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Transcriptional Downregulation (transcriptional + downregulation)

Distribution by Scientific Domains
Medical Sciences40%

Selected Abstracts

Hypermethylation and Transcriptional Downregulation of the TIMP3 Gene is Associated with Allelic Loss on 22q12.3 and Malignancy in Meningiomas

BRAIN PATHOLOGY, Issue 3 2010
Dimitri Barski
Abstract The gene for the tissue inhibitor of metalloproteinase 3 (TIMP3) on 22q12.3 had been reported to be inactivated by promoter methylation in various types of cancers, with controversial findings in meningiomas. We performed direct sodium bisulfite sequencing in a series of 50 meningiomas, including 27 benign meningiomas [World Health Organization (WHO) grade I], 11 atypical meningiomas (WHO grade II) and 12 anaplastic meningiomas (WHO grade III), and found hypermethylation of TIMP3 in 67% of anaplastic meningiomas, but only 22% of atypical and 17% of benign meningiomas. Moreover, TIMP3 methylation scores were significantly inversely correlated with TIMP3 mRNA expression levels (P = 0.0123), and treatment of the meningioma cell line Ben-Men-1 with demethylating agents induced an increased TIMP3 mRNA expression. TIMP3 is located in the chromosomal band 22q12, the allelic loss of which occurs early in meningioma tumorigenesis and preferentially targets the NF2 tumor suppressor gene. In our tumor panel, all meningiomas with TIMP3 hypermethylation,except for a single case,exhibited allelic losses on 22q12.3. Thus, TIMP3 inactivation by methylation seems fairly exclusive to meningiomas with allelic losses on 22q12 but,in contrast to NF2 mutation,appears to be involved in meningioma progression as it is associated with a more aggressive, high-grade meningioma phenotype. [source]

Requirements for chromatin reassembly during transcriptional downregulation of a heat shock gene in Saccharomyces cerevisiae

FEBS JOURNAL, Issue 11 2008
Mette M. Jensen
Heat shock genes respond to moderate heat stress by a wave of transcription. The induction phase is accompanied by the massive eviction of histones, which later reassemble with DNA during the ensuing phase of transcription downregulation. In this article, we identify determinants of this reassembly throughout the heat shock protein 104 gene (HSP104) transcription unit. The results show that, although histone H3 lacking amino acids 4,30 of its N-terminal tail (H3,4,30) is normally deposited, reassembly of H3,4,40 is obliterated with an accompanying sustained transcription. On mutation of the histone chaperones Spt6p and Spt16p, but not Asf1p, reassociation of H3 with DNA is compromised. However, despite a lasting open chromatin structure, transcription ceases normally in the spt6 mutant. Thus, transcriptional downregulation can be uncoupled from histone redeposition and ongoing transcription is not required to prevent chromatin reassembly. [source]

Epigenetic inactivation of secreted Frizzled-related proteins in acute myeloid leukaemia

BRITISH JOURNAL OF HAEMATOLOGY, Issue 5 2008
E. Jost
Summary The Wnt signalling pathway has a key function in stem cell maintenance and differentiation of haematopoietic progenitors. Secreted Frizzled-related protein genes (SFRPs), functioning as Wnt signalling antagonists, have been found to be downregulated by promoter hypermethylation in many tumours. To analyse epigenetic dysregulation of SFRPs in acute myeloid leukaemia (AML), we examined the promoter methylation status of SFRP1, - 2, - 4 and - 5 in AML cell lines by methylation-specific polymerase chain reaction (MSP). Aberrant CpG island methylation was found for all four SFRP genes. By real-time reverse transcription-PCR, corresponding transcriptional silencing for SFRP1 and - 2 was demonstrated and treatment of cell lines with 5-aza -2,-deoxycytidine resulted in re-expression. The methylation status of the SFRP genes was analysed in 100 specimens obtained from AML patients at diagnosis. The frequencies of aberrant methylation among the patient samples were 29% for SFRP1, 19% for SFRP2, 0% for SFRP4 and 9% for SFRP5. For SFRP2, a correlation between promoter hypermethylation and transcriptional downregulation was found in primary AML samples. Among AML cases with a favourable karyotype, hypermethylation of SFRP genes was restricted to patients with core binding factor (CBF) leukaemia, and aberrant methylation of the SFRP2 promoter was an adverse risk factor for survival in CBF leukaemia. [source]

Bacterial exotoxins downregulate cathelicidin (hCAP-18/LL-37) and human ,-defensin 1 (HBD-1) expression in the intestinal epithelial cells

CELLULAR MICROBIOLOGY, Issue 12 2008
Krishnendu Chakraborty
Summary Cathelicidin (hCAP-18/LL-37) and ,-defensin 1 (HBD-1) are human antimicrobial peptides (AMPs) with high basal expression levels, which form the first line of host defence against infections over the epithelial surfaces. The antimicrobial functions owe to their direct microbicidal effects as well as the immunomodulatory role. Pathogenic microorganisms have developed multiple modalities including transcriptional repression to combat this arm of the host immune response. The precise mechanisms and the pathogen-derived molecules responsible for transcriptional downregulation remain unknown. Here, we have shown that enteric pathogens suppress LL-37 and HBD-1 expression in the intestinal epithelial cells (IECs) with Vibrio cholerae and enterotoxigenic Escherichia coli (ETEC) exerting the most dramatic effects. Cholera toxin (CT) and labile toxin (LT), the major virulence proteins of V. cholerae and ETEC, respectively, are predominantly responsible for these effects, both in vitro and in vivo. CT transcriptionally downregulates the AMPs by activating several intracellular signalling pathways involving protein kinase A (PKA), ERK MAPKinase and Cox-2 downstream of cAMP accumulation and inducible cAMP early repressor (ICER) may mediate this role of CT, at least in part. This is the first report to show transcriptional repression of the AMPs through the activation of cellular signal transduction pathways by well-known virulence proteins of pathogenic microorganisms. [source]