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)

Metabolism of the extracellular matrix (ECM) is a complex process that becomes disregulated in disease states characterized by chronic inflammation of joints, as is seen in rheumatoid arthritis or fibrosis of the lung. The participation of certain cytokines in this process is generally accepted (transforming growth factor-beta induces fibrosis), while the roles of other cytokines are less clear. Oncostatin M (OSM) is a member of the interleukin-6/leukaemia inhibitory factor (or gp130) cytokine family, and its participation in inflammation and the regulation of ECM metabolism is supported by a number of activities identified in vitro, including regulation of matrix metalloproteinase-1 and tissue inhibitor of metalloproteinases-1. Local overexpression of transforming growth factor-beta has been shown to be fibrogenic in mouse lung, whereas local OSM overexpression via intra-articular administration has been shown to induce a pannus-like inflammatory response in the synovium of mouse knee joints. Here we examine the effects of OSM in the context of those of transforming growth factor-beta using an established adenovirus vector that expresses mOSM (AdmOSM). We administered the virus intra-nasally into Balb/C mice to achieve high expression of OSM in the lung, and examined the effects at various time points. AdmOSM resulted in a vigorous inflammatory response by day 7 which was characterized by an elevation of neutrophil and mononuclear cell numbers and a marked increase in collagen deposition. These data support the use of such systems to study the ECM in vivo, and indicate a potential role for OSM in inflammatory responses that can modulate steady-state ECM deposition in Balb/C mice.
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PMID:Modulation of extracellular matrix using adenovirus vectors. 1202 35

Human T-cell leukemia virus type I (HTLV-I), the causative agent of adult T-cell leukemia/lymphoma, is transmitted vertically by breast milk and sexually by semen. The transforming growth factor-beta (TGF-beta), a pleiotropic cytokine that is abundant in breast milk and semen, facilitates replication of HTLV-I in lymphocytes derived from asymptomatic HTLV-I carriers and transmission to cord blood lymphocytes in vitro. Transient expression assays revealed that TGF-beta can transactivate HTLV-I long terminal repeat promoter. These results suggest that TGF-beta may play a role in replication and transmission of HTLV-I.
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PMID:Transforming growth factor-beta enhances human T-cell leukemia virus type I infection. 1211 37

Activin A, a cytokine member of the transforming growth factor-beta superfamily, is expressed locally by the mesenchymal component of the hemopoietic microenvironment. Its expression is regulated on the mRNA level by different cytokines, and the biological activity of the protein is tightly controlled by several inhibitory molecules. Activin A affects hemopoietic cells of various lineages, as evidenced by in vitro studies of leukemia and lymphoma cell lines, which were used to elucidate the mechanism of its action. In the B-cell lineage, activin A is a cell cycle inhibitor, a mediator of apoptosis, and a cytokine antagonist. Limited information is available on the effects of activin A on normal hemopoietic cells. Recent studies suggest that it might be a negative regulator of normal B lymphopoiesis. Whereas the functions of activin A in vitro are well established, further research tools are needed to elucidate its role within specific hemopoietic microenvironments in vivo.
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PMID:The role of activin a in regulation of hemopoiesis. 1245 57

Cytokines are regulatory proteins involved in haematopoiesis, immune cell development, inflammation and immune responses. Several cytokines have direct effects on testicular cell functions, and a number of these are produced within the testis even in the absence of inflammation or immune activation events. There is compelling evidence that cytokines, in fact, play an important regulatory role in the development and normal function of the testis. Pro-inflammatory cytokines including interleukin-1 and interleukin-6 have direct effects on spermatogenic cell differentiation and testicular steroidogenesis. Stem cell factor and leukaemia inhibitory factor, cytokines normally involved in haematopoiesis, also play a role in spermatogenesis. Anti-inflammatory cytokines of the transforming growth factor-beta family are implicated in testicular development. Consequently, local or systemic up-regulation of cytokine expression during injury, illness or infection may contribute to the disruption of testicular function and fertility that frequently accompanies these conditions. The aim of this review is to provide a very brief summary of the extensive literature dealing with cytokines in testicular biology, and to follow this with some speculation concerning the significance of these molecules in interactions between the immune system and the testis.
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PMID:Cytokines and the immune-testicular axis. 1260 22

B cell chronic lymphocytic leukemia (B-CLL) is the most common leukemia in western societies, and is currently incurable. B cells of some B-CLL patients are resistant to the anti-proliferative effects of transforming growth factor-beta (TGF-beta). Herein, we identified two mutations within the putative signal sequence of TGF-beta type I receptor (TbetaR-I) gene of TGF-beta-resistant B-CLL patients (i.e., a Leu12Gln substitution together with an in-frame single Ala deletion). Although TbetaR-I mutants were expressed to the cell surface and interacted normally with TGF-beta-bound TbetaR-II, their expression significantly reduced gene transcription stimulated by TGF-beta, suggesting a causal relationship in the development of TGF-beta-resistant B-CLL. Screening of additional B-CLL patients solely for the presence of TbetaR-I signal sequence mutations showed that these mutations correlated with and predicted for B-CLL patient insensitivity to TGF-beta. Our results demonstrate that TGF-beta-resistant B-CLL is linked to signal sequence mutations within the TbetaR-I gene, and may eventually be employed as a prognostic indicator in B-CLL.
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PMID:Transforming growth factor-beta (TGF-beta)-resistant B cells from chronic lymphocytic leukemia patients contain recurrent mutations in the signal sequence of the type I TGF-beta receptor. 1504 Oct 79

Smad5 belongs to the receptor-activated Smad that function as intracellular signal transducers for transforming growth factor-beta superfamily. Smad5 protein is composed of N-terminal domain responsible for DNA-binding, C-terminal domain primarily required for protein-protein interaction, and the linker region containing motif essential for ubiquitinized degradation. Recent investigation reveals Smad5 as a negative regulator of embryonic hematopoiesis in a haploinsufficiency fashion, helping to elucidate the cytogenetic mechanism, by which Smad5 acts as leukemia suppressor. To date, osteogenesis governed by Smad5-mediated signals is delicately orchestrated by its comprehensive interactions with global osteogenesis regulator Runx2, transcriptional repressor Rob and Smad-interacting protein 1. Further delineation of its roles in hematopoiesis and osteogenesis will undoubtedly provide valuable insights into leukemia therapy and tissue engineering.
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PMID:Smad5: signaling roles in hematopoiesis and osteogenesis. 1506 Nov 32

The Runt domain transcription factors (RUNXs) play essential roles in normal development and neoplasias. Genetic analyses of animals and humans have revealed the involvement of RUNX1 in hematopoiesis and leukemia, RUNX2 in osteogenesis and cleidocranial dysplasia, and RUNX3 in the development of T-cells and dorsal root ganglion neurons and in the genesis of gastric cancer. Here we report that RUNX3 is a target of the acetyltransferase activity of p300. The p300-dependent acetylation of three lysine residues protects RUNX3 from ubiquitin ligase Smurf-mediated degradation. The extent of the acetylation is up-regulated by the transforming growth factor-beta signaling pathway and down-regulated by histone deacetylase activities. Our findings demonstrate that the level of RUNX3 protein is controlled by the competitive acetylation and deacetylation of the three lysine residues, revealing a new mechanism for the posttranslational regulation of RUNX3 expression.
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PMID:Transforming growth factor-beta stimulates p300-dependent RUNX3 acetylation, which inhibits ubiquitination-mediated degradation. 1513 60

Tumorigenesis in rodents, as well as in humans, has been shown to be a multistep process, with each step reflecting an altered gene product or gene regulatory process leading to autonomy of cell growth. Initial genetic mutations are often associated with dysfunctional growth regulation, as is demonstrated in several transgenic mouse models. These changes are often followed by alterations in tumor suppressor gene function, allowing unchecked cell cycle progression and, by genomic instability, additional genetic mutations responsible for tumor metastasis. Here we show that reduced transforming growth factor-beta signaling in T lymphocytes leads to a rapid expansion of a CD8+ memory T-cell population and a subsequent transformation to leukemia/lymphoma as shown by multiple criteria, including peripheral blood cell counts histology, T-cell receptor monoclonality, and host transferability. Furthermore, spectral karyotype analysis of the tumors shows that the tumors have various chromosomal aberrations. These results suggest that reduced transforming growth factor-beta signaling acts as a primary carcinogenic event, allowing uncontrolled proliferation with consequent accumulation of genetic defects and leukemic transformation.
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PMID:Transforming growth factor-beta pathway serves as a primary tumor suppressor in CD8+ T cell tumorigenesis. 1537 63

Chromosome translocations are detected in 50-70% of human leukaemia. The promyelocytic leukaemia (PML) gene is involved in the t(15;17) chromosomal translocation of acute promyelocytic leukaemia (APL). PML gene encodes a protein, which was shown to be concentrated in PML-nuclear bodies. Histone acetyltransferases and deacetylases, and chromatin-modifying proteins are accumulated in complexes with PML protein in these nuclear bodies giving the evidence of their role in transcription regulation. Physical interactions of PML protein with transcription factors, co-activators and co-repressors of transcription correspond with the role of PML in transcription regulation. PML plays an important role in apoptosis, proliferation and senescence of cells. PML gene is a tumour-suppressor gene and a product of its expression acts as a potent cell growth suppressor. All these activities of PML protein are ascribed to its nuclear functions. Cytoplasmic form of PML (cPML) is also very important and it is critical for transforming growth factor-beta (TGF-beta) signalling. Cytoplasmic PML interacts with two TGF-beta receptors (TbetaBRI and TbetaRII) and acts as a bridging factor between protein called Smad anchor of receptor activation (SARA) and Smad proteins and it plays a role in the transport of whole complex into the early endosomes in TGF-beta signalling. The loss of functional cPML induces not only APL but it might influence behaviour of cancer cells and their resistance to TGF-beta.
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PMID:[Promyelocytic leukaemia protein and defect in transforming growth factor-beta signal pathway in acute promyelocytic leukaemia]. 1580 93

Evi-1 is a transcription factor that is implicated in leukemic transformation of hematopoietic cells. Two distinct alternative forms, Evi-1a and Evi-1c, are generated from the EVI-1 gene. Whereas Evi-1a is widely recognized as an oncoprotein, a role for Evi-1c, which has an additional PR domain in the amino-terminus of Evi-1a, in leukemogenesis, has not been elucidated thus far. Aberrant oligomerization of transcription factors has recently emerged as a prevalent mechanism for activating their oncogenic potential in hematopoietic malignancies. Here, to study the mechanisms that underlie Evi-1-mediated oncogenesis, we investigated formation of oligomeric complexes by the Evi-1 proteins. We show that Evi-1a forms homo-oligomers, whereas Evi-1c exclusively exists as a monomer in mammalian cells. Remarkably, Evi-1c has lost the ability to interact with CtBP, a transcriptional corepressor that associates with Evi-1a. As a consequence, the ability of Evi-1c to repress transforming growth factor-beta (TGF-beta) signaling is significantly abrogated. These results identify a novel function of a PR domain to regulate oligomerization of transcription factors and suggest that homo-oligomerization may play a critical role in corepressor recruitment by the Evi-1 proteins. In addition, we found that the chimeric oncoprotein acute myelocytic leukemia (AML)1-Evi-1, generated in t(3;21) leukemia, also forms homo-oligomers and hetero-oligomers with Evi-1a, while it did not interact with Evi-1c. Consistent with the results, repression of TGF-beta by AML1-Evi-1 was significantly enhanced by Evi-1a, whereas it was hardly affected by the presence of Evi-1c. These results suggest that oligomerization may contribute to the oncogenic potential of Evi-1-containing proteins.
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PMID:Oligomerization of Evi-1 regulated by the PR domain contributes to recruitment of corepressor CtBP. 1589 67


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