Tipping the balance between senescence and proliferation
An arrest in cell proliferation, also referred to as cellular senescence, occurs as a natural result of aging and in response to cellular stress. Senescent cells accumulate with age and are associated with many aging phenotypes, and removal of these cells by the immune system is important for preventing cancer and other disorders. The tumor suppressor p53 coordinates a signaling network that is important for cell arrest. p53 is produced as various isoforms as the result of alternative splicing and promoter usage. One isoform, p53β, accelerates cellular arrest, while another isoform, Δ133p53 represses replicative senescence in cultured cells. In this issue of the Journal of Clinical Investigation, Abdul Mondal and colleagues at the National Cancer Institute evaluated the expression of these two p53 isoforms in T lymphocytes from healthy donors and donors with lung cancer. In healthy patients, the authors observed an age dependent accumulation of senescent cells and that these cells had an increase in p53β compared to Δ133p53. In lung tumor-associated cells, there was a higher level of the Δ133p53 isoform. Furthermore, in senescent cells, expression of Δ133p53 induced replication and proliferation, while induction of p53β in tumor-associated cells promoted senescence. This study defines the contribution of two p53 isoforms to senescence regulation, and suggests that altering the Δ133p53:p53β ratio may be an effect therapeutic strategy for treating immunosenescence disorders.
TITLE: p53 isoforms regulate aging- and tumor-associated replicative senescence in T lymphocytes
AUTHOR CONTACT: Abdul Mondal
Center for Cancer Research, NCI, NIH, Bethesda, MD, USA
Phone: 301-496-7358; Fax: 301-496-0497; E-mail: mondalam@mail.nih.gov
View this article at: http://www.jci.org/articles/view/70355?key=054fc22a1c3c779c7719
Persistent gene therapy in muscle may not require immunosuppression
Successful gene therapy is based on the effective delivery and maintained expression of healthy copies of a gene into tissues of individuals with a disease-associated genetic mutation. Recombinant adeno-associated virus (rAAV) vectors have shown promise in early clinical trials as effective therapies for several genetic diseases, including Leber congenital amaurosis, Parkinson disease, and hemophilia. Unfortunately, delivery of rAAV vectors to tissues other than the retina and CNS often results in development of an immune response against the viral capsid. The development of a neutralizing response against the rAAV vector prevents sustained expression of the healthy gene in the absence of immunosuppression. In this issue of the Journal of Clinical Investigation, Christian Mueller and colleagues at the University of Massachusetts Medical School evaluated the persistence of rAAV-mediated expression the gene encoding M-type α-1 antitrypsin (M-AAT) in patients that were AAT deficient. Patients received multiple intramuscular doses without immunosuppression, and M-ATT expression was evaluated in muscle biopsies. The authors determined that subjects sustained M-ATT expression in muscle tissue for at least one year, despite an initial influx of immune cells. Further evaluation of muscle fibers revealed a substantial population of regulatory T cells in patients with persistent M-ATT expression. Together, the results from this study suggests that delivery of an M-ATT-encoding rAAV vector promotes a regulatory immune response that allows for long term gene expression that does not require immune suppression.
TITLE: Human Treg responses allow sustained recombinant adeno-associated virus–mediated transgene expression
AUTHOR CONTACT: hristian Mueller
UMass Medical School, Worcester, MA, USA
Phone: 5088564358; E-mail: chris.mueller@umassmed.edu
View this article at: http://www.jci.org/articles/view/70314?key=27723e971d599c2f6ce6
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Title: Whole-brain circuit dissection in free-moving animals reveals cell-specific mesocorticolimbic networks
AUTHOR CONTACT: Michael Michaelides
Icahn School of Medicine at Mount Sinai, New York, USA.
Phone: 2128239002; E-mail: michael.michaelides@mssm.edu
View this article at: http://www.jci.org/articles/view/72117?key=6aa20a801c27a6da6766
ACCOMPANYING ARTICLE
TITLE: Impaired periamygdaloid-cortex prodynorphin is characteristic of opiate addiction and depression
AUTHOR CONTACT: Yasmin Hurd
Icahn School of Medicine at Mount Sinai, New York, NY, USA
Phone: 2128249314; E-mail: yasmin.hurd@mssm.edu
View this article at: http://www.jci.org/articles/view/70395?key=fac41744fa3d85cad83b
TITLE: Systems pharmacology identifies drug targets for Stargardt disease–associated retinal degeneration
AUTHOR CONTACT: Krzysztof Palczewski
Case Western Reserve University, Cleveland, OH, USA
Phone: 216-368-4631; E-mail: kxp65@case.edu
View this article at: http://www.jci.org/articles/view/69076?key=93e58d97fb12d4d2be4d
TITLE: Balancing GRK2 and EPAC1 levels prevents and relieves chronic pain
AUTHOR CONTACT: Huijing Wang
Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, , NLD
Phone: +31 88 755 4358; E-mail: hwang@umcutrecht.nl
View this article at: http://www.jci.org/articles/view/66241?key=606cb47333584245d158
TITLE: Impaired periamygdaloid-cortex prodynorphin is characteristic of opiate addiction and depression
AUTHOR CONTACT: Sarah Ann Anderson
Icahn School of Medicine at Mount Sinai, New York, NY, USA
Phone: 2122419975; E-mail: sarahann.anderson@mssm.edu
View this article at: http://www.jci.org/articles/view/70395?key=fac41744fa3d85cad83b
TITLE: Immune response to RB1-regulated senescence limits radiation-induced osteosarcoma formation
AUTHOR CONTACT: David M. Thomas
Peter MacCallum Cancer Center, East Melbourne, UNK, AUS
Phone: +61396561111; Fax: +61396561411; E-mail: david.thomas@petermac.org
View this article at: http://www.jci.org/articles/view/70559?key=a87386390e351e79063b
TITLE: Topical hypochlorite ameliorates NF-κB–mediated skin diseases in mice
AUTHOR CONTACT: Thomas Leung
Stanford University, School of Medicine, Stanford, CA, USA
Phone: 3102108988; E-mail: thomas.leung@gmail.com
View this article at: http://www.jci.org/articles/view/70895?key=1ea46ed9b18966f13390
TITLE: Inhibition of mitochondrial fragmentation diminishes Huntington's disease–associated neurodegeneration
AUTHOR CONTACT: Xin Qi
Case Western Reserve University, Cleveland, , USA
Phone: 2163684459; E-mail: xxq38@case.edu
View this article at: http://www.jci.org/articles/view/70911?key=019d526fef8962547156
TITLE: Inhibition of the TRPC5 ion channel protects the kidney filter
AUTHOR CONTACT: Anna Greka
Massachusetts General Hospital, Charlestown, MA, USA
Phone: (617) 726-9363; Fax: (617) 726-5669; E-mail: greka.anna@mgh.harvard.edu
View this article at: http://www.jci.org/articles/view/71165?key=e26e1234395ef52d73c5
Journal
Journal of Clinical Investigation