Exellent work on cancer resistance in a small rodent, naked mole-rat. Indeed, this animal is outstanding from its lifespan (28 years) to its apparent invincibility to cancer. That’s extremely useful property, so, as authors said,
Department of Biology, University of Rochester, Rochester, NY 14627.
The naked mole-rat is the longest living rodent with a maximum lifespan exceeding 28 years. In addition to its longevity, naked mole-rats have an extraordinary resistance to cancer as tumors have never been observed in these rodents. Furthermore, we show that a combination of activated Ras and SV40 LT fails to induce robust anchorage-independent growth in naked mole-rat cells, while it readily transforms mouse fibroblasts. The mechanisms responsible for the cancer resistance of naked mole-rats were unknown. Here we show that naked mole-rat fibroblasts display hypersensitivity to contact inhibition, a phenomenon we termed “early contact inhibition.” Contact inhibition is a key anticancer mechanism that arrests cell division when cells reach a high density. In cell culture, naked mole-rat fibroblasts arrest at a much lower density than those from a mouse. We demonstrate that early contact inhibition requires the activity of p53 and pRb tumor suppressor pathways. Inactivation of both p53 and pRb attenuates early contact inhibition. Contact inhibition in human and mouse is triggered by the induction of p27(Kip1). In contrast, early contact inhibition in naked mole-rat is associated with the induction of p16(Ink4a). Furthermore, we show that the roles of p16(Ink4a) and p27(Kip1) in the control of contact inhibition became temporally separated in this species: the early contact inhibition is controlled by p16(Ink4a), and regular contact inhibition is controlled by p27(Kip1). We propose that the additional layer of protection conferred by two-tiered contact inhibition contributes to the remarkable tumor resistance of the naked mole-rat.
Very troughout review about how 95% of genes are alternatively spliced. Splicing and spliceosome assembly figure, description of participating proteins. Good figures help to comprehend the current picture.
Department of Biological Sciences, Columbia University, New York, New York 10027, USA.
Alternative splicing of mRNA precursors provides an important means of genetic control and is a crucial step in the expression of most genes. Alternative splicing markedly affects human development, and its misregulation underlies many human diseases. Although the mechanisms of alternative splicing have been studied extensively, until the past few years we had not begun to realize fully the diversity and complexity of alternative splicing regulation by an intricate protein-RNA network. Great progress has been made by studying individual transcripts and through genome-wide approaches, which together provide a better picture of the mechanistic regulation of alternative pre-mRNA splicing.
Preview to a paper describing the role of TGFB in cell motility. Increased TGFB signaling makes cells more self-standing and self-migratory. Cells that have suppressed TGFB signalling migrate collectively. Features of single and collective cell motility summarized in Table 1, as well as in Figure 1.
Nat Cell Biol. 2009 Nov;11(11):1281-1284. Epub 2009 Oct 18.
Lauren Matise, Michael Pickup and Harold Moses are at the Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN 37232-6838, USA. hal.moses@vanderbilt.edu.
Intravital imaging demonstrates that TGF-beta signalling regulates the mode of cancer cell motility. Cells with active TGF-beta signalling migrate as single cells and are capable of hematogenous and lymphatic spread, whereas cells lacking TGF-beta signalling invade lymphatics collectively.
Short RNAs are good for silencing, but what do they silence? Here’s an idea about multiple targets of short RNAs. shRNA produce less off-target effect. But still one should watch out what exactly is affected.
This review considers comparisons of the off-target effects of siRNA to shRNA and their potential impact on the efficacy and toxicity of RNAi based therapeutics.
Methylation regulates which genes are transcribed, when, and how fast. This mini-review tells about methylation patterns of the DNA, how it is maintained and transferred to daughter cells during replications, and how responsible enzymes interact. But still we don’t know how methylation patterns are created at the first place.
Peter A. Jones and Gangning Liang are at the Department of Urology, Biochemistry and Molecular Biology, USC/Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90089-9181, USA. jones_p@ccnt.usc.edu
DNA methylation patterns are set up early in mammalian development and are then copied during the division of somatic cells. A long-established model for the maintenance of these patterns explains some, but not all, of the data that are now available. We propose a new model that suggests that the maintenance of DNA methylation relies not only on the recognition of hemimethylated DNA by DNA methyltransferase 1 (DNMT1) but also on the localization of the DNMT3A and DNMT3B enzymes to specific chromatin regions that contain methylated DNA.
Exellent poster about complex nature of transcription. Start site organization, bidirectional transcription, miRNA transcription from introns – just to name a few features. Zoom in and read.
Exellent summary of how p53 was discovered and its wide roles unfolded. This is a perfect example how complex may be a single gene, which gives not less than 9 alternatively spliced isoforms. Firstly discoveres as an oncogene, than p53 become tumor suppressor, and implications in nearly all biological processes followed. Trerapeutic approaches of targeting p53 and its co-players. And challenges that are just beginning to unfold when interactions of p53 with other proteins come to light.
Arnold J. Levine is at the Institute for Advanced Study, School of Natural Sciences, Einstein Drive, Princeton, New Jersey 08540, USA. alevine@ias.edu
Thirty years ago p53 was discovered as a cellular partner of simian virus 40 large T-antigen, the oncoprotein of this tumour virus. The first decade of p53 research saw the cloning of p53 DNA and the realization that p53 is not an oncogene but a tumour suppressor that is very frequently mutated in human cancer. In the second decade of research, the function of p53 was uncovered: it is a transcription factor induced by stress, which can promote cell cycle arrest, apoptosis and senescence. In the third decade after its discovery new functions of this protein were revealed, including the regulation of metabolic pathways and cytokines that are required for embryo implantation. The fourth decade of research may see new p53-based drugs to treat cancer. What is next is anybody’s guess.
Theory about cooperative action of “normal” cancer cells and cells in EMT state. The latter invade and pave a way for regular cancer cells. That’s how metastasis happen. Therefore we need to target both types of cells to eradicate them all.
Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
The role of epithelial-mesenchymal transition (EMT) in metastasis remains controversial. EMT has been postulated as an absolute requirement for tumor invasion and metastasis. Three different models including incomplete EMT, mesenchymal-epithelial transition (MET), and collective migration have been proposed for the role of EMT in cancer invasion and metastasis. However, skepticism remains about whether EMT truly occurs during cancer progression, and if it does, whether it plays an indispensible role in metastasis. Our recent findings suggest that EMT cells are responsible for degrading the surrounding matrix to enable invasion and intravasation of both EMT and non-EMT cells. Only non-EMT cells that have entered the blood stream are able to re-establish colonies in the secondary sites. Here, we discuss an alternative model for the role of EMT in cancer metastasis in which EMT and non-EMT cells cooperate to complete the entire process of spontaneous metastasis.
Very complete review about subject. Landmark studies, splicing frequency, functional consequences, problems with detection. Validation on large scale techniques, unraveling mechanisms of splicing regulation. Bioinformatics challenges.
Department of Chemistry, University of California Los Angeles, Los Angeles, California 90095-1570, USA.
Recent genome-wide analyses of alternative splicing indicate that 40-60% of human genes have alternative splice forms, suggesting that alternative splicing is one of the most significant components of the functional complexity of the human genome. Here we review these recent results from bioinformatics studies, assess their reliability and consider the impact of alternative splicing on biological functions. Although the ‘big picture’ of alternative splicing that is emerging from genomics is exciting, there are many challenges. High-throughput experimental verification of alternative splice forms, functional characterization, and regulation of alternative splicing are key directions for research. We recommend a community-based effort to discover and characterize alternative splice forms comprehensively throughout the human genome.
Exellent review about cancer stem cells theory, clinical evidences, animal models, therapeutics approaches, signaling pathways and mechanisms. It is long, but worth reading.
Oncology Discovery, Wyeth Research, 401 North Middletown Road, Pearl River, New York 10965, USA. zhoub@wyeth.com
The hypothesis that cancer is driven by tumour-initiating cells (popularly known as cancer stem cells) has recently attracted a great deal of attention, owing to the promise of a novel cellular target for the treatment of haematopoietic and solid malignancies. Furthermore, it seems that tumour-initiating cells might be resistant to many conventional cancer therapies, which might explain the limitations of these agents in curing human malignancies. Although much work is still needed to identify and characterize tumour-initiating cells, efforts are now being directed towards identifying therapeutic strategies that could target these cells. This Review considers recent advances in the cancer stem cell field, focusing on the challenges and opportunities for anticancer drug discovery.
Aother part of big picture, which we’re not paying enough attention. Description of new type of microRNA, so-called small vault RNA (svRNA). Very similar to canonical microRNAs, they are produced from vault RNA (vRNA) by Drosha-independent mechanism. Still, Dicer does parcticipate in svRNA cleavage.
Department of Oncology and CREATE Health Strategic Centre for Clinical Cancer Research, Lund University, BMC, 221 84 Lund, Sweden.
Vault particles are conserved organelles implicated in multidrug resistance and intracellular transport. They contain three different proteins and non-coding vault RNAs (vRNAs). Here we show that human vRNAs produce several small RNAs (svRNAs) by mechanisms different from those in the canonical microRNA (miRNA) pathway. At least one of these svRNAs, svRNAb, associates with Argonaute proteins to guide sequence-specific cleavage and regulate gene expression similarly to miRNAs. We demonstrate that svRNAb downregulates CYP3A4, a key enzyme in drug metabolism. Our findings expand the repertoire of small regulatory RNAs and assign, for the first time, a function to vRNAs that may help explain the association between vault particles and drug resistance.
Exellent review about physical behavior of transcription factors, their diffusion through nucleus, short interactions with chromatin. Chromatin remodeling, nucleosome repositioning. Local and distal interactions, and assembling transcription complexes. Pulsing interactions with chromatin – stochastic by nature.
National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. hagerg@mail.nih.gov
All aspects of transcription and its regulation involve dynamic events. The basal transcription machinery and regulatory components are dynamically recruited to their target genes, and dynamic interactions of transcription factors with chromatin–and with each other–play a key role in RNA polymerase assembly, initiation, and elongation. These short-term binding dynamics of transcription factors are superimposed by long-term cyclical behavior of chromatin opening and transcription factor-binding events. Its dynamic nature is not only a fundamental property of the transcription machinery, but it is emerging as an important modulator of physiological processes, particularly in differentiation and development.
Very comprehensive visual tutorial to get you understand different strains of mice. If FVB/N or C57BL/6-Tg(CAG-EGFP)1Obs/J makes you uncomfortable, this tutorial really gets one started to understand. Exellent, and one can download it.
Maybe, good musical ear can distinguish some break in harmony. But for me normal and cancer cells sound pretty nice. If some avant-garde notes are pop up, does it hurt the melody?
How miRNA influence protein output. Results – comparable suppression of mRNA and proteins, but at different degree. Some proteins go down while mRNA stays constant and vice versa. Summary of methods for miRNA target predictions, they use overlap among the lists.
Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA.
MicroRNAs are endogenous approximately 23-nucleotide RNAs that can pair to sites in the messenger RNAs of protein-coding genes to downregulate the expression from these messages. MicroRNAs are known to influence the evolution and stability of many mRNAs, but their global impact on protein output had not been examined. Here we use quantitative mass spectrometry to measure the response of thousands of proteins after introducing microRNAs into cultured cells and after deleting mir-223 in mouse neutrophils. The identities of the responsive proteins indicate that targeting is primarily through seed-matched sites located within favourable predicted contexts in 3′ untranslated regions. Hundreds of genes were directly repressed, albeit each to a modest degree, by individual microRNAs. Although some targets were repressed without detectable changes in mRNA levels, those translationally repressed by more than a third also displayed detectable mRNA destabilization, and, for the more highly repressed targets, mRNA destabilization usually comprised the major component of repression. The impact of microRNAs on the proteome indicated that for most interactions microRNAs act as rheostats to make fine-scale adjustments to protein output.
Another Nature’s review comparing ChIP-seq with more old, and therefore well-known, ChIP-on-Chip technology. Examples of data analysis from ChIP-seq, software, ideas of what can and can not be called significant. As always, Nature does not disappoint - good figures, easy to read, helpful footnotes and boxes.
Harvard Medical School, 10 Shattuck Street, Boston, MA 02115, USA. peter_park@harvard.edu
Chromatin immunoprecipitation followed by sequencing (ChIP-seq) is a technique for genome-wide profiling of DNA-binding proteins, histone modifications or nucleosomes. Owing to the tremendous progress in next-generation sequencing technology, ChIP-seq offers higher resolution, less noise and greater coverage than its array-based predecessor ChIP-chip. With the decreasing cost of sequencing, ChIP-seq has become an indispensable tool for studying gene regulation and epigenetic mechanisms. In this Review, I describe the benefits and challenges in harnessing this technique with an emphasis on issues related to experimental design and data analysis. ChIP-seq experiments generate large quantities of data, and effective computational analysis will be crucial for uncovering biological mechanisms.
Oncomine is an exellent platform for co- and antiexpression analysis. Press release. One can get an idea what poorly annotated genes are doing in different systems, tissues and conditions. The up side is it’s free version is poverful enough. Tho down side is Oncomine’s database is all about cancer only.
24 SEP 2009
INTRODUCING ONCOMINE 4 RESEARCH EDITION with Dr. Dan Rhodes
1:00-2:00 p.m. EDT
Learn how to make discoveries and validate hypotheses with cancer genomics data using the new Oncomine 4.
We’ll discuss how Oncomine was utilized in recent high-impact studies published in Science, Cancer Cell and PNAS.
New technology aimed to supersede microarrays. Description of other “canonical” sequencing-oriented technologies, such as SAGE, CAGE, MPSS, tiling microarrays. Pluses and minuses, and what one can get out of RNA-Seq. Indeed, knowledge of sequence AND expression will lead to new breakthroughs. But one should not forget to study networks of interactions in time.
Department of Molecular, Cellular and Developmental Biology, Yale University, 219 Prospect Street, New Haven, Connecticut 06520, USA.
RNA-Seq is a recently developed approach to transcriptome profiling that uses deep-sequencing technologies. Studies using this method have already altered our view of the extent and complexity of eukaryotic transcriptomes. RNA-Seq also provides a far more precise measurement of levels of transcripts and their isoforms than other methods. This article describes the RNA-Seq approach, the challenges associated with its application, and the advances made so far in characterizing several eukaryote transcriptomes.
Definition of epistasis, and XOR interactions as an example. Multifactor Dimensionality Reduction (MDR) method to understand genetic associations. Path fromclassical single gene approach to SNPs and genes interactions.
Computational Genetics Laboratory, Department of Genetics and Department of Community and Family Medicine, Dartmouth Medical School, Lebanon, NH 03756, USA. jason.h.moore@dartmouth.edu
The widespread availability of high-throughput genotyping technology has opened the door to the era of personal genetics, which brings to consumers the promise of using genetic variations to predict individual susceptibility to common diseases. Despite easy access to commercial personal genetics services, our knowledge of the genetic architecture of common diseases is still very limited and has not yet fulfilled the promise of accurately predicting most people at risk. This is partly because of the complexity of the mapping relationship between genotype and phenotype that is a consequence of epistasis (gene-gene interaction) and other phenomena such as gene-environment interaction and locus heterogeneity. Unfortunately, these aspects of genetic architecture have not been addressed in most of the genetic association studies that provide the knowledge base for interpreting large-scale genetic association results. We provide here an introductory review of how epistasis can affect human health and disease and how it can be detected in population-based studies. We provide some thoughts on the implications of epistasis for personal genetics and some recommendations for improving personal genetics in light of this complexity.
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