THE S100A8–SERUM AMYLOID A3–TLR4 PARACRINE CASCADE ESTABLISHES A PRE-METASTATIC PHASE
The S100A8–serum amyloid A3–TLR4 paracrine cascade establishes a pre-metastatic phase
Nature Cell Biology 10, 1349 (2008). doi:10.1038/ncb1794
Authors: Sachie Hiratsuka, Akira Watanabe, Yoshiko Sakurai, Sachiko Akashi-Takamura, Sachie Ishibashi, Kensuke Miyake, Masabumi Shibuya, Shizuo Akira, Hiroyuki Aburatani & Yoshiro Maru
A large number of macrophages and haematopoietic progenitor cells accumulate in pre-metastatic lungs in which chemoattractants, such as S100A8 and S100A9, are produced by distant primary tumours serving as metastatic soil. The exact mechanism by which these chemoattractants elicit cell accumulation is not known. Here, we show that serum amyloid A (SAA) 3, which is induced in pre-metastatic lungs by S100A8 and S100A9, has a role in the accumulation of myeloid cells and acts as a positive-feedback regulator for chemoattractant secretion. We also show that in lung endothelial cells and macrophages, Toll-like receptor (TLR) 4 acts as a functional receptor for SAA3 in the pre-metastatic phase. In our study, SAA3 stimulated NF-κB signalling in a TLR4-dependent manner and facilitated metastasis. This inflammation-like state accelerated the migration of primary tumour cells to lung tissues, but this was suppressed by the inhibition of either TLR4 or SAA3. Thus, blocking SAA3–TLR4 function in the pre-metastatic phase could prove to be an effective strategy for the prevention of pulmonary metastasis.
DNA TESTING EXPLAINED, IN VIDEO
DDC has recently added videos to its Science and Technology section. Science enthusiasts, students, and anyone interested in DNA testing can view a series of 7 short videos explaining the science of DNA testing. Through the use of 3D animation and live footage from DDC’s laboratory, the video series explains how paternity testing works, and goes [...]MALTESE MINISTER FOR COMMUNICATIONS DELIVERS KEY NOTE SPEECH AT NETSUPPORTS ANNUAL PARTNER CONFERENCE
NetSupport's international channel partners have gathered in Malta for the software developers Annual Partner Event.
Managing Director Al Kingsley will once again be outlining the company's development plans for the year ahead and with NetSupport sales continuing to forge ahead despite the current economic climate these are certainly exciting times for resellers of the NetSupport product range.
Malta was seen as a natural location for this years event. Sales of NetSupport products have increased dramatically in the country over recent years as the government drives forward an ambitious programme to improve its IT infrastructure and increase the availability of ICT training.
As testament to the relationship built up between NetSupport and the Maltese Government, Austin Gatt, the Minister for Communications, opened the conference with a rousing key note speech which emphasised the countries plans to increase the number of ICT g....
PROOF-BY-SYNTHESIS OF THE TRANSCRIPTIONAL LOGIC OF MAMMALIAN CIRCADIAN CLOCKS
Proof-by-synthesis of the transcriptional logic of mammalian circadian clocks
Nature Cell Biology 10, 1154 (2008). doi:10.1038/ncb1775
Authors: Maki Ukai-Tadenuma, Takeya Kasukawa & Hiroki R. Ueda
JADE-1 INHIBITS WNT SIGNALLING BY UBIQUITYLATING ?-CATENIN AND MEDIATES WNT PATHWAY INHIBITION BY PVHL
Jade-1 inhibits Wnt signalling by ubiquitylating β-catenin and mediates Wnt pathway inhibition by pVHL
Nature Cell Biology 10, 1208 (2008). doi:10.1038/ncb1781
Authors: Vipul C. Chitalia, Rebecca L. Foy, Markus M. Bachschmid, Liling Zeng, Maria V. Panchenko, Mina I. Zhou, Ajit Bharti, David C. Seldin, Stewart H. Lecker, Isabel Dominguez & Herbert T. Cohen
The von Hippel–Lindau protein pVHL suppresses renal tumorigenesis in part by promoting the degradation of hypoxia-inducible HIF-α transcription factors; additional mechanisms have been proposed. pVHL also stabilizes the plant homeodomain protein Jade-1, which is a candidate renal tumour suppressor that may correlate with renal cancer risk. Here we show that Jade-1 binds the oncoprotein β-catenin in Wnt-responsive fashion. Moreover, Jade-1 destabilizes wild-type β-catenin but not a cancer-causing form of β-catenin. Whereas the well-established β-catenin E3 ubiquitin ligase component β-TrCP ubiquitylates only phosphorylated β-catenin, Jade-1 ubiquitylates both phosphorylated and non-phosphorylated β-catenin and therefore regulates canonical Wnt signalling in both Wnt-off and Wnt-on phases. Thus, the different characteristics of β-TrCP and Jade-1 may ensure optimal Wnt pathway regulation. Furthermore, pVHL downregulates β-catenin in a Jade-1-dependent manner and inhibits Wnt signalling, supporting a role for Jade-1 and Wnt signalling in renal tumorigenesis. The pVHL tumour suppressor and the Wnt tumorigenesis pathway are therefore directly linked through Jade-1.
TARGETING OF THE F-ACTIN-BINDING PROTEIN DREBRIN BY THE MICROTUBULE PLUS-TIP PROTEIN EB3 IS REQUIRED FOR NEURITOGENESIS
Targeting of the F-actin-binding protein drebrin by the microtubule plus-tip protein EB3 is required for neuritogenesis
Nature Cell Biology 10, 1181 (2008). doi:10.1038/ncb1778
Authors: Sara Geraldo, Umme K. Khanzada, Maddy Parsons, John K. Chilton & Phillip R. Gordon-Weeks
Interactions between dynamic microtubules and actin filaments (F-actin) underlie a range of cellular processes including cell polarity and motility. In growth cones, dynamic microtubules are continually extending into selected filopodia, aligning alongside the proximal ends of the F-actin bundles. This interaction is essential for neuritogenesis and growth-cone pathfinding. However, the molecular components mediating the interaction between microtubules and filopodial F-actin have yet to be determined. Here we show that drebrin, an F-actin-associated protein, binds directly to the microtubule-binding protein EB3. In growth cones, this interaction occurs specifically when drebrin is located on F-actin in the proximal region of filopodia and when EB3 is located at the tips of microtubules invading filopodia. When this interaction is disrupted, the formation of growth cones and the extension of neurites are impaired. We conclude that drebrin targets EB3 to coordinate F-actin–microtubule interactions that underlie neuritogenesis.
MODULATION OF CELLULAR RESPONSE TO ANTICANCER TREATMENT BY CAFFEINE: INHIBITION OF CELL CYCLE CHECKPOINTS, DNA REPAIR AND MORE.
Current pharmaceutical biotechnology, Vol. 9, No. 4. (August 2008), pp. 325-336.Caffeine and other methylxanthines produce multiple physiologic effects throughout the human body, many of these effects could potentially modulate the activity of anticancer therapy. Caffeine may directly interfere with drug transport to tumor cells by formation of mixed stacking complexes with polyaromatic drugs. If formed in cells, these complexes may also prevent of intercalating drugs from DNA binding and, in this way, lower their antitumor activity. Since many of potent carcinogens are polyaromatic compounds, formation of stacking complexes with carcinogens could be associated with anti-genotoxic activity of caffeine and its use in cancer chemoprevention. Caffeine has also been reported to inhibit ATM and ATR kinases which leads to the disruption of multiple DNA damage-responsive cell cycle checkpoints and greatly sensitizes tumor cells to antitumor agents which induce genotoxic stress. Caffeine may inhibit repair of DNA lesions through a direct interference with DNA-PK activity and other repair enzymes. A number of in vitro and in vivo studies demonstrated that caffeine modulates both innate and adaptive immune responses via inhibition of cyclic adenosine monophosphate (cAMP)-phosphodiesterase. Finally, another group of effects induced by caffeine is mediated through its inhibitory action on adenosine receptors. This may modulate the stability of HIF1 alpha as well as VEGF and interleukin-8 expression in tumor cells, which could have a direct impact on neovascularization of human tumors. In this review, we present different molecular mechanisms by which caffeine and other methylxanthines may directly or indirectly modulate the effect of antitumor treatment in tumor cells and in cancer patients.
M Sabisz, A Skladanowski
DNA DAMAGE SIGNALLING GUARDS AGAINST ACTIVATED ONCOGENES AND TUMOUR PROGRESSION.
Oncogene, Vol. 26, No. 56. (10 December 2007), pp. 7773-7779.DNA damage response (DDR), the guardian of genomic integrity, emerges as an oncogene-inducible biological barrier against progression of cancer beyond its early stages. Recent evidence from both cell culture and animal models as well as analyses of clinical specimens show that activation of numerous oncogenes and loss of some tumour suppressors result in DNA replication stress and DNA damage that alarm the cellular DDR machinery, a multifaceted response orchestrated by the ATR-Chk1 and ATM-Chk2 kinase signalling pathways. Such activation of the DDR network leads to cellular senescence or death of oncogene-transformed cells, resulting in delay or prevention of tumorigenesis. At the same time, the ongoing chronic DDR activation creates selective pressure that eventually favours outgrowth of malignant clones with genetic or epigenetic defects in the genome maintenance machinery, such as aberrations in the ATM-Chk2-p53 cascade and other DDR components. Furthermore, the executive DDR machinery is shared by at least two anticancer barriers, as both the oncogene-induced DNA replication stress and telomere shortening impact the cell fate decisions through convergence on DNA damage signalling. In this study, we highlight recent advances in this rapidly evolving area of cancer research, with particular emphasis on mechanistic insights, emerging issues of special conceptual significance and discussion of major remaining challenges and implications of the concept of DDR as a tumorigenesis barrier for experimental and clinical oncology.
J Bartek, J Bartkova, J Lukas
GPHR IS A NOVEL ANION CHANNEL CRITICAL FOR ACIDIFICATION AND FUNCTIONS OF THE GOLGI APPARATUS
GPHR is a novel anion channel critical for acidification and functions of the Golgi apparatus
Nature Cell Biology 10, 1135 (2008). doi:10.1038/ncb1773
Authors: Yusuke Maeda, Toru Ide, Masato Koike, Yasuo Uchiyama & Taroh Kinoshita
A FUNCTIONAL RNAI SCREEN LINKS O-GLCNAC MODIFICATION OF RIBOSOMAL PROTEINS TO STRESS GRANULE AND PROCESSING BODY ASSEMBLY
A functional RNAi screen links O-GlcNAc modification of ribosomal proteins to stress granule and processing body assembly
Nature Cell Biology 10, 1224 (2008). doi:10.1038/ncb1783
Authors: Takbum Ohn, Nancy Kedersha, Tyler Hickman, Sarah Tisdale & Paul Anderson
Stress granules (SGs) and processing bodies (PBs) are microscopically visible ribonucleoprotein granules that cooperatively regulate the translation and decay of messenger RNA. Using an RNA-mediated interference-based screen, we identify 101 human genes required for SG assembly, 39 genes required for PB assembly, and 31 genes required for coordinate SG and PB assembly. Although 51 genes encode proteins involved in mRNA translation, splicing and transcription, most are not obviously associated with RNA metabolism. We find that several components of the hexosamine biosynthetic pathway, which reversibly modifies proteins with O-linked N-acetylglucosamine (O-GlcNAc) in response to stress, are required for SG and PB assembly. O-GlcNAc-modified proteins are prominent components of SGs but not PBs, and include RACK1 (receptor for activated C kinase 1), prohibitin-2, glyceraldehyde-3-phosphate dehydrogenase and numerous ribosomal proteins. Our results suggest that O-GlcNAc modification of the translational machinery is required for aggregation of untranslated messenger ribonucleoproteins into SGs. The lack of enzymes of the hexosamine biosynthetic pathway in budding yeast may contribute to differences between mammalian SGs and related yeast EGP (eIF4E, 4G and Pab1 containing) bodies.
