Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Supportive care with red cell and platelet transfusions and use of growth factors has long been the standard of care for patients with myelodysplastic syndromes (MDS) ineligible for stem cell transplantation. Although these measures improve quality of life, their impact on the natural history of the disease is questionable. Recently, three new agents have been approved for the treatment of MDS. These include: 5-azacytidine, lenalidomide and, more recently, 5-aza-2 -deoxycytidine (decitabine). Decitabine is a hypomethylating agent that is incorporated into DNA and forms irreversible covalent adducts with DNA-methyltransferases. At high concentrations, this leads to cell death. At low concentrations, decitabine is considered to exert its anticancer effects by inducing DNA hypomethylation. This results in reactivation of epigenetically repressed genes, such as tumour suppressor genes and, potentially, cell differentiation. In a randomized, Phase III trial of decitabine versus best supportive care in patients with MDS, the overall response rate with decitabine was 17%, including 9% complete remissions. Patients at high risk had a statistically significant prolongation of time to acute myelogenous leukemia transformation or death. This experience has been followed by a study of low-dose decitabine using a five-times daily 1-h infusion schedule, with significant efficacy in patients with MDS observed. Ongoing studies are evaluating the activity and safety of the combination of decitabine with several histone deacetylase inhibitors and other indications. This article summarizes the experience in with decitabine in MDS.
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PMID:The role of decitabine in the treatment of myelodysplastic syndromes. 1716 8

Tumour suppressor gene inactivation is critical to the pathogenesis of cancers; such loss of function may be mediated by irreversible processes such as gene deletion or mutation. Alternatively tumour suppressor genes may be inactivated via epigenetic processes a reversible mechanism that promises to be more amenable to treatment by therapeutic agents. The CpG dinucleotide is under-represented in the genome, but it is found in clusters within the promoters of some genes, and methylation of these CpG islands play a critical role in the control of gene expression. Inhibitors of the DNA methyltransferases DNMT1 and DNMT3b have been used in a clinical setting, these nucleotide analogues lack specificity but the side effects of low dose treatments were minimal and in 2004 Vidaza (5-azacitidine) was licensed for use in myelodysplastic syndrome. Methylation inhibitors are also entering trials in conjunction with another class of epigenetic modifiers, the histone deacetylase inhibitors and this epigenetic double bullet offers hope of improved treatment regimes. Recently there has been a plethora of reports demonstrating epigenetic inactivation of genes that play important roles in development of cancer, including Ras-association domain family of genes. Epigenetic inactivation of RASSF1A (Ras-association domain family 1, isoform A) is one of the most common molecular changes in cancer. Hypermethylation of the RASSF1A promoter CpG island silences expression of the gene in many cancers including lung, breast, prostate, glioma, neuroblastoma and kidney cancer. Several recent studies have illustrated the diagnostic and prognostic potential of RASSF1A methylation. This presents RASSF1A methylation as an attractive biomarker for early cancer detection which, for most cancers, results in improved clinical outcome. DNA methylation analysis is applicable to a range of body fluids including serum, urine, bronchioalveolar lavage and sputum. The ease with which these body fluids can be acquired negates the need for invasive procedures to obtain biopsy material. This review will discuss the feasibility of using RASSF1A methylation as a diagnostic and prognostic marker in cancer management.
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PMID:The role of RASSF1A methylation in cancer. 1732 27

The past decade has seen an explosion of interest in the epigenetics of cancer, with an increasing understanding that this form of genomic modification plays a critical role in pathogenesis. The malignant phenotype results from a step-wise increase of both genetic abnormalities and epigenetic modifications, leading to dysregulation of critical genes controlling cell growth, differentiation and apoptosis. The methylation of CpG islands within gene promoters is a major epigenetic transcriptional control mechanism that is frequently dysregulated in human cancer. This phenomenon (methylation of CpG islands) plays a critical role in the transcriptional silencing of tumour suppressor genes in cancer and has prompted the development and testing of several demethylating agents aimed at reversing this process. Clinical trials using epigenetically targeted therapies have yielded particularly promising results in the myelodysplastic syndromes (MDS), in which tumour suppressor gene silencing by promoter methylation is a frequent event. Several genes and gene pathways disrupted by aberrant CpG island methylation have now been identified in haematological malignancies, the most frequently studied being the cell cycle inhibitors p16 (now termed CDKN2A; mostly methylated in lymphoid malignancy) and p15 (now termed CDKN2B; commonly methylated in lymphoid and myeloid malignancies). This review will discuss the role that aberrant gene silencing by promoter hypermethylation plays in the molecular pathogenesis of haematological malignancies and assess the clinical potential of demethylating agents for the management of patients.
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PMID:Gene silencing by DNA methylation in haematological malignancies. 1748 80

Shwachman-Diamond syndrome (SDS) is an inherited bone marrow failure disorder with cytopenia and a high propensity for myelodysplastic syndrome (MDS) and leukaemia, particularly acute myeloid leukaemia. The mechanism of leukaemogenesis in SDS is unknown. In accordance to the multi-hit theory of carcinogenesis, it is likely that several molecular and cellular hits occur before MDS/leukaemia become apparent. This study used oligonucleotide microarray to identify gene expression patterns, which were shown to be associated with leukaemogenesis, in marrow mononuclear cells of nine SDS patients without overt transformation compared to healthy controls. Among 154 known leukaemia-related genes, several oncogenes were found to be upregulated, including LARG, TAL1 and MLL, and of several tumour suppressor genes were downregulated, including DLEU1, RUNX1, FANCD2 and DKC1. Real time polymerase chain reaction confirmed statistically higher expression of LARG and TAL1 in SDS marrows. We conclude that SDS marrow mononuclear cells exhibit abnormal gene expression patterns, which might result in continuous stimulation favouring evolution or progression of malignant clones. Additional molecular and cytogenetic events are probably necessary for the malignant process to be irreversible and complete.
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PMID:Leukaemia-related gene expression in bone marrow cells from patients with the preleukaemic disorder Shwachman-Diamond syndrome. 1753 75

Somatic chromosomal deletions in cancer are thought to indicate the location of tumour suppressor genes, by which a complete loss of gene function occurs through biallelic deletion, point mutation or epigenetic silencing, thus fulfilling Knudson's two-hit hypothesis. In many recurrent deletions, however, such biallelic inactivation has not been found. One prominent example is the 5q- syndrome, a subtype of myelodysplastic syndrome characterized by a defect in erythroid differentiation. Here we describe an RNA-mediated interference (RNAi)-based approach to discovery of the 5q- disease gene. We found that partial loss of function of the ribosomal subunit protein RPS14 phenocopies the disease in normal haematopoietic progenitor cells, and also that forced expression of RPS14 rescues the disease phenotype in patient-derived bone marrow cells. In addition, we identified a block in the processing of pre-ribosomal RNA in RPS14-deficient cells that is functionally equivalent to the defect in Diamond-Blackfan anaemia, linking the molecular pathophysiology of the 5q- syndrome to a congenital syndrome causing bone marrow failure. These results indicate that the 5q- syndrome is caused by a defect in ribosomal protein function and suggest that RNAi screening is an effective strategy for identifying causal haploinsufficiency disease genes.
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PMID:Identification of RPS14 as a 5q- syndrome gene by RNA interference screen. 1820 30

Isochromosome of the long arm of chromosome 20 with loss of interstitial material [ider(20q)] is a variant of deletion of chromosome 20q and a rare abnormality in myelodysplastic syndrome (MDS). We studied seven cases with an ider(20q) in MDS. Fluorescence in situ hybridization (FISH) studies showed all proximal breakpoints to be consistently located in 20q11.21 band whereas distal breakpoints were variable. Amplification of HCK, TNFRSF6B and DIDO1 genes included in retained regions associated with loss of tumour suppressor genes in deleted regions could explain cell tumour progression and possibly the less favourable prognosis of ider(20q) compared with del(20q).
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PMID:Fluorescence in situ hybridization characterization of ider(20q) in myelodysplastic syndrome. 1903 15

A combination of demethylating agents and histone deacetylase inhibitors (HDACi) has been proposed as a novel therapy in leukemia and myelodysplasia. In HL-60 cells azacytidine (AZA) and Metacept-1 (MCT-1), a novel HDACi augmented inhibition of cell growth and increased apoptosis. In identifying a molecular mechanism responsible for these effects MCT-1 alone and in combination with AZA induced p15INK4b, p21WAF1/CIP1 and Caspase-3 whilst attenuating Bcl-XL expression. Interestingly, MCT-1 in combination with AZA significantly induced the recently identified suppressor of leukemogenesis Nur77 and attenuated AZA-induced MMP-9 expression. The combination of MCT-1 and AZA is more effective in inhibiting leukemic cell growth and induction of apoptosis. Regulation of a recently identified tumour suppressor gene together with cell cycle, apoptosis and matrix degrading proteases may underpin the molecular mechanism responsible for these effects.
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PMID:The anti-leukemic effect of a novel histone deacetylase inhibitor MCT-1 and 5-aza-cytidine involves augmentation of Nur77 and inhibition of MMP-9 expression. 1914 94

The myelodysplastic syndromes (MDSs) are a heterogeneous group of clonal haematological diseases characterized by ineffective haematopoiesis and predisposition to acute myeloid leukaemia (AML). The pathophysiology of MDSs remains unclear. A definition of the molecular biology of MDSs may lead to a better classification, new prognosis indicators and new treatments. We studied a series of 40 MDS/AML samples by high-density array-comparative genome hybridization (aCGH). The genome of MDSs displayed a few alterations that can point to candidate genes, which potentially regulate histone modifications and WNT pathways (e.g. ASXL1, ASXL2, UTX, CXXC4, CXXC5, TET2, TET3). To validate some of these candidates we studied the sequence of ASXL1. We found mutations in the ASXL1 gene in four out of 35 MDS patients (11%). To extend these results we searched for mutations of ASXL1 in a series of chronic myelomonocytic leukaemias, a disease classified as MDS/Myeloproliferative disorder, and found mutations in 17 out of 39 patients (43%). These results show that ASXL1 might play the role of a tumour suppressor in myeloid malignancies.
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PMID:Mutations of polycomb-associated gene ASXL1 in myelodysplastic syndromes and chronic myelomonocytic leukaemia. 1938 38

Treatment with the demethylating drugs 5-azacytidine (AZA) and decitabine (DAC) is now recognised as an effective therapy for patients with Myelodysplastic Syndromes (MDS), a range of disorders arising in clones of hematopoietic progenitor cells. A variety of cell models have been used to study the effect of these drugs on the methylation of promoter regions of tumour suppressor genes, with recent efforts focusing on the ability of these drugs to inhibit DNA methylation at low doses. However, it is still not clear how nano-molar drug treatment exerts its effects on the methylome. In this study, we have characterised changes in DNA methylation caused by prolonged low-dose treatment in a leukemic cell model (SKM-1), and present a genome-wide analysis of the effects of AZA and DAC. At nano-molar dosages, a one-month continuous treatment halved the total number of hypermethylated probes in leukemic cells and our analysis identified 803 candidate regions with significant demethylation after treatment. Demethylated regions were enriched in promoter sequences whereas gene-body CGIs were more resistant to the demethylation process. CGI methylation in promoters was strongly correlated with gene expression but this correlation was lost after treatment. Our results indicate that CGI demethylation occurs preferentially at promoters, but that it is not generally sufficient to modify expression patterns, and emphasises the roles of other means of maintaining cell state.
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PMID:Prolonged treatment with DNMT inhibitors induces distinct effects in promoters and gene-bodies. 2394 Jun 95

Prions are renowned for their role in neurodegenerative diseases in humans and animals. These are manifested as transmissible spongiform encephalopathies (TSEs) that result from the conversion of the normal glycosylphosphatidylinositol (GPI) anchored cellular prion protein (PrP(c)) to a misfolded, aggregated and pathogenic form, prion protein scrapie (PrP(Sc)) via a post-translational process followed by the accumulation of PrP(Sc) within the central nervous system. New research in this area has demonstrated that PrP is over-expressed in a variety of cancers including gastric, pancreatic and breast cancers, affecting the growth and invasiveness of these cancers as well as playing an important role in the acquisition of multi-drug resistant (MDR) gastric cancer. Prion-like doppel protein (Dpl), sharing 25% amino acid sequence homology to PrP and whose function remains elusive, has also been shown to exhibit a high level of expression in a number of cancers including acute myeloid leukemia's, myelodysplastic syndromes, gastric adenocarcinoma, anaplastic meningioma and astrocytomas. Furthermore, the tumour suppressor protein, p53, already known for its involvement in cancer development, has recently been shown to display prion-like tendencies. This review provides an overview of prions and prion-like proteins in mammals discussing their structure, function and role in cell function and disease. Furthermore, current research progress on the role of prion/prion-like proteins in the development, progression, and drug resistance of various cancers will be summarized. Potential implications for future development of new therapeutic treatments targeting prion and prion-like proteins will be discussed.
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PMID:Significance of prion and prion-like proteins in cancer development, progression and multi-drug resistance. 2401 88


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