The Chin-Sang Lab Reads

Papers Selected in 2009


  The Worm Breeder's Gazette has returned after a 6 year hiatus.

Turning of FOXL2 in female mice caused ovary cells to change to testicular cells. This study challenges the assumption that the female fate is default pathway in sex determination.  In males SOX9 seems to be the key gene that keeps FOXL2 off.

 

A systems approach to look at ephrin-B1 and EphB2 cell-specific  signaling

during cell sorting.

 

Most oncogenic mutation of PI3K are in the p110 catalytic subunit but Jaiswal et al. report mutations in the p85alpha subunit that promotes tumor formation.  These mutation affect the inhibitory role of p85 on p110.

 

Defective autophagy can lead to tumors through the inability to eliminate p62 through autophagy. p62 is a multifunctional protein that binds polyubiquitinated proteins  and forms aggregates to target proteins to the autophagosomes for degradation. p62 also up regulates NF-kB to promote tumorgenesis.

 

 

Two reviews on next-generation sequencing

 

$5000 Prize for finding a new Caenorhabditis species has still yet to be won. How to isolate wild  C. elegans and other related nematodes. 

 

Another example that introns are not junk DNA: Myosin genes have a intronic miRNAs that control muscle gene expression and performance.

 

Alterations in DNA (mutation) can lead to uncontrolled and invasive growth (cancer).  Here the authors describe a mechanism for an epigentic switch (no alteration in DNA sequence) that promotes transformation of breast cancer cells through multiple generations. This switch mechanism they describe could allow transient events like inflammation or exposure to environmental factors (not necessarily altering DNA sequence) to produce a cancerous state just like a mutations that inactivate a tumor suppressor or activate and oncogene.

From 1959: Can a single injury cause cancer? This author says no. But these new epigenetic mechanisms suggest maybe.

A new role for slit and robo in keeping cell boundaries and compartments.  This role is similar to what the Eph Receptors do.

 

A perspective on the following two papers:

Two  G-protein coupled receptors mediate the dauer pheromone signal.


 

Another form of C. elegans diapuse (in addition to L1 arrest and dauer).  Adult reproductive diapuase (ARD) in C. elegans allows the worm to delay reproduction by 15 fold and extend life span at least threefold. ARD requires apoptotic death of the germline, except for the germline stem cells.  The NHR-49 nuclear receptor is required for entry and recovery of ARD.

 

EphB receptors have a paradoxical function: int intestinal epithelium they can promote cell proliferation (i.e. oncogenic) but can also act as a tumor suppressor in colon cancer development.

Here Genander et al. report that the EphB2 receptors regulates two separate pathways. EphB2  suppresses cell migration through the PI3K pathway in a kinase independent manner and regulates cell proliferation through Abl-cyclin D1 in a kinase dependent manner.  See preview by Roberta Noberini and Elena Pasquale.

 

PI(4,5)P2 and NCK cooperate in N-WASP-stimulated actin polymerization.

Review on the field of developmental neuroscience.

Herbert et al. show that coordinated signaling mechanisms including Ephrin B2 and EphB4 drives angioblast migration and arterial-venous segregation during vessel development.

P-REX2a (phosphatidylinositol 3,4,5-trisphosphate RAC exchanger 2a (P-REX2a) binds to PTEN to inhibit PTEN lipid phohsphatase to increase PI3K/AKT signaling. See also this perspecitve.

Tips on how to give a good talk. See also my tips.

The budding yeast Saccharomyces cerevisiae lacks RNAi. But now Dinnernberg et al. show that RNAi can be restored in S. cerevisiae, by introducing Dicer and Argonaute genes of S. castellii.

Nile Red on live worms does not correlate with fat biochemical quantification. Nutritional cues perceive in the intestine regulate fat independent of neuroendocrine cues. Specific peptides may provide regulating fat metabolism and fat storage.

Janes et al. show that tyrosine phosphorylation of EphA3 changes the tyrosine kinase domain conformation away from the plama membrane to allow ADAM10 to come in contact with its substrate, ephrinA5.

Injection of  miR-124 into fertilized mouse eggs resulted in a 30% increase in body size. But the surprising part is that it lasted into adulthood and the males could epigenetically pass this phenotype to their offspring.  The researchers suggest that modification of the Sox-9 gene is involved.

LTR is a leucine-rich repeat transmembrane protein expressed in tendons. LTR  acts as a lignad for Robo during muscle cell migration towards the tendon cells.

Goldstein lab review on apical constriction mechanisms.

A gene targeting approach for C. elegans.

Mechanism of transcription termination in C. elegans and the importance of the first intron downstream of polycistronic pre-mRNAs in expression a role in preventing premature pol II transcription termination.

 

A mathematical model shows PTEN protein expression to be the key determinant of resistance to anti-HER2 therapy (eg. trastuzumab aka Herceptin). Note that Nagata  et al (2004) also showed that PTEN deficiency is a powerful predictor for trastuzumab.

 

Bruce Alberts' editorial encouraging research funding agencies to fund research in more accessible organisms not just human cells. The most profound impact on cancer treatments  comes form basic research on model organisms, rather than form studies of highly complex human tumors. 

 

Qian et al. have provided a novel mode of regulation for an SH2 domain.  The SH2 domain of tensin-3 is phosphoylated by Src tyrosine kinase and this phosphorylation promotes the oncogenic function of tensin-3. Whether other SH2 domins are regulated by tyrosine kinases remains to be shown.

 

 

Andrew Chisholm and Yishi Jin Labs' show thai in C. elegans neurons the DLK-1 pathway acts via the MAPKAP kinase, MAK-2, to promote stabilization of the mRNA of the bZip protein CEBP-1, resulting in enhanced CEBP-1 translation. This mechanism is also required for the regenerative responses of adult neurons.

 

Fine et al. identified P-REX2a, a guanine nucleotide exchange factor (GEF) for the RAC small guanosine triphosphatase as a binding partner for PTEN. P-REX2a inhibited catalytic activity of PTEN.  P-REX2a thus provides a mechanism through which tumor cells may inactivate PTEN. Ian's notes: The closest match to P-REX2a in C. elegans is VAV-1 which is a Rho/Rac GEF and orthologous to the Vav prto-oncogene.  VAB-1 has been shown to function with VAB-1/EphR in oocytes Govindan et al. 2006 and Cheng et al. 2008.

Here, Bear and Gertler try to resolve the controversy of the anti-capping role for Ena/VASP.  In addition, they describe several alternate mechanisms that Ena/VASP proteins may utilize to regulate actin dynamics in vivo, including inhibition of branching, bundling and profilin-actin recruitment. 

 

 

Review on PI3K signaling in cancer. 

Review on mutations that affect sleep. [PDF]

Selected by Jun: This new Cell paper shows that SH2 domain also binds to a non-canonical site on the RTK (non pY) in a kinase independent manner. They discover that "N-SH2 domain of PLCγ utilizes an additional region separate from its canonical pY binding site for binding to a region in the C-lobe of the tyrosine kinase domain of FGFR1 in a phosphorylation-independent manner"

A description of Pdk-1 dependent and independent  effects  in different cells with pten deleted.

Integrin clustering can be initiated by Eph/Ephrin reverse signaling to form the ECM.

 

 

Some evidence to support the apparent paradox of EphA2  roles in cell migration and invasion. The oncogenic role of EphA2 is ligand independent and required the S897 phosphorylation by AKT. Interestingly ephrin-A1 stimulation could reverse the S897 caused by AKT. 

An interesting paper describing how a subunit of the WAVE complex (Cyfip1) may act as a invasion suppression gene. This is a surprising result given that proteins that promote actin-based protrusions (i.e. WAVE/SCAR) are thought to be needed for invasion during metastasis. 

Review on the roles of Eph signaling at the synapse.

A-class Eph receptor/ephrin interactions involve smaller rearrangements in the interacting partners, better described by a 'lock-and-key'-type binding mechanism, in contrast to the 'induced fit' mechanism defining the B-class molecules.

selected by Jun: Long lived C. elegans (due to decreased insulin-like signalling) have misexpression of germline genes (eg. pie-1  and pgl-1 ) in somatic tissues. DAF-16, the major transcriptional effector of insulin-like signalling, regulates pie-1 expression by directly binding to the pie-1 promoter. Thus the somatic tissues of insulin-like mutants are more germline-like and protected from genotoxic stress.

Selected by Jun. Another Eph Receptor (EphA3) binds to the NCK1 adaptor. PY602 of EphA3 binds tot he SH2 domain of NCK1. The interaction is much greater on "activated" EphA3 when stimulated with Ephrin-A5.

Talking mice? The Foxp2 gene is thought to be involved in the evolution of human speech and language.  This group put the human version of Fox2p in mice and found that these mice have different vocalizations (lower pitched) and have increased synaptic plasticity in the brain regions thought to be important for speech.

XIAP closest match in C. elegans is encoded by the  bir-2

MicroRNA miR-26a negatively regulates PTEN

 

Selected by Jun: Dendrite shape is not only cause by an "out growth" but instead the dendritic tip can anchor itself and  and the cell body migrates away from it. DEX-1 and DYF-7 are Transmembrane proteins (Tectorin-like) that are required for proper anchoring of the dendrites.

 

Using a novel genetic screen Hammarlund et al.  identified DLK-1 MAP kinase kinase kinase (MAPKKK) as a protein requierd of axon regenration.  Also see O'Brien and Sagasti Science signalling [perpespetive]

An interesting study that shows the Src family tyrosine kinase, Rak,  binds to and can phosphorylate PTEN and stabilizes it by protecting it from ubiquitin-mediated degradation. As such, Rak acts as a strong tumor suppressor.  However, it should be noted that this paper has results that are opposite to what Lu et al 2003 found  which shows Src kinase family inhibits PTEN activity and stability. See: http://www.jbc.org/cgi/content/full/278/41/40057

 

Review on vertebrate cilia and physiological consequences of abnormal cilliogenesis.

Definition: “An epigenetic trait is a stably heritable phenotype resulting from changes in a chromosome without alterations in the DNA sequence.”

During L1 arrest RNA Polymerase II binds to promoters of growth and development genes in anticipation of favorable condition.

Review on protein phophatases

 

crml-1 was identified as a suppressor of unc-34/ena.  CRML-1 inhibitory binding to UNC-73 causes lower SAX-3/Robo levels

P granule components are degraded by autophagy.

 

the role of phosphoinositides in developmental signaling

 

A new model for apical constriction: In contrast to a "purse-string " model constriction pulses (asynchronous) are powered by actin-myosin network of contractions that occur at the medial apical cortex and pull discrete adherens junction sites inwards. The transcription factors snail and   twist  regulate the pulse constrictions.  See preview in DevCell

15 examples published by Nature that provide evidence for evolution by natural selection.