Role of microRNA deregulation in the pathogenesis of diffuse large B-cell lymphoma (DLBCL)

AbstractMicroRNAs (miRNAs) are small endogenous RNA molecules that regulate gene expression at the post-transcriptional level through its sequence complementation with target mRNAs. An individual miRNA species can simultaneously influence the expression of multiple genes and conversely, several miRNAs can synchronously control expression of specific gene product mRNA levels. Thus, miRNAs expression in cells has to be precisely regulated and alterations in miRNA levels may cause an aberrant expression of genes involved in oncogenic pathways and consequently result in cancer development. Indeed, miRNA expression is often deregulated in many cancers, including B-cell lymphomas. Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of B-cell lymphomas with different genetic backgrounds, morphologic features, and responses to therapy. Over the past decade, miRNAs emerged as a new tool for understanding DLBCL biology, and promising candidate molecular markers in DLBCL classification and treatment. In this review, we will focus on miRNAs aberrantly expressed in DLBCL and discuss the putative mechanisms of this deregulation. Additionally, we will summarize miRNAs’ involvement in the identification of DLBCL subgroups, and their potential role as diagnostic/prognostic biomarkers as well as specific therapeutic targets for DLBCL

An annotated catalogue of the fungal biota of the Roztocze Upland. Richness, diversity and distribution

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Identification of a Signature Motif in Target mRNAs of RNA-binding Protein AUF1

The ubiquitous RNA-binding protein AUF1 promotes the degradation of some target mRNAs, but increases the stability and translation of other targets. Here, we isolated AUF1-associated mRNAs by immunoprecipitation of (AUF1–RNA) ribonucleoprotein (RNP) complexes from HeLa cells, identified them using microarrays, and used them to elucidate a signature motif shared among AUF1 target transcripts. The predicted AUF1 motif (29–39 nucleotides) contained 79% As and Us, consistent with the AU-rich sequences of reported AUF1 targets. Importantly, 10 out of 15 previously reported AUF1 target mRNAs contained the AUF1 motif. The predicted interactions between AUF1 and target mRNAs were recapitulated in vitro using biotinylated RNAs. Interestingly, further validation of predicted AUF1 target transcripts revealed that AUF1 associates with both the pre-mRNA and the mature mRNA forms. The consequences of AUF1 binding to 10 predicted target mRNAs were tested by silencing AUF1, which elevated the steady-state levels of only four mRNAs, and by overexpressing AUF1, which also lowered the levels of only four mRNAs. In total, we have identified a signature motif in AUF1 target mRNAs, have found that AUF1 also associates with the corresponding pre-mRNAs, and have discovered that altering AUF1 levels alone only modifies the levels of subsets of target mRNAs

Ornithine Decarboxylase mRNA is Stabilized in an mTORC1-dependent Manner in Ras-transformed Cells

Upon Ras activation, ODC (ornithine decarboxylase) is markedly induced, and numerous studies suggest that ODC expression is controlled by Ras effector pathways. ODC is therefore a potential target in the treatment and prevention of Ras-driven tumours. In the present study we compared ODC mRNA translation profiles and stability in normal and Ras12V-transformed RIE-1 (rat intestinal epithelial) cells. While translation initiation of ODC increased modestly in Ras12V cells, ODC mRNA was stabilized 8-fold. Treatment with the specific mTORC1 [mTOR (mammalian target of rapamycin) complex 1] inhibitor rapamycin or siRNA (small interfering RNA) knockdown of mTOR destabilized the ODC mRNA, but rapamycin had only a minor effect on ODC translation initiation. Inhibition of mTORC1 also reduced the association of the mRNA-binding protein HuR with the ODC transcript. We have shown previously that HuR binding to the ODC 3′UTR (untranslated region) results in significant stabilization of the ODC mRNA, which contains several AU-rich regions within its 3′UTR that may act as regulatory sequences. Analysis of ODC 3′UTR deletion constructs suggests that cis-acting elements between base 1969 and base 2141 of the ODC mRNA act to stabilize the ODC transcript. These experiments thus define a novel mechanism of ODC synthesis control. Regulation of ODC mRNA decay could be an important means of limiting polyamine accumulation and subsequent tumour development

Transcriptional Profiling of Aging in Human Muscle Reveals a Common Aging Signature

We analyzed expression of 81 normal muscle samples from humans of varying ages, and have identified a molecular profile for aging consisting of 250 age-regulated genes. This molecular profile correlates not only with chronological age but also with a measure of physiological age. We compared the transcriptional profile of muscle aging to previous transcriptional profiles of aging in the kidney and the brain, and found a common signature for aging in these diverse human tissues. The common aging signature consists of six genetic pathways; four pathways increase expression with age (genes in the extracellular matrix, genes involved in cell growth, genes encoding factors involved in complement activation, and genes encoding components of the cytosolic ribosome), while two pathways decrease expression with age (genes involved in chloride transport and genes encoding subunits of the mitochondrial electron transport chain). We also compared transcriptional profiles of aging in humans to those of the mouse and fly, and found that the electron transport chain pathway decreases expression with age in all three organisms, suggesting that this may be a public marker for aging across species

Transcription factor TFII-I fine tunes innate properties of B lymphocytes

The ubiquitously expressed transcription factor TFII-I is a multifunctional protein with pleiotropic roles in gene regulation. TFII-I associated polymorphisms are implicated in Sjögren’s syndrome and Lupus in humans and, germline deletion of the Gtf2i gene in mice leads to embryonic lethality. Here we report a unique role for TFII-I in homeostasis of innate properties of B lymphocytes. Loss of Gtf2i in murine B lineage cells leads to an alteration in transcriptome, chromatin landscape and associated transcription factor binding sites, which exhibits myeloid-like features and coincides with enhanced sensitivity to LPS induced gene expression. TFII-I deficient B cells also show increased switching to IgG3, a phenotype associated with inflammation. These results demonstrate a role for TFII-I in maintaining immune homeostasis and provide clues for GTF2I polymorphisms associated with B cell dominated autoimmune diseases in humans