed between 10 treatment groups: medium alone control (CT), Vero (VR) cells, leukaemia inhibitory factor (1 ng/ml), interleukin-6 (1 ng/ml), transforming growth factor (TGF) alpha (2 ng/ml), epidermal growth factor (EGF) (4 ng/ml), platelet-derived growth factor (1 ng/ml), insulin-like growth factor (IGF)-I (30 ng/ml), IGF-II (1 ng/ml) and TGFbeta (2 ng/ml). At 4, 8, 20, 30 and 48 h, a digitized image of each thawed embryo was captured and stored for later analysis. The following parameters were examined: blastocoel formation, blastocyst expansion, zona thickness and hatching. At termination of the experiment, cell number per embryo was determined by bisbenzimide staining. When contrasted to the medium alone control, co-culture consistently accelerated the development of frozen-thawed morulae to the hatched blastocyst stage, allowing embryos to recover rapidly from any damage sustained during the cryopreservation process. While no single growth factor/cytokine was able to completely mimic the results achieved with co-culture, all of the growth factors impacted positively on at least one of the morphological parameters studied. Cell proliferation was significantly stimulated by just 48 h exposure to growth factors, either through co-culture or by direct media supplementation. Co-culture again yielded the best results with a mean cell count of 217 +/- 76 cells per blastocyst as compared with 131 +/- 36 in control medium alone. Amongst the factors tested, IGF-I, IGF-II and EGF had the greatest impact, with mean cell counts of 172 +/- 50, 168 +/- 50 and 179 +/- 55 respectively. Whereas only 5% of CT embryos developed to blastocysts with > 200 cells, 51% of thawed embryos placed on co-culture monolayers and 25-32% of embryos cultured with IGF-I, IGF-II or EGF had > 200 cells. This study for the first time systematically describes the effect of culture regimen and growth factor additives on the post-thaw development of cryopreserved embryos.
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PMID:Assessment of growth factor effects on post-thaw development of cryopreserved mouse morulae to the blastocyst stage. 1065 14

The Smad family proteins are critical components of the transforming growth factor (TGF)-beta signaling pathway. TGF-beta is a multipotent cytokine that elicits many biological functions. In particular, TGF-beta exhibits effects on the cell cycle manifested by G1-phase arrest, differentiation, or apoptosis of several target cells, suggesting that disruption of TGF-beta signaling pathway could be involved in cancer formation. Here we show one missense mutation of the Smad4 gene in the MH1 domain (P102L) and one frame shift mutation resulting in termination in the MH2 domain (Delta(483 - 552)) in acute myelogeneous leukemia. Both of the mutated Smad4 proteins lack transcriptional activities. Concomitant expression of the P102L mutant with wild-type Smad4 inactivates wild-type Smad4 through inhibiting its DNA-binding ability. The Delta(483 - 552) mutant blocks nuclear translocation of wild-type Smad4 and thus disrupts TGF-beta signaling. This is the first report showing that mutations in the Smad4 gene are associated with the pathogenesis of acute myelogeneous leukemia and the obtained results should provide useful insights into the mechanism whereby disruption of TGF-beta signaling pathway could lead to acute myelogeneous leukemia. Oncogene (2001) 20, 88 - 96.
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PMID:Mutations of the Smad4 gene in acute myelogeneous leukemia and their functional implications in leukemogenesis. 1124 7

Human T-cell leukemia virus type I (HTLV-I) Tax is a potent transcriptional regulator that can activate or repress specific cellular genes and that has been proposed to contribute to leukemogenesis in adult T-cell leukemia. Previously, HTLV-I- infected T-cell clones were found to be resistant to growth inhibition by transforming growth factor (TGF)-beta. Here it is shown that Tax can perturb Smad-dependent TGF-beta signaling even though no direct interaction of Tax and Smad proteins could be detected. Importantly, a mutant Tax of CREB-binding protein (CBP)/p300 binding site, could not repress the Smad transactivation function, suggesting that the CBP/p300 binding domain of Tax is essential for the suppression of Smad function. Because both Tax and Smad are known to interact with CBP/p300 for the potentiation of their transcriptional activities, the effect of CBP/p300 on suppression of Smad-mediated transactivation by Tax was examined. Overexpression of CBP/p300 reversed Tax-mediated inhibition of Smad transactivation. Furthermore, Smad could repress Tax transcriptional activation, indicating reciprocal repression between Tax and Smad. These results suggest that Tax interferes with the recruitment of CBP/p300 into transcription initiation complexes on TGF-beta-responsive elements through its binding to CBP/p300. The novel function of Tax as a repressor of TGF-beta signaling may contribute to HTLV-I leukemogenesis. (Blood. 2001;97:2137-2144)
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PMID:Human T-cell leukemia virus type I oncoprotein Tax represses Smad-dependent transforming growth factor beta signaling through interaction with CREB-binding protein/p300. 1126 82

Dramatic changes to the architecture of the airway walls have been commonly described in the airways of patients with asthma, cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). Much research has focused on how airway inflammation drives these structural changes, particularly in terms of the mechanisms/mediators that are involved, and a number of parallels are observed between the disease phenotypes. For example, the increased deposition of extracellular matrix (ECM) at focal sites in the airway wall is seen in asthma and all interstitial lung diseases that involve fibrosis. In addition, increased expression of a number of well characterized cytokines and growth factors, such as TGF-beta and epidermal growth factor (EGF) have been demonstrated in these diseases. However, the role of the lesser-known cytokines, including the leukaemia inhibitory factor (LIF) and other members of the IL-6 family of cytokines in the pathogenesis of airway remodelling and fibrosis is largely unknown. However, the use of genetic manipulation in vivo and more specific inhibitors/antibodies in vitro has now provided increasing evidence to support the hypothesis that a complex interaction exists between these cytokines, ECM and integrins in regulating the function of both epithelial cells and fibroblasts.
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PMID:Epithelium-fibroblast interactions in response to airway inflammation. 1126 11

We have tested the hypothesis that functional dendritic cells (DC) may be generated from patients with acute lymphoblastic leukaemia (ALL). We evaluated the production of DC from blast cells taken at presentation from nine children with ALL. Blast cells were expanded in serum-free medium supplemented with Flt3L, G-CSF, GM-CSF, IL-3, IL-6 and SCF for 7 days and subsequently stimulated with Flt3L, GM-CSF and TGF-beta for a further 14 days, with the addition of TNF-alpha for the final 48 h of culture. Cultured cells had the morphological appearance of DC and expressed the DC-associated antigens CD1A (range 2-87%) and CD83 (15-44%). Expression of the co-stimulatory molecules CD80 and CD86 was increased and the majority of these cells retained their expression of CD34 (73+/-4%) and HLA-DR (79+/-5%). Seven of the nine ALL had a leukaemia-specific abnormality and DC generated from five of these seven cases were derived from the leukaemic clone. Leukaemic DC derived from four HLA-A*02-positive ALL pulsed with CMV-associated peptides could induce significant proliferation of peptide-specific CD8+ T cells. This specificity was verified using tetrameric complexes of HLA class l/antigenic peptide. DC could also be generated from cells taken at times of complete remission of ALL and from normal controls using these culture conditions. These findings show that functional DC can be generated both from ALL blasts and from patients in remission; these might be utilised in future for immunotherapeutic strategies in the treatment of ALL.
Leukemia 2001 Oct
PMID:An optimised biphasic culture system for the generation of functional dendritic cells from patients with acute lymphoblastic leukaemia at presentation and in clinical remission. 1158 18

To determine whether platelet-derived growth factor (PDGF) and transforming growth factor-beta 1 (TGF-beta 1) are involved in organ fibrosis in patients with transient myeloproliferative disorder (TMD) in Down syndrome, the expression of PDGF and TGF-beta 1 mRNA in blast cells of TMD was investigated using real-time quantitative reverse transcription polymerase chain reaction. Blasts and liver tissue from TMD patients with hepatic fibrosis showed a significantly elevated expression of PDGF gene. The expression of TGF-beta 1 gene was higher in TMD and acute megakaryoblastic leukaemia than in the control group. These results suggest that PDGF in combination with TGF-beta 1 plays a role in organ fibrosis of TMD.
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PMID:High expression of platelet-derived growth factor and transforming growth factor-beta 1 in blast cells from patients with Down Syndrome suffering from transient myeloproliferative disorder and organ fibrosis. 1170 51

Increased expression of the molecule CD200 in mice receiving renal allografts is associated with immunosuppression leading to increased graft survival, and altered cytokine production in lymphocytes harvested from the transplanted animals. Preferential production of IL-4, IL-10 and TGFbeta occurs on donor-specific restimulation in vitro, with decreased production of IL-2, IFNgamma and TNFalpha. These effects are enhanced by simultaneous infusion of CD200 immunoadhesin (CD200Fc) and donor CD200 receptor (CD200r) bearing macrophages to transplanted mice. C57BL/6 mice do not normally resist growth of EL4 or C1498 leukaemia tumour cells. Following transplantation of cyclophosphamide-treated C57BL/6 with T-depleted C3H bone marrow cells, or for the EL4 tumour, immunization of C57BL/6 mice with tumour cells transfected with a vector encoding the co-stimulatory molecule CD80 (EL4-CD80), mice resist growth of tumour challenge. Immunization of C57BL/6 mice with EL4 cells overexpressing CD86 (EL4-CD86) is ineffective. Protection from tumour growth in either model is suppressed by infusion of CD200Fc, an effect enhanced by co-infusion of CD200r+ macrophages. CD200Fc acts on both CD4+ and CD8+ cells to produce this suppression. These data are consistent with the hypothesis that immunosuppression following CD200-CD200r interaction can regulate a functionally important tumour growth inhibition response in mice.
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PMID:Evidence of a role for CD200 in regulation of immune rejection of leukaemic tumour cells in C57BL/6 mice. 1170 64

Adult T-cell leukemia (ATL) is associated with prior infection with human T-cell leukemia virus type 1 (HTLV-1). TAX, the major transactivator of HTLV-1, has been implicated in the immortalization of infected T-cells, but molecular mechanisms of in vivo malignant cell transformation induced by HTLV-1 remain unclear. To investigate the role of TAX in the monoclonal proliferation of ATL cells, we determined the nucleotide sequence of tax DNA clones obtained from 6 ATL patients and analysed the biological function of their products. We found that ATL cells from 2 of these patients possessed tax with a nonsense or frame-shift mutation resulting in the premature termination of its protein product, which was no longer functional. This strongly argued against an indispensable role of TAX for the maintenance of ATL cells in vivo. On the other hand, the frequency of nucleotide substitutions found in non-functional tax DNA clones from these patients was significantly lower than those in functional tax DNA clones from the others, suggesting a role for TAX in the genome instability of infected cells. Although mismatch repair defects in the microsatellite markers, including those in hMSH3, hMSH6, BAX, TGF-beta RII, and E2F4 genes, were infrequent, we found an increase in the number of CAG repeats of the E2F4 microsatellite marker in 1 patient. These findings indicate that while TAX may be a necessary prerequisite for malignant transformation of infected cells, it is not essential for the maintenance of ATL cells in vivo.
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PMID:HTLV-1 proviruses encoding non-functional TAX in adult T-cell leukemia. 1172 64


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