Papers Selected in 2007


 

 

 

 

 

Wood et al. (2007) add to previous work providing a more complete picture of the cancer genome. They provide evidence that most tumors arise form a large number of mutations and not a common "cancer" gene. Cancers are composed of a handful of commonly mutated gene "mountains" and a much larger number of gene "hills" that are mutated at low frequency. The number of driver genes (those that cause tumor progression) seems large but likely to reflect changes in a limited number of signaling pathways (predicted less than 20). Thus it is important to understand signaling pathways and how they interact with each other. This interpretation of cancer is consistent with virtually all screens in model organisms, which have generally shown thatthe same phenotype can arise from alterations in any of several genes.

See also perspective by Trent and Touchman (2007)

Table S4A Colorectal CAN-genes (note EphA3,ephB6  and ROBO1 are present)

Table S4B Breast CAN-genes

Overmigration: when Dab1 down-regulation fails to occur

Slit presumably binds Robo to elicit a calcium wave at the growth cone which in turn redistributes active RhoA towards the soma and causes repulsive movement.

These findings implicate HIF-1 as an important transcription factor in the hormone-mediated regulation of hunger and wakefulness.

 

Physiological roles of autophagy

 

 

 

"Microarray technology is transitioning from an esoteric tool used primarily to measure mRNA levels to a general approach that might soon be as common as Southern blotting and PCR."

 

Sytems-level mathematical models of ras signaling.

 

 

 A special issue of Science highlighting Cell signaling. See life with oxygen

 

Knock down of WNT signaling inhuman breast cancer reduced proliferation.

 

 

Synthetic genetic interaction (SGI) analysis reveals the largest network of gene interaction to date.

 

 

 

SAX-3/Robo has another co-receptor for Slit signaling.

 

Electric fields might guide migration of cancer cells (cells moved toward the anode). EGF receptor signaling is involved.

 

 

A new way to look at fat. No probes like Nile red are needed.

 

A cooperation of Wnt and smaphoring signaling with Myc/Mondo proteins in ray 1 precusors cell migration.

 

Wow a remote controlled worm! Using light activated channels to excite and inhibit neurons. Watch a streaming video of this new technology (optogenetics)  here

 

 

Heat shock factor is required for tumor initiation and maintenance in a variety of cancers.

 Refers  to Dai et al. 2007

VAB-1/Eph RTK mutants regenerate their cut neurons with less errors than wild-type worms.

 

The complex network of adhesion

 

LAR tyrosine phosphtase and Src tyrosine kinase regulate the activity of of DAPK tumor suppressor. Link to C. elegans  DAPK-1  (aka mor-3)

 

Two papers in Neuron report that the Rac-GAP, a2-chimaerin is an effector of ephrinB3/EphA-4 signal transduction during mouse axon guidance and neural circuit formation in mice.Wegmeyer et al 2007  and Beg et al 2007

Closest C. elegans match to alpha2-chimaerin is BE003N10.2  and tag-341

 movie from: http://images.neuron.org/images/EdImages/Neuron/sept6_img.gif

For those of us who are starting to notice gray hairs this preview might be of interest: The role of the transcription factor Foxn1 in the "pigment receiving cells".

 

A preview on Katz et al 2007 which show how tensin isoforms weaken the association of b1 integrin at focal adhesions.

Yeast iinvasive growth-specific genes have internal ribosome entry sites (IRESs)  allow their translation without the need for the 5' cap. In contrast to viral IRESs, these cellular IRESs seem to consist of an unstructured sequence of adenosines that recruits the poly-A binding protein.

RPM-1 acts together with GLO-4, a RAB GEF, to regulate vesicular trafficking at the presynaptic terminal, in part through the adaptor protein complex AP3 and the late endosome/lysosome. These new findings show how membrane trafficking can influence nervous system development. glo-4 mutants also show PLM overextension. It is still an open question whether stable synaptic connections regulate axon terminations or vice versa.

 

The trials and tribulations of finding therapeutics that target ocogenic Ras.

 

Dab homologue in worms is required for endocytosis of the yolk lipoprotein.

Use of quantitative Mass Spec. methods to profile protein changes in insulin signaling mutants.

 

EFN-4 and Plexin PLX-2  play redundant roles in semaphorin dependent cell sorting

 

 

A review of tools and resources for C. elegans researchers.

Link to online resources

 

A unique way to kill cells by expressing subunits of Caspases behind your favorite promoters.

The latest review on formin proteins

AF6/Afadin has two splice variants with the short isoform localizing to subnuclear compartments during cell cycle progression and active transcription.

 

 

 

PDZ domains are not just for clustering target proteins.

 

The brain is the site where reduced insulin-like signaling can extend a mouse life span.

 

Interesting role of cilia in cell signaling

 

Preview on two papers describing the dynamics of the Bicoid gradient.

 

 

 

N-cadherin-associated -catenin is transported to the nucleus after Robo-associated Abl phosphorylation.

 

The authors propose that somatic support cells extend processes and enclose germ cells in Drosophila testes by differential activation of the small GTPase Rac1 via polarized reception of an Egf class signal from the neighboring germ cells.

 

Perspective on Vartianen et al. report (Treisman's lab) on G-actin regulating the MAL transcription factor  nuclear localization.

 

Meeting Abstracts

 

JNK signaling is upregulated in PTEN null cells.

 

Selected by Annie: Authors utilizes florescent real time microscopyto determine the mechanisms that control and coordinate actin polymerization. ADF/cofilin is the dominant factor in determining actin filament length. They suggest that the stability of actin is determined by its association or lack of, to other actin fibers. Actin-bundles are less at risk of severing compared to single filaments due to inefficient binding of ADF/cofilin.

 

Selected by Annie: This paper reveals in detail the structure of daam-1 formin in humans. Interestingly, in contrast to what has been found in other animals, the human homolog of daam-1 seems to have weak actin assembly activity. However, a mutation in its structure has been found to upregulate actin activity.

 

Nature's news report on the ability to reprogram mouse skin cells to an ES like state.

 

 

PHA-4 and SKN-1 are involved in dietary restriction longevity. SKN-1 is needed in the ASI neurons.

Panowski, et al. Nature 447, 550–555 (2007). | Article |

Bishop & Guarente Nature 447, 545–549 (2007). | Article |

 

A review on the use and meaning of error bars. Here is another paper explaining the differences between standard deviation and standard error and when to use each.

 

A program to covert your cDNA sequence into music. Here is what VAB-1 sounds like.

 

 

A new ligand for Eph receptors.  Azurin is a metalloprotein that binds to EphB2 and can interfere with EphB2 signaling. Ian's note: EphB2 is the closest human homolog to VAB-1 (VAB-1 intracellular is closest to EphA3) and C. elegans EFN-1-3 are closest to human ephrinB2 while EFN-4 is closest to human ephrin A1. 

 

 

 

Selected by Sarah: This paper is a nice review and shout-out to the usefulness of C. elegans with reference to the "Krogh Principle" which states that there likely exists an ideal model organism from which every physiological problem could be studied. The author suggests that because of the integrated molecular, genetic and physiological methods used to study C. elegans; this organism represents a very probable candidate to fulfill Krogh’s Principle and may therefore be used to develop a systems biological understanding of fundamental physiological processes common to all animals.

 

Selected by Sarah: This paper presents some neat evidence that sperm are involved in promoting egg-laying from the uterus of C. elegans. It was found that the cellular basis of the defect in the egg-laying defective mutant, egl-32, is likely sperm related as mating an egl-32 hermaphrodite with a wild-type male corrects rescues the defect. Conversely, mating a wild-type hermaphrodite with an egl-32 male induces the egl-32 phenotype in the hermaphrodite. Taken together, these results shed some light on the role that sperm plays in regulating female physiological processes in a hermaphroditic organism.

 

Selected by Annie:  Understanding the mechanisms involved in ensuring the totipotency of germ cells remains to be elucidated. In this paper the authors identify MRG-1, a gene involved in cell proliferation and development. Maternal contribution of mrg-1 gene is crucial for the germ line and proper embryo development.

Selected by Jun:  This review uses EGFR signaling pathway as an example to show that signal transduction is not linear but an integrative network instead. They cover pathway cross-talk, feed-back regulation, miRNA regulation, and systems biology, etc.

 

 

 

Surprisingly Xenopus retinal axons with mislocalized Ena/VASP did not display axon guidance defects but showed defects in the formation of axon branches.

 

A new pathway in somatic cells for aging in C. elegans.

 

Selected by Ahmed: RNAi does not function efficiently in the nervous system and thus prevents the use of this tool for molecular analysis of axon guidance.  The authors report the isolation of a new RNAi-hypersensitive strain, nre-1(hd20) lin-15(hd126), where known axon guidance genes can be phenocopied with high penetrance. 

 

Selected by Sarah: Acrylamide is a known neurotoxin, but mounting evidence suggests that it could also be a carcinogen. This review outlines the current understanding of the properties of Acrylamide, its effects and the occurrence of it in various sources ranging from laboratory use to common foods. Ian's note: The unpolymerized or powder form of acrylamide is a known neurotoxin.  The polymerized gels have lower toxic effects but nonetheless should be handled and disposed of properly.

 

 

Selected by Annie: In Drosophila, DAAM is involved in the regulation of the actin cytoskeleton of the tracheal system. More specifically it is necessary to prevent the collapse of the tracheal tubes.

 

 

 [Nature News & Views]

Using a technique called stimulated emission depletion (STED) microscopy these authors defy the maximum resolution using traditional fluorescence microscopy (~200nm). The authors can resolve individual vesicles (~40nm)in the synapse.

 

Selected by Jun: A biochemist's guide to C. elegans provides an overview, an idea of what to consider, and where to find additional resources and necessary information" for worm research. It also offers practical examples for forward and reverse genetics too.

 

Bottlenecks are proteins in protein networks that connect various nodes or hubs.  Yu et al. show that these bottleneck proteins are likely to be essential. Previously, much attention has been given to the "hub" proteins but non hub proteins that function as bottleneck proteins should also be scrutinized as an essential components in signaling networks.

 

Selected by Sarah: This review provides a good overview of some of the known downstream targets of Ras signaling as well as connects aberrancies in these targets to numerous developmental disorders such as Noonan Syndrome and Cardio-facio-cutaneous syndrome and associated cancers. The author does a really nice job connecting the laboratory molecular work regarding the Ras pathways to the clinical level to give a good framework for understanding the importance of this cellular effector.

Selected by Ahmed: It is generally held that nonallelic noncomplementation between mutations of two different loci signifies a physical interaction between the products of the genes.  The authors of this paper show that nonallelic noncomplementation is not limited to molecules that physically interact, but can also be observed between proteins that do not directly interact but are members of the same complex. 

 

Selected by Annie: Annual review (2007) about formins. Formin structure and function are described. The role of formins on actin assembly and regulation, motility, morphogenesis are explored with lots of figures and hypothetical models to aid in understanding.

 

Selected by Ahmed: Recombinant full length WASP and N-WASP was used to test the ability of various activators to activate these proteins.  This is novel in the sense that all other previous work was carried out using truncated versions of WASP and N-WASP.  The authors were able to show how different activators such as Cdc42, Rac1, PIP2, Nck1 and Nck2 differentially regulate WASP and N-WASP.

 

Selected by Jun:  primary cell culture system for C. elegans. See also Christensen et al. (2002)

 

Selected by Sarah: Molecular biology is now viewed as a routine set of techniques in some academic circles, with nothing left to 'figure out'. There is speculation that Nanotechnology is going to be the wave of the future and answer all questions molecular biology was unable to. This review discusses the potential uses of Nanotechnology as well as the associated risks. The author postulates that while this new field has many benefits to understanding biological systems, it must be approached with extreme caution to preserve the sanctity of science and human kind.

Forward signaling downstream of EphA inhibits insulin secretion, whereas reverse signaling downstream of ephrinA signaling stimulates insulin secretion. See also Cell  Preview
 

Selected by Annie:  The paper talks about the role of Daam1 with respect to cell movement and morphogenesis. Daam1 regulates the endocytosis of EphB molecules and cytoskeleton remodeling to coordinate cell behavior during notochord development.

Selected by Annie: This paper talks about the role of Dia-Interaction Protein (DIP) in the control of actin-filament assembly that is mediated by Diaphanous-related formins and activators of Arp2/3. It points to a role for formins in the control of actin dynamics at the cytoskeleton and plasma membrane. DIP was shown to act as a negative regulator of mDia2. More specifically DIP can inhibit mDia2 mediated actin nucleation, bundling, its ability to assemble filopodia and promotes nonapoptotic membrane blebbing.

 

Selected by Ahmed: Ahmed's Notes

Selected by Jun: This paper offers another link of GEF to Eph receptors. Also see "New exchanges in Eph Dependent Growth cone dynamics" (Neuron 2005) for a brief intro about different GEFs involved in Eph signaling. Note that in the Neuron 2005 paper, Tiam1 is shown to be involved in EphA signaling, and this paper links Tiam1 to EphB.

Selected by Sarah: Eph receptors and their ephrin ligands have found to be expressed in the developing and adult brain of the honeybee. More specifically, in situ labeling has found these proteins to be differentially localized in the glomeruli of antenna lobes and the medial lobe of the mushroom body. These two regions are involved in olfactory learning and memory, suggesting that eph receptor signaling may help regulate memory formation.

 

A special issue of Science devoted to the germline

 

A short review with lots of good refs on germline regulation in C. elegans and Drosophila.

 

Highlights recent work in Drosophila morphogenic movements. A new gene T48 regulates RhoGEF2 and adherens junctions to the apical side of the cell. Note there is no C. elegans or human T48 ortholog.

 

Proteins that bind PI(4,5)P2 rich membranes to cause cell protrusions and may contribute to cell motility. Note that a product of PTEN is PI(4,5)P2.  MIM homolog in C. elegans M04F3.5  (most similar to BAIAP)

 

Detail kinetics cell fusion maps of the C. elegans epidermal cells. [cover caption]

 

What genes make a Great Dane so much bigger than a Chihuahua? Sutter et al. provide an answer to this very interesting question. They show that the Insuling Growth Factor (IGF-1) is a major determinant of dog size. IGF 1 binds type 1 IGF receptor, a receptor tyrosine kinase.

Imagine making DNA constructs without restriction enzymes or ligase--this is what recombineering is all about. This paper presents a novel way to make C. elegans GFP reporter constructs using a series of recombineering steps in bacteria.  

Sarah's pick: Procrastination is associated with tasks in which people know they are being evaluated. To eliminate procrastination in academic/laboratory settings, tasks should be masked as enjoyable.

While procrastination has long been thought to be associated with negative outcomes in the target task and poor self-esteem of the procrastinator, recent findings suggest that in some, procrastination may be a sign of high self-esteem, where the individual prefers to work under pressure because they know they are capable of accomplishing the task at hand.

This paper presents data that show the function of Slit and Robo signaling during midline axon guidance is not only to repress Netrin attraction in Drosophila but has other functions. This is consistent with C. elegans work that show DCC/UNC-40 can potentiate SAX-3/Robo independent of the UNC-6/Netrin.

 

 

 

This work show that it is likely that the number of mutated human cancer genes is larger than previously thought. Nature podcast

 

 

The Hmga2 3' UTR has conserved sites complementary to the let-7 RNA. De-repression of Hmga2 enhancesoncogenic transformation and this work support the let-7 miRNA acts as a tumor-suppressor gene.

 

PTP1B has positive effect on two tumorgenic pathways  Ras/MAP Kinase and PI3 Kinase/PKB.

 

 This is another example where Eph signaling inhibit Ras/ERK pathway (see also Miao et al. 2001Elowe et al. 2001 and

Miller et al. 2003)

 

Paper from Tom Moss' lab that shows Nckb binds to EphA4 in Xenopus and activates PAK1 to block Cdc42during loss of cell adhesion. Made gain-of-function EphA4 using chimera EGFR extracellular and EphA4 intracellular. Note that overexpression of Nckb acts as a dominant negative in suppressing the EphA4 gain-of-function phenotype. Ncka had no affect.

 

 

 

         Evolutionary conservation of cell migration     [PDF]

 

 

 

 

Selected by Ahmed: Ahmed's Notes

 

 

 

 

 

 

 

 

 

 

Ena/VASP contributes to the cell repulsion (destabilised lamellipodia) downstream of Eph receptor activation. Ena is localized to sites of activated Eph Receptors and this localization is needed for repulsion and internalization by endocytosis. They do not show how the Eph RTK links to Ena/VASP though.

 

 

 Using C. elegans  for drug discovery.