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Cytotoxic T lymphocytes release granzymes (Gzm) A and B to induce apoptosis or programmed cell death of virally infected or tumor cells. In this issue of Cell, Fan et al. identify the tumor metastasis suppressor NM23-H1 as a GzmA-activated, apoptosis-inducing DNase and the oncoprotein SET as its inhibitor. Work from the Lieberman and Wang groups indicates a surprising role for a group of acidic nucleo-cytoplasmic...
The vomeronasal organ (VNO) of the mouse has two neuronal compartments expressing distinct families of pheromone receptors, the V1Rs and the V2Rs. We report here that two families of major histocompatibility complex (MHC) class Ib molecules, the M10 and the M1 families, show restricted expression in V2R-expressing neurons. Our data suggest that neurons expressing a given V2R specifically co-express...
During nervous system development, neurons form reproducible synapses onto specific targets. Here, we analyze the development of stereotyped synapses of the C. elegans HSNL neuron in vivo. Postsynaptic neurons and muscles were not required for accurate synaptic vesicle clustering in HSNL. Instead, vulval epithelial cells that contact HSNL act as synaptic guidepost cells that direct HSNL presynaptic...
Growth factor receptors activate Ras by recruiting the nucleotide exchange factor son of sevenless (SOS) to the cell membrane, thereby triggering the production of GTP-loaded Ras. Crystallographic analyses of Ras bound to the catalytic module of SOS have led to the unexpected discovery of a highly conserved Ras binding site on SOS that is located distal to the active site and is specific for Ras.GTP...
We used representational difference analysis to identify homozygous genomic deletions selected during tumor progression in the mouse NF2 and TP53 tumor model. We describe a deletion targeting DOCK4, a member of the CDM gene family encoding regulators of small GTPases. DOCK4 specifically activates Rap GTPase, enhancing the formation of adherens junctions. DOCK4 mutations are present in a subset of...
Granzyme A (GzmA) induces a caspase-independent cell death pathway characterized by single-stranded DNA nicks and other features of apoptosis. A GzmA-activated DNase (GAAD) is in an ER associated complex containing pp32 and the GzmA substrates SET, HMG-2, and Ape1. We show that GAAD is NM23-H1, a nucleoside diphosphate kinase implicated in suppression of tumor metastasis, and its specific inhibitor...
In development, cell identity is maintained by epigenetic functions that prevent changes in cell type-specific transcription programs. Recent insights into gene silencing mechanisms by Polycomb group (PcG) and trithorax group (trxG) proteins reveal that the memory system involves a concerted process of chromatin modification, blocking of RNA polymerase II, and synthesis of noncoding RNA. Remarkably,...
In S. cerevisiae cells undergoing anaphase, a ras-related GTPase, Tem1, is located on the spindle pole body that enters the daughter cell and activates a signal transduction pathway, MEN, to allow mitotic exit. MEN activation must be reversed after mitotic exit to reset the cell cycle in G1. We find that daughter cells activate an Antagonist of MEN pathway (AMEN) in part through induction of the Amn1...
Plasticity of the nervous system is dependent on mechanisms that regulate the strength of synaptic transmission. Excitatory synapses in the brain undergo long-term potentiation (LTP) and long-term depression (LTD), cellular models of learning and memory. Protein phosphorylation is required for the induction of many forms of synaptic plasticity, including LTP and LTD. However, the critical kinase substrates...
In this issue of Cell, Meneghini et al. demonstrate that replacement of canonical histone H2A with the histone variant H2A.Z within euchromatin prevents silent chromatin proteins from migrating into regions of the chromosome that normally are transcriptionally active. Thus, this highly conserved histone variant is critical for defining chromatin domains.
Boundary elements hinder the spread of heterochromatin, yet these sites do not fully account for the preservation of adjacent euchromatin. Histone variant H2A.Z (Htz1 in yeast) replaces conventional H2A in many nucleosomes. Microarray analysis revealed that HTZ1-activated genes cluster near telomeres. The reduced expression of most of these genes in htz1Δ cells was reversed by the deletion of SIR2...
Granulocytes and monocytes/macrophages of the myeloid lineage are the chief cellular agents of innate immunity. Here, we have examined the inflammatory response in mice with conditional knockouts of the hypoxia responsive transcription factor HIF-1α, its negative regulator VHL, and a known downstream target, VEGF. We find that activation of HIF-1α is essential for myeloid cell infiltration and activation...
Functionally similar neurons can share common dendrite morphology, but how different neurons are directed into similar forms is not understood. Here, we show in embryonic and larval development that the level of Cut immunoreactivity in individual dendritic arborization (da) sensory neurons correlates with distinct patterns of terminal dendrites: high Cut in neurons with extensive unbranched terminal...
The p53 tumor suppressor exerts anti-proliferative effects in response to various types of stress including DNA damage and abnormal proliferative signals. Tight regulation of p53 is essential for maintaining normal cell growth and this occurs primarily through posttranslational modifications of p53. Here, we describe Pirh2, a gene regulated by p53 that encodes a RING-H2 domain-containing protein with...
c-Abl is normally regulated by an autoinhibitory mechanism, the disruption of which leads to chronic myelogenous leukemia. The details of this mechanism have been elusive because c-Abl lacks a phosphotyrosine residue that triggers the assembly of the autoinhibited form of the closely related Src kinases by internally engaging the SH2 domain. Crystal structures of c-Abl show that the N-terminal myristoyl...
Molecular genetics has been key in allowing developmental biologists to uncover many of the molecules that participate in pattern formation. Cell biology is now beginning to help developmental biologists in their quest to understand how these molecules interact within cells to direct tissue behavior. This is particularly true in the areas of membrane trafficking and cell motility. Recent work has...
The cohesin complex is essential for sister chromatid cohesion during mitosis. Its Smc1 and Smc3 subunits are rod-shaped molecules with globular ABC-like ATPases at one end and dimerization domains at the other connected by long coiled coils. Smc1 and Smc3 associate to form V-shaped heterodimers. Their ATPase heads are thought to be bridged by a third subunit, Scc1, creating a huge triangular ring...
Protein translocation across and insertion into membranes is a process essential to all life forms. In higher eukaryotes, this process is initiated by targeting the translating ribosome to the endoplasmic reticulum via the signal recognition particle (SRP) and its membrane-associated heterodimeric receptor (SR). This targeting step is regulated by three G proteins, SRP54, SRα, and SRβ, which act in...
Mammals detect temperature with specialized neurons in the peripheral nervous system. Four TRPV-class channels have been implicated in sensing heat, and one TRPM-class channel in sensing cold. The combined range of temperatures that activate these channels covers a majority of the relevant physiological spectrum sensed by most mammals, with a significant gap in the noxious cold range. Here, we describe...
We investigated positioning of chromosomes during the cell cycle in live mammalian cells with a combined experimental and computational approach. By non-invasive labeling of chromosome subsets and tracking by 4D imaging, we could show that no global rearrangements occurred in interphase. Using the same assay, we also observed a striking order of chromosomes throughout mitosis. By contrast, our computer...
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