EDITOR'S PICK
p53 gene mutations and inflammation trigger skin cancer
Squamous cell carcinoma (SCC) is a form of nonmelanoma skin cancer, which is the most common type of human malignancy with over 1 million new cases in the USA each year. In the July 2 issue of the Journal of Clinical Investigation, two separate studies by research teams at Glasgow University and Baylor College of Medicine uncover 2 previously unidentified regulators of SCC development, providing insights into the development of this potentially lethal disease.
Mutations in the p53 tumor suppressor gene have been implicated in tumor formation: some give rise to a loss-of-function whereas the majority of mutations result in a gain-of-function. In the first of these two studies, Dennis Roop, Carlos Caulin, and colleagues from Baylor College of Medicine, set out to determine whether gain-of-function or loss-of-function mutations in p53 are more critical for SCC development. The authors show that certain p53 mutations occurring in human SCCs demonstrate gain-of-function properties that accelerate the frequency and progression of malignant SCC. Future studies will hopefully discover ways to target these mutations for therapeutic purposes.
A link between skin inflammation and SCC formation was first reported in the 19th century. In the second of these 2 new JCI studies, Robert Nibbs, Gerard Graham, and colleagues from Glasgow University show that the chemokine receptor D6 acts to sequester inflammatory molecules known as chemokines and as such is essential to suppressing the development of skin cancer. They show that D6-deficient mice are acutely sensitive to SCC formation and that D6 expression is induced in cells in close proximity to invasive SCC cells from human oral SCCs. In the absence of D6, skin inflammation sensitizes skin cells to tumor formation.
In an accompanying commentary on these two studies, David Owens from Columbia University in New York comments that “if a heightened inflammatory state in the skin can influence p53 gain-of-function status, this may have important implications for the prognosis of SCCs”.
TITLE: An inducible mouse model for skin cancer reveals distinct roles for gain- and loss-of-function p53 mutations
AUTHOR CONTACT:
Dennis R. Roop
University of Colorado at Denver and Health Sciences Center, Denver, Colorado, USA.
E-mail: dennis.roop@uchsc.edu
Carlos Caulin
MS Anderson Cancer Center, Houston, Texas, USA.
Phone: (713) 794-5603; Fax: (713) 745-2234; E-mail: ccaulin@mdanderson.org
View the PDF of this article at: https://www.the-jci.org/article.php?id=31721
RELATED MANUSCRIPT
TITLE: The atypical chemokine receptor D6 suppresses the development of chemically induced skin tumors
AUTHOR CONTACT:
Robert J.B. Nibbs or Gerard J. Graham
Glasgow University, Glasgow, United Kingdom.
Phone: 44-141-330-3960 (R.N.); Phone: 44-141-330-3982 (G.G.); Fax: 44-141-330-4297; E-mail: r.nibbs@clinmed.gla.ac.uk or g.graham@clinmed.gla.ac.uk
View the PDF of this article at: https://www.the-jci.org/article.php?id=30068
ACCOMPANYING COMMENTARY
TITLE: p53, chemokines, and squamous cell carcinoma
AUTHOR CONTACT:
David M. Owens
Columbia University College of Physicians and Surgeons, New York, New York, USA.
Phone: (212) 851-4544; Fax: (212) 851-4540; E-mail: do2112@columbia.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=32719
BACTERIOLOGY
Neutrophils stand guard against tuberculosis infection
In the July 2 issue of the Journal of Clinical Investigation, Adrian Martineau, Robert Wilkinson, and colleagues from the Wellcome Trust Center for Research in Clinical Tropical Medicine in London report that the activity of white blood cells known as neutrophils is one reason why some individuals exposed to the infectious bacterium Mycobacterium tuberculosis resist developing evidence of tuberculosis (TB) infection for longer than their peers.
The authors studied 189 adults in London that had been in contact with TB and evaluated them for evidence of TB infection. They found that the risk of TB infection was inversely associated with the number of peripheral blood neutrophils in exposed individuals. The ability of whole blood that lacked neutrophils to restrict the growth of M. tuberculosis was impaired 3-fold. The authors went on to show that the neutrophil peptides cathelicidin LL-37 and lipocalin-2 restricted growth of the organism. Together, the data indicate that neutrophils substantially contribute to the innate resistance of an individual to M. tuberculosis infection, and this activity is associated with neutrophil antimicrobial peptides. Further work to identify how these antimicrobial peptides are regulated may facilitate prevention and treatment of TB.
TITLE: Neutrophil-mediated innate immune resistance to mycobacteria
AUTHOR CONTACT:
Adrian R. Martineau or Robert J. Wilkinson
Wellcome Trust Center for Research in Clinical Tropical Medicine, Imperial College London, United Kingdom.
Phone: 44-207-594-3915; Fax: 44-207-594-3894; E-mail: a.martineau@imperial.ac.uk or r.j.wilkinson@imperial.ac.uk
View the PDF of this article at: https://www.the-jci.org/article.php?id=31097
CARDIOLOGY
Mending a broken heart: Dysferlin repairs cardiac cell rupture
Kevin Campell and fellow University of Iowa researchers have shown that a protein known as dysferlin plays a critical role in repairing the plasma membranes of cardiac muscle cells that are torn as a result of strain-induced injury. Inadequate cell membrane repair may be involved in heart failure and muscular dystrophy. Their results appear in the July 2 issue of the Journal of Clinical Investigation.
Given the considerable shape changes that skeletal and heart muscle undergo as part of their natural function, it’s remarkable that muscle cells just don’t tear apart. In fact, cell membrane rupture occurs frequently under normal conditions but to prevent cell death cells have developed mechanisms to reseal ruptured membranes. In this issue of the JCI, Campbell et al. observed that membrane repair is impaired in cardiac muscle cells that lack the protein dysferlin and that stress exercise was sufficient to disturb normal cardiac function in dysferlin-deficient mice. Cardiac damage was even more severe in mice bred by crossing dysferlin-deficient and dystrophin-deficient mice. Lack of dystrophin is involved in muscular dystrophy. While the precise repair mechanism remains unclear, it is thought that dysferlin-carrying repair vesicles are recruited to the rupture site and fuse with the plasma membrane through interaction with proteins known as annexins.
In an accompanying commentary, Jan Lammerding and Richard Lee from Harvard Medical School discuss these results and how mutations that predispose cells to membrane damage or impair the normal repair process cause the accumulation of dying cells in mechanically active tissues, resulting in muscular dystrophies and cardiomyopathy. The discovery of alternative, better-tolerated drugs that can drive the membrane repair process would represent a significant advance.
TITLE: Dysferlin-mediated membrane repair protects the heart from stress-induced left ventricular injury
AUTHOR CONTACT:
Kevin P. Campbell
University of Iowa, Iowa City, Iowa, USA.
Phone: (319) 335-7867 or (319) 335-6978; Fax: (319) 335-6957; E-mail: kevin-campbell@uiowa.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=30848
ACCOMPANYING COMMENTARY
TITLE: Torn apart: membrane rupture in muscular dystrophies and associated cardiomyopathies
AUTHOR CONTACT:
Richard T. Lee
Brigham and Women’s Hospital, Harvard Medical School, Cambridge, Massachusetts, USA.
Phone: (617) 768-8282; Fax: (617) 768-8270; E-mail: rlee@partners.org
View the PDF of this article at: https://www.the-jci.org/article.php?id=32686
CARDIOLOGY
Calcium handling and cardiac arrhythmias: how the beat goes on
In the normal heart, the cycling of intracellular calcium in cardiac muscle cells is critical to the heart’s mechanical contraction and relaxation. Mutations in calcium-handling proteins in the heart have been linked to exercise-induced sudden cardiac death. The best characterized of these have been mutations in the cardiac calcium release channel known as the ryanodine receptor (RyR2), which result in calcium “leak” from the sarcoplasmic reticulum (SR) that can trigger fatal cardiac arrhythmias during stress. In the July 2 issue of the Journal of Clinical Investigation, Jonathan Seidman and colleagues from Harvard Medical School show that mutations in another SR calcium-binding protein, calsequestrin 2 (CASQ2), in mice result not only in reduced CASQ2 expression, but also in a surprising compensatory elevation in both the calcium-binding protein calreticulin and RyR2, culminating in premature release of calcium from cardiac muscle cells, causing stress-induced arrhythmia.
An accompanying commentary by Jonathan Lederer and colleagues from University of Maryland and Ohio State University discusses the pathways involved in calcium signaling in the heart. Mutations in RyR2 or CASQ2 may provide therapeutic targets for the treatment of inherited cardiac arrhythmias.
TITLE: Calsequestrin 2 (CASQ2) mutations increase expression of calreticulin and ryanodine receptors, causing catecholaminergic polymorphic ventricular tachycardia
AUTHOR CONTACT:
Jonathan G. Seidman
Harvard Medical School, Boston, Massachusetts, USA.
Phone: (617) 432-7871; Fax: (617) 432-7832; E-mail: seidman@genetics.med.harvard.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=31080
ACCOMPANYING COMMENTARY
TITLE: Chain-reaction Ca2+ signaling in the heart
AUTHOR CONTACT:
W. Jonathan Lederer
University of Maryland Biotechnology Institute, Baltimore, Maryland, USA.
Phone: (410) 706-8181; Fax: (410) 510-1545; E-mail : lederer@umbi.umd.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=32496
HEMATOLOGY
Hemoglobin production gets a helping hand
Normal human hemoglobin picks up oxygen in the lungs and delivers it to needy cells in order to keep their molecular and cellular engines operating at maximal efficiency. Hemoglobin is comprised of pairs of alpha- and beta-globin chains in combination with heme. Recently, the small alpha hemoglobin–stabilizing protein (AHSP) was identified and found to specifically bind to and stabilize alpha-globin, limiting the toxic effects of excess alpha-globin in the inherited blood disorder beta-thalassemia. In the July 2 issue of the Journal of Clinical Investigation, Mitchell Weiss and colleagues from The Children’s Hospital of Philadelphia show that, in mice, AHSP is important not only for dealing with newly synthesized excess alpha-globin, but also in the assembly and stabilization of normal amounts of hemoglobin, even when alpha-globin is deficient, indicating unique and previously unidentified roles for this molecule.
In an accompanying commentary, Arthur Bank from Columbia University discusses the identification of AHSP as a unique hemoglobin helper and the role it may play in diseases in which alpha- or beta-globin production is altered.
TITLE: An erythroid chaperone that facilitates folding of alpha-globin subunits for hemoglobin synthesis
AUTHOR CONTACT:
Mitchell J. Weiss
The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Phone: (215) 590-0565; Fax: (215) 590-4834; E-mail: weissmi@email.chop.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=31664
ACCOMPANYING COMMENTARY
TITLE: AHSP: a novel hemoglobin helper
AUTHOR CONTACT:
Arthur Bank
Columbia College of Physicians and Surgeons, New York, New York, USA.
Phone: (212) 305-4186; Fax: (212) 923-2090; E-mail : ab13@columbia.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=32362
HEMATOLOGY
Recombinant Hemojuvelin protein: a treatment option for anemia
In the July 2 issue of the Journal of Clinical Investigation, Jodie Babitt and colleagues from Harvard Medical School show that administration of a recombinant form of the protein hemojuvelin (HJV) to mice was able to mobilize iron stored in the spleen to the blood, thereby increasing serum iron levels. This protein or other compounds that modulate this signaling pathway may be useful in treating anemia.
Iron plays an important role in the function of molecules such as hemoglobin that transport oxygen throughout the body. The concentration of iron is tightly regulated by hepcidin, a peptide hormone secreted by the liver. High hepcidin levels result in anemia while decreased hepcidin levels cause iron overload diseases. In this issue of the JCI, Babitt et al. show that injection into mice over a period of weeks of a recombinant form of HJV binds bone morphogenetic proteins (BMPs), acts as an antagonist of BMP, thereby decreasing hepcidin expression and raising liver and serum iron levels.
In an accompanying commentary, Jerry Kaplan from the University of Utah School of Medicine discusses several reasons why these results are important. “First, they suggest the possibility of pharmacological intervention for disorders resulting from excessive hepcidin production, as seen in…anemia. Second, they provide a mechanistic explanation for the role of HJV in iron overload disease.”
TITLE: Modulation of bone morphogenetic protein signaling in vivo regulates systemic iron balance
AUTHOR CONTACT:
Jodie L. Babitt
Harvard Medical School, Boston, Massachusetts, USA.
Phone: (617) 643-3181; Fax: (617) 643-3182; E-mail: jbabitt@partners.org
View the PDF of this article at: https://www.the-jci.org/article.php?id=31342
ACCOMPANYING COMMENTARY
TITLE: Hepcidin regulation: ironing out the details
AUTHOR CONTACT:
Jerry Kaplan
University of Utah School of Medicine, Salt Lake City, Utah, USA.
Phone: (801) 581-7427; Fax: (801) 581-4517; E-mail : jerry.kaplan@path.utah.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=32701
METABOLIC DISEASE
Triggering the autoimmune response against islets in type 1 diabetes
Type 1A diabetes is an autoimmune disease that specifically affects beta cells within the pancreas and researchers have long asked why only certain organs are targeted in autoimmune disease.
In so-called NOD mice (an animal model of type 1 diabetes) T and B cells that infiltrate the pancreatic islets have been shown to target insulin B chain amino acids 9–23 (insulin B:9–23), and NOD mice lacking insulin B:9–23 are protected from diabetes. This suggests that insulin, specifically the insulin B:9–23 sequence, may be essential for the initiation of spontaneous diabetes in NOD mice.
In the July 2 issue of the Journal of Clinical Investigation, George Eisenbarth and colleagues posed the question: In which tissue would expression of the native insulin sequence restore anti-insulin autoimmunity" The authors found that transplanted islet cells, but not bone marrow cells, expressing native B16:Y insulin (tyrosine at position 16 of insulin B chain) restored anti-insulin autoimmunity in mice that lacked native insulin genes. In addition, immunization with the native B16:Y insulin B:9–23 peptide, but not a mutated B16:A insulin B:9–23 peptide (alanine at position 16 of insulin B chain), rendered CD4+ T cells able to rapidly transfer diabetes to these animals when the recipient mouse also had the native B16:Y insulin B:9–23 sequence in its islets. The data demonstrate the dependence on just a single amino acid change (alanine versus tyrosine) in insulin B:9–23 for the development of anti-islet cell autoimmunity in a mouse model of type 1 diabetes.
TITLE: Priming and effector dependence on insulin B:9–23 peptide in NOD islet autoimmunity
AUTHOR CONTACT:
George S. Eisenbarth
University of Colorado Health Sciences Center, Aurora, Colorado, USA.
Phone: (303) 724-6847; Fax: (303) 724-6839; E-mail: george.eisenbarth@uchsc.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=31368
Journal
Journal of Clinical Investigation