EDITOR’S PICK: Therapeutic peptide frees the protein p73 to kill tumor cells
The protein p53 suppresses tumor development by potently inducing tumor cell death, making it an obvious target for anticancer therapeutics. However, this therapeutic approach is confounded by the fact that genetic mutations cause loss or inactivation of p53 in approximately 50% of human cancers. As the p53-related protein p73, which can also induce tumor cell death, is rarely mutated in human cancers, researchers from the Beatson Institute for Cancer Research, United Kingdom, hypothesized that it might represent a more viable target than p53 for the development of broadly applicable anticancer therapeutics.
In the study, which appears online on March 8 in advance of publication in the April print issue of the Journal of Clinical Investigation, Kevin Ryan and colleagues show that a peptide of 37 amino acids in length, which they generated from human p53 (termed 37AA), killed both p53-sufficient and p53-deficient human tumor cell lines. 37AA mediated tumor cell death by binding to the negative regulator of p53-family proteins iASPP and preventing it from repressing the death-inducing function of p73. Furthermore, systemic administration of 37AA to mice with established tumors of human origin (both p53-sufficient and p53-deficient tumors) induced tumor regression in a p73-dependent manner. These data suggest that targeting the p73-mediated pathway of tumor cell death might provide a new avenue of research for the development of anticancer therapeutics.
TITLE: A p53-derived apoptotic peptide derepresses p73 to cause tumor regression in vivo
AUTHOR CONTACT:
Kevin M. Ryan
Beatson Institute for Cancer Research, Glasgow, United Kingdom.
Phone: +44-1413303655; Fax: +44-1419426521; E-mail: k.ryan@beatson.gla.ac.uk.
View the PDF of this article at: https://www.the-jci.org/article.php?id=28920
EDITOR’S PICK: CDX2: a protein that promotes leukemia
Researchers from Harvard Medical School, Boston, have found that most individuals with acute myeloid leukemia (AML) inappropriately express a protein known as CDX2 in their leukemic cells. CDX2 regulates the expression of a number of genes that encode members of the HOX family of proteins, which might provide a new set of targets for the treatment of individuals with AML.
In the study, which appears online on March 8 in advance of publication in the April print issue of the Journal of Clinical Investigation, Stefan Fröhling and colleagues show that the gene encoding CDX2 is expressed in 90% of the patients with AML that they analyzed. Moreover, reducing the amount of CDX2 in human AML cell lines decreased their ability to proliferate, indicating that CDX2 has a causal role in the pathogenesis of AML. Further evidence of this was provided by the observation that mouse hematopoietic cells engineered to express CDX2 were induced to proliferate and were able to cause full-blown AML when transplanted into mice. Expression of CDX2 in the mouse hematopoietic cells induced altered expression of a number of genes that encode HOX family of proteins, leading the authors to conclude that aberrant expression of CDX2 drives the dysregulated HOX gene expression observed in most individuals with AML.
TITLE: The homeobox gene CDX2 is aberrantly expressed in most cases of acute myeloid leukemia and promotes leukemogenesis
AUTHOR CONTACT:
Stefan Fröhling
Brigham and Women’s Hopsital, Harvard Medical School, Boston, Massachusetts, USA
Phone: (617) 355-9085; Fax: (617) 355-9093; E-mail: sfrohling@rics.bwh.harvard.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=30182
PULMONARY: Mesenchymal stem cells are long-term tissue residents
The process of repairing a damaged tissue requires the generation of a new set of the cells that form that tissue. Most tissues contain connective tissue cells and these can be derived from mesenchymal stem cells (MSCs). However, it has not been clearly determined whether MSCs are recruited to a damaged tissue from the bone marrow or whether each tissue has its own population of resident MSCs.
In a study that appears online on March 8 in advance of publication in the April print issue of the Journal of Clinical Investigation, Vibha Lama and colleagues from the University of Michigan, Ann Arbor, show that in transplanted human lungs there is a tissue-resident population of MSCs. Cells that expressed the cell surface molecules known to characterize MSCs and that were able to generate various connective tissue cells were isolated from transplanted human lungs. In cases where the transplant donor and recipient were not of the same sex it was determined that the MSCs were nearly all (97.2% ± 2.1%) of donor origin, indicating that they had persisted in the tissue since the time of transplantation. This study indicates that the lung contains a population of long-lived tissue-resident MSCs, raising the possibility that other organs also have a tissue-resident MSC population.
TITLE: Evidence for tissue-resident mesenchymal stem cells in human adult lung from studies of transplanted allografts
AUTHOR CONTACT:
Vibha N. Lama
University of Michigan Health System, Ann Arbor, Michigan, USA.
Phone: (734) 936-5201; Fax: (734) 936-8266; E-mail: vlama@umich.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=29713
PULMONARY: SPDEF makes the lungs more “asthma-like”
Chronic lung diseases such as asthma and cystic fibrosis are characterized by an increase in the number of cells known as goblet cells and an increase in the production of lung mucous. Although the molecular details of how these changes are regulated are not well defined, a new study by researchers from Cincinnati Children’s Hospital indicates that a protein known as SPDEF has an important role in controlling these processes.
In the study, which appears online on March 8 in advance of publication in the April print issue of the Journal of Clinical Investigation, Jeffrey Whitsett and colleagues show that in vivo expression of SPDEF in mouse lung epithelial cells is increased by IL-13 (a soluble factor associated with asthma) and exposure to dust mite allergens. This increased SPDEF expression was associated with an increase in the number of goblet cells. In vitro, SPDEF was shown to interact with a protein known as TFF-1 and to increase the expression of genes encoding proteins that caused the epithelial cells to become goblet cells and to produce mucous proteins. This study therefore indicates that SPDEF has a crucial role in endowing the lung with the characteristics of chronic lung disease.
TITLE: SPDEF regulates goblet cell hyperplasia in the airway epithelium
AUTHOR CONTACT:
Jeffrey A. Whitsett
Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA.
Phone: (513) 636-4830; Fax: (513) 636-7868; E-mail: jeff.whitsett@cchmc.org.
View the PDF of this article at: https://www.the-jci.org/article.php?id=29176
HEMATOLOGY: SHIP1 in platelets practices first aid
Platelets are cell fragments in the blood that have a central role in regulating hemostasis, the physiologic process whereby bleeding is stopped. Deregulation of platelet function can therefore lead to uncontrolled bleeding or to the formation of thrombi, which can block blood vessels and, in the heart and brain, lead to heart attacks and strokes. In a new study appearing online on March 8 in advance of publication in the April print issue of the Journal of Clinical Investigation, Marie-Pierre Gratacap and colleagues from Toulouse, France, show that in mice, the protein SHIP1 is important for normal hemostasis. Mice lacking SHIP1 bled longer after tail injury and formed smaller thrombi that contained fewer platelets than normal mice. Consistent with these in vivo studies, when platelets from SHIP1-deficient mice were stimulated in vitro they formed smaller aggregates than platelets from normal mice. This study therefore identifies a new function for SHIP1 in regulating platelet function to sustain normal hemostasis.
TITLE: Deficiency of Src homology 2 domain–containing inositol 5-phosphatase 1 affects platelet responses and thrombus growth
AUTHOR CONTACT:
Marie-Pierre Gratacap
Centre de Physiopathologie de Toulouse Purpan et Université Paul Sabatier, Toulouse, France.
Phone: +33-562-74-45-22; Fax: +33-562-74-45-58; E-mail: marie-pierre.gratacap@toulouse.inserm.fr.
View the PDF of this article at: https://www.the-jci.org/article.php?id=29967
Journal
Journal of Clinical Investigation