VIROLOGY Replication of immunodeficiency virus in humans
The acquired immunodeficiency syndrome (AIDS) pandemic is caused by the human immunodeficiency virus (HIV-1), which attacks the immune system and leaves infected individuals susceptible to opportunistic infections. AIDS and HIV-1 are thought to have a relatively short history in humans, with the first infections likely occurring around the turn of the 20th century. HIV-1 is derived from highly related simian immunodeficiency viruses (SIVs) that infect modern primates, including chimpanzees. SIVs must have crossed the species barrier to infect humans at some point in the past, but the molecular adaptations that permitted a new host are unknown. Drs. Beatrice Hahn and Frank Kirchoff led an international research effort to understand what adaptations allow a chimpanzee strain of SIV to replicate in human tissues. They found that SIV is capable of replicating in human immune tissues, but that replication occurs at very low levels. By introducing a single amino acid change into the SIV Gag protein, a structural protein that makes up the viral capsid, the research team found that viral replication in cultured human tissues increased dramatically, while replication in chimpanzee-derived immune cells was decreased. Their work indicates that species-specific adaptation of Gag is critical for viral replication efficiency and suggests that changes in Gag potentially played a role in the emergence of HIV/AIDS.
TITLE:
Efficient SIVcpz replication in human lymphoid tissue requires viral matrix protein adaptation
AUTHOR CONTACT:
Frank Kirchhoff
Institute for Molecular Virology, 89081 Ulm, , DEU
Phone: 49-731-500 65150; Fax: 49-731-500 65153; E-mail: frank.kirchhoff@uni-ulm.de
View this article at: http://www.jci.org/articles/view/61429?key=b299fdfbdc1c9633aa06
AUTOIMMUNITY Understanding bone loss in rheumatoid arthritis patients
Rheumatoid arthritis causes joint stiffness and pain for over 2 million Americans. The disease is caused by an errant attack on healthy tissue by the body's immune system. Antibodies found in some patients target specific types of modified proteins, called citrullinated proteins, and are associated with an increased risk of bone destruction. Dr. Georg Schett and fellow researchers at University of Erlangen-Nuremberg in Germany suspected that these particular self-reactive antibodies directly influence bone loss that can sometimes occur in rheumatoid arthritis. They found that antibodies against citrullinated proteins bind to osteoclasts, specialized cells that break down bone tissue. In a mouse model system, they demonstrated that infusion of antibodies recognizing a cirtullinated protein activated osteoclasts and triggered bone resorption, resulting in the breakdown of bone and release of calcium. Their study provides strong evidence for a direct link between antibodies recognizing citrullinated proteins and bone loss.
TITLE:
Induction of osteoclastogenesis and bone loss by human autoantibodies against citrullinated vimentin
AUTHOR CONTACT:
Georg Schett
University of Erlangen-Nuremberg, Erlangen, UNK, DEU
Phone: ++4991318539131; E-mail: georg.schett@uk-erlangen.de
View this article at: http://www.jci.org/articles/view/60975?key=184312bf01374b6947de
ONCOLOGY Role in the family defined: ERK3 function in tumor invasiveness uncovered
The proteins extracellular signal-regulated kinase 1 (ERK1) and extracellular signal-regulated kinase 2 (ERK2) have been extensively studied for their role in transmitting cellular signals that stimulate cell division. The ERK1 and ERK2 signaling cascade is frequently dysregulated in tumors, facilitating the unscheduled cellular proliferation that is a hallmark cancer. In contrast to ERK1 and ERK2, very little is known about the function of a highly related protein, ERK3. A research team led by Burt O'Malley at the Baylor College of Medicine in Houston, Texas wanted to understand the cellular function of ERK3 and determine if ERK3 also played a role in cancer progression. They found that several human cancers show increased expression of ERK3 which was associated with tumor invasiveness. They went on to demonstrate that ERK3 upregulates matrix metalloproteinases, which degrade extracellular matrix, and that this pathway promotes invasiveness of lung cancer cells in a mouse model system. Their work defines a new function for ERK3 in cellular signaling and suggests that therapeutics targeting ERK3 could potentially decrease lung cancer invasiveness.
TITLE:
ERK3 signals through SRC-3 coactivator to promote human lung cancer cell invasion
AUTHOR CONTACT:
Bert W. O'Malley
Baylor College of Medicine, Houston, TX, USA
Phone: 713-798-6205; Fax: 713-798-5599; E-mail: berto@bcm.edu
View this article at: http://www.jci.org/articles/view/61492?key=605f04267259c4322205
VIROLOGY Dying for a response: A DC receptor that recognizes dead cells promotes anti-viral immunity
The dendritic cell, natural killer lectin group receptor-1 (DNGR-1) is a dendritic cell (DC)-restricted receptor that promotes cytotoxic T lymphocyte (CTL) responses against necrotic cell antigens. Because many viruses induce significant cell death, DNGR-1 signaling may be important for triggering T cell responses during a cytopathic infection. Two complementary research articles in the Journal of Clinical Investigation-authored by David Sancho and colleagues at the Centro Nacional de Investigaciones Cardiovasculares and Caetano Reis e Sousa and colleagues at the Cancer Research UK London Research Institute-report that DNGR-1 signaling is critical for cross-priming T cells against viral antigens from dead cells following both vaccination and viral infection. Sancho's team examined the role of DNGR-1 in mice and found that DNGR-1 signaling is critical for CTL responses during vaccination with antigen-bearing dead cells and during infection with herpes simplex virus type I. They further suggest that DNGR-1 functions by diverting necrotic material into a recycling endosomal compartment that enables cross-presentation to T cells. The Reis e Sousa group found that DNGR-1 signaling is required for protective CTL activity during vaccinia virus infection and vaccination in mice. Thus, these findings demonstrate the importance of DNGR-1 signaling for promoting protective immune responses during vaccination and viral infection.
TITLE:
The DC receptor DNGR-1 mediates cross-priming of CTLs during vaccinia virus infection in mice
AUTHOR CONTACT:
David Sancho
CNIC- Centro Nacional de Investigaciones Cardiovasculares, Madrid, UNK, ESP
Phone: (+34) 914531200 ext 2010; Fax: (+34) 914531245; E-mail: dsancho@cnic.es
View this article at: http://www.jci.org/articles/view/60660?key=5cb1d55d03eaa92c1c7d
ACCOMPANYING ARTICLE
TITLE:
The dendritic cell receptor DNGR-1 controls endocytic handling of necrotic cell antigens to favor cross-priming of CTLs in virus-infected mice
AUTHOR CONTACT:
Caetano Reis e Sousa
Cancer Research UK, London, GBR
Phone: + 44 20 7269 2832; E-mail: caetano@cancer.org.uk
View this article at: http://www.jci.org/articles/view/60644?key=7c1846ab5e519d754ec8
ONCOLOGY Akt-mediated phosphorylation of Bmi1 modulates its oncogenic potential, E3 ligase activity, and DNA damage repair activity in mouse prostate cancer
Prostate cancer (PCa) is a major lethal malignancy in men, however the molecular events and their interplay underlying prostate carcinogenesis remain poorly understood. Using conditional transgenic mice we show that elevation of Polycomb-group protein Bmi1 induces prostatic intraepithelial neoplasia, and elicits invasive adenocarcinoma when combined with PTEN haploinsufficiency. Consistently, Bmi1 and the PI3K/Akt pathway are co-activated in a substantial fraction of human high-grade tumors. We found that Akt mediates Bmi1 phosphorylation, a posttranslational modification that enhances its oncogenic potential in an Ink4a/Arf-independent manner, modulates DNA damage response, and affects genomic stability. Altogether, our findings demonstrate the etiological role of Bmi1 in PCa, unravel a novel oncogenic collaboration between Bmi1 and PI3K/Akt pathway, and provide mechanistic insights into the modulation of Bmi1 functions by phosphorylation during prostate carcinogenesis.
TITLE:
Akt-mediated phosphorylation of Bmi1 modulates its oncogenic potential, E3 ligase activity, and DNA damage repair activity in mouse prostate cancer
AUTHOR CONTACT:
Maarten van Lohuizen
Netherlands Cancer Institute, Amsterdam, , NLD
Phone: +31205122030; E-mail: m.v.lohuizen@nki.nl
View this article at: http://www.jci.org/articles/view/57477?key=0866de6b120ed97648de
ONCOLOGY Epithelial-mesenchymal transition can suppress major attributes of epithelial tumor-initiating cells
Malignant progression in cancer requires populations of tumor-initiating cells (TICs) endowed with unlimited self-renewal, survival under stress and establishment of distant metastases. Additionally, the acquisition of invasive properties driven by epithelial-mesenchymal transition (EMT) is critical for the evolution of neoplastic cells into fully metastatic populations. Here we characterize cellular models derived from prostate and bladder cancer cell lines in which tumor subpopulations expressing a strong epithelial gene program are enriched in highly metastatic TICs, while a second subpopulation with stable mesenchymal traits is impoverished in TICs. Constitutive overexpression of the transcription factor Snai1 in the epithelial/TIC-enriched populations engaged a mesenchymal gene program and suppressed their self-renewal and metastatic phenotypes. Conversely, knockdown of EMT factors in the mesenchymal-like prostate cancer cell subpopulation caused a gain in epithelial features and properties of TICs. Both tumor cell subpopulations cooperated among them, such that the non-metastatic mesenchymal-like prostate cancer subpopulation enhanced the in vitro invasiveness of the metastatic epithelial subpopulation and, in vivo, promoted the escape of the latter from primary implantation sites and accelerated their metastatic colonization. Our models provide new insights into how dynamic interactions between epithelial, self-renewal and mesenchymal gene programs determine the plasticity of epithelial tumor-initiating cells.
TITLE:
Epithelial-mesenchymal transition can suppress major attributes of epithelial tumor-initiating cells
AUTHOR CONTACT:
Timothy M. Thomson
Institute for Molecular Biology (IBMB-CSIC), Barcelona, UNK, ESP
Phone: +34934020199; Fax: +34934034979; E-mail: titbmc@ibmb.csic.es
View this article at: http://www.jci.org/articles/view/59218?key=6de2585543fad2b15613
MUSCLE BIOLOGY Satellite cell senescence underlies the myopathy in a mouse model of limb girdle muscular dystrophy 2H
Mutations in the E3 ubiquitin ligase TRIM32 are responsible for the disease Limb Girdle Muscular Dystrophy 2H (LGMD2H). Previously, we generated Trim32 knock out mice (Trim32-/-) and showed that they display a myopathic phenotype accompanied by neurogenic features. Here, we utilize these mice to investigate the muscle specific defects that arise from the absence of TRIM32, which underlie the myopathic phenotype. In two models of induced atrophy, we show that TRIM32 is dispensable for muscle atrophy. Conversely, TRIM32 is necessary for muscle regrowth after atrophy. Furthermore, TRIM32-deficient primary myoblasts undergo premature senescence and impaired myogenesis due to accumulation of PIAS4, an E3 SUMO ligase, which is a TRIM32 substrate, previously associated with senescence. Premature senescence of myoblasts was also observed in vivo, using an atrophy/regrowth model. Trim32-/- muscles have substantially fewer activated satellite cells, increased PIAS4 levels, and growth failure, compared to wild type (Trim32+/+) muscles. Moreover, Trim32-/- muscles exhibited features of premature sarcopenia, such as selective type II fast fiber atrophy. These studies imply that premature senescence of muscle satellite cells is an underlying pathogenic feature of LGMD2H and reveal a new mechanism of muscular dystrophy associated with reductions in available satellite cells and premature sarcopenia.
TITLE:
Satellite cell senescence underlies the myopathy in a mouse model of limb girdle muscular dystrophy 2H
AUTHOR CONTACT:
Melissa J. Spencer
David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
Phone: 310 794 5225; Fax: 310 206-1998; E-mail: mspencer@mednet.ucla.edu
View this article at: http://www.jci.org/articles/view/59581?key=72e45f3e0e804928ada2
Journal
Journal of Clinical Investigation