Under conditions of stress, molecular mechanisms stop cells from consuming their source of energy, ATP, and trigger them to begin to produce ATP. This is done by inducing cells to stop any biochemical pathways that use energy and by turning on processes that take up glucose and free fatty acids from their surroundings in order to rebuild their ATP reservoir. The main protein involved in this switch is called AMP-activated protein kinase (AMPK). One situation of obvious energy stress on cells is during a heart attack. Lawrence Young and colleagues at Yale University School of Medicine, have now investigated the biological importance of AMPK during heart trauma in mice, and find that AMPK is vital for protecting cells under conditions of a heart attack. The authors used a transgenic mouse that had an inactivated AMPK and found that under normal circumstances the hearts of these mice and those of wild-type mice were generally similar in form and function. These mutant mice did have slightly lower diastolic pressure in the left ventricle. Upon reduction of blood flow to the heart, to simulate a heart attack, they found that the mice without a functioning AMPK could not stimulate glucose uptake, although the molecular mechanisms for glucose uptake were intact, nor did they breakdown fatty acids to replenish ATP. Once blood flow returned, contractile function in the left ventricle of the mutant mice was impaired. The authors found that there was an increased amount of cell death in these tissues, both through necrosis and programmed cell death, called apoptosis. These data indicate that AMPK is responsible for altering cellular mechanisms for energy in the heart and plays an important protective role during and after a heart attack. The identification of novel AMPK targets and/or the possible use of AMPK activators may be useful in providing therapy for healing during or after a heart attack.
A related commentary in this issue by D. Grahame Hardy from the University of Dundee places these data in the context of what is currently understood about the molecular mechanisms for altering energy use under conditions of stress and how these finding might provide new directions for therapy in heart disease.
TITLE: AMP-activated protein kinase mediates ischemic glucose uptake and prevents postischemic cardiac dysfunction, apoptosis, and injury
AUTHOR CONTACT:
Lawrence H. Young Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA
Phone: (203) 785-4102; Fax: (203) 785-7567; E-mail: lawrence.young@yale.edu
View the PDF of this article at: https://www.the-jci.org/press/19297.pdf
ACCOMPANYING COMMENTARY: AMP-activated protein kinase: the guardian of cardiac energy status
AUTHOR CONTACT:
D. Grahame Hardie University of Dundee, Dow Street, Dundee, DD1 5EH, Scotland,
UK
Phone: 44-1382-344253; Fax: 44-1382-345783; E-mail: d.g.hardie@dundee.ac.uk
View the PDF of this article at: https://www.the-jci.org/press/22683.pdf
Progress in Breast Cancer Progression
Breast cancer is the most common cancer among women and the second leading cause of cancer death among women. The prognosis for cancer patients is related to the stage of the tumor. The latter stages are the most deadly as the tumors have become metastatic, meaning they have become mobile and are able to invade other tissues in the body. Understanding how tumors progress from early to later stages is essential for devising appropriate therapies. Thomas Wirth and colleagues, from Ulm University in Germany, used a breast cancer model system to show that a protein called NF-kB, which works in the cell by turning on a variety of other genes, is involved in tumor progression when its activity in the cell is altered. The authors showed that NF-kB is essential for the initial transition stage called epithelial-mesenchymal transition, which is thought to be important for allowing tumors to be able to invade other tissues. Using a cell line that would undergo this transition when given a growth factor, the authors showed that when NF-kB activity was blocked, these cells could not undergo the transition. Furthermore, if the NF-kB pathway was over-activated, the cells no longer required the addition of the growth factor to transition, but instead would spontaneously undergo the epithelial-mesenchymal transition. Further, inhibiting NF-kB after transition had already occurred caused these cells to revert back to their original state. To test this in a living model, the authors blocked the NF-kB pathway in nude mice that were injected with breast cancer cells. Under these conditions, these breast cancer cells were unable become metastatic, unlike those that were injected in nude mice where the NF-kB pathway was not blocked. Taken together, these data provide evidence for an essential role of NF-kB in the induction and maintenance of the transition that cancer cells undergo to become invasive and mark the NF-kB pathway as a potential anti-metastatic therapeutic target.
TITLE: NF-kB is essential for epithelial-mesenchymal transition and metastasis in a model of breast cancer progression
AUTHOR CONTACT:
Thomas Wirth Ulm University, Albert-Einstein-Allee 11, D-89081 Ulm, Germany
Phone: 49-731-500-23270; Fax: 49-731-500-22892; E-mail: thomas.wirth@medizin.uni-ulm.de
View the PDF of this article at: https://www.the-jci.org/press/21358.pdf
MICs Shed Light on Prostate Cancer
The body's immune system has built in anti-tumor mechanisms. In order for cancers to form, one of the molecular steps that must occur is for the tumor cells to develop the means to avoid being attacked by this defense mechanism. There are several different methods by which the immune system can eradicate tumors early in their development. One tumor immune surveillance mechanism utilizes the fact that a specific molecule, the MHC class I chain–related molecule (MIC), is often expressed on the surface of some tumor cells. MICs interact with the immune system's natural killer cells and trigger them to destroy the tumor cells. Jennifer Wu and colleagues, at the University of Washington, now investigate how prostate cancers evade this anti-tumor defense strategy. The researchers found that MIC-expressing prostate cancer cell lines were able to activate natural killer cells, thus, initially, this defense mechanism appeared intact. Analysis of prostate tumor biopsies showed that the cell surface localization of MIC was highest in early-stage tumors. The researchers noted that tumors from later-stage patients, however, could no longer activate natural killer cells, and that there were high levels soluble MIC in the blood serum of these patients. These data showed that the later stage tumors were shedding the MIC from their cell surfaces, and that this was the means by which prostate cancer cells could overcome this particular form of immune surveillance. The deficiency in the ability to activate natural killer cells could be overcome in tissue culture by stimulating the cells with the cytokine IL-2 or IL-15. The authors further investigated how soluble MIC level in serum related to prostate-specific antigen (PSA); PSA measurements are used as a biomarker for the presence of prostate cancer. Soluble MIC serum levels did not correspond with PSA serum levels, but they were highly correlative with high-grade and invasive tumor status in prostate cancer patients. This work indicates that development of the means to evade the MIC activated immune surveillance system may be a mechanism for prostate cancer progression, that soluble MIC measurement may be a useful biomarker for disease progression, and that cytokine treatment may aid in reestablishing natural killer cell anti-tumor activity.
TITLE: Prevalent expression of the immunostimulatory MHC class I chain–related molecule is counteracted by shedding in prostate cancer
AUTHOR CONTACT:
Jennifer D. Wu University of Washington, 325 9th Ave., Seattle, WA 98104, USA
Phone: (206) 341-5349; Fax: (206) 341-5302. E-mail: wuj@u.washington.edu
View the PDF of this article at: https://www.the-jci.org/press/22206.pdf
Having an Affinity for Diabetes
Insulin autoantibodies (IAAs) are often the first antibodoies directed against self that are recognized in the natural history of childhood diabetes. Not all IAA-positive children, however, go on to develop additional autoantibodies against antigens from pancreas islet cells and, from there, progress to type 1 diabetes mellitus (T1DM). In a standard immune response, antibody maturation through repeated exposure to antigen results in increased antibody affinity. Ezio Bonifacio and colleagues, from the Diabetes Research Institute in Germany, analyzed IAA affinity in IAA-positive samples from children of the BABYDIAB cohort to examine the relationship of antibody affinity to development of T1DM. Using a competitive radiobinding assay, the authors found that the presence of high-affinity IAAs in a sample correlated with the individual having HLA DRB1*04 and subsequently developing multiple islet autoantibodies and T1DM. In examining epitope specificity, they further found that high- and low-affinity IAAs were reactive with different insulin epitopes and that high-affinity IAAs were reactive with (pro)insulin, while low-affinity antibodies were not. The findings here indicate that early exposure to (pro)insulin may be important for disease pathology and that relative IAA affinity and epitope reactivity may be useful in classifying islet cell autoimmunity stages and establishing diabetes risk.
TITLE: Mature high-affinity immune responses to (pro)insulin anticipate the autoimmune cascade that leads to type 1 diabetes
AUTHOR CONTACT:
Ezio Bonifacio Diabetes Research Institute, Kölner Platz 1, 80804 Munich, Germany
Phone: 49-89-3079-3121; Fax: 49-89-3081-733; E-mail: Ezio.Bonifacio@lrz.uni-muenchen.de
View the PDF of this article at: https://www.the-jci.org/press/21307.pdf
Collecting Duct Collects ET-1 Data
Endothelin-1 (ET-1) is thought to play an important role in regulating Na reabsorption. Many of the biological details of ET-1 activity have been defined in vitro, while conclusive physiological data from in vivo studies have been limited by the lethality of ET-1–knockout mice and by an inability to discriminate between ET-1 effects in the nephron and those in the vasculature in conditional mutants. Donald Kohan and colleagues, from the University of Utah Health Sciences Center, have now created a mouse model in which ET-1 is selectively disrupted in the collecting duct (CD) and investigated its physiological importance. These mice, when fed a normal Na diet, were hypertensive, but their body weight, Na excretion, urinary aldosterone excretion and plasma renin activity were similar to those in wild-type mice. When the mice were given a high-Na diet, hypertension worsened, but they additionally had excessive weight gain and reduced Na excretion, which indicates that ET-1 affects salt retention under Na-loading conditions. Treatment of normal- or high-Na–diet mice with the natriuretic agents amiloride or furosemide reduced blood pressure and alleviated Na retention, which suggests that CD-derived ET-1 regulates Na reabsorption through inhibition of tubule Na reabsorption. These data define an important physiological role for CD-derived ET-1 in regulating systemic blood pressure and renal Na excretion.
TITLE: Collecting duct–specific knockout of endothelin-1 causes hypertension and sodium retention
AUTHOR CONTACT:
Donald E. Kohan University of Utah Health Sciences Center, Salt Lake City, UT 84132, USA
Phone: (801) 581-6709; Fax: (801) 581-4343; E-mail: donald.kohan@hsc.utah.edu
View the PDF of this article at: https://www.the-jci.org/press/21064.pdf
OTHER PAPERS IN THIS ISSUE
Bone Differentiation Gets NFAT
TITLE: Critical roles of c-Jun signaling in regulation of NFAT family and RANKL-regulated osteoclast differentiation
AUTHOR CONTACT:
Riko Nishimura Osaka University Graduate School of Dentistry, 1-8 Yamadaoka, Suita, Osaka 565-0871, Japan
Phone: 81-6-6879-2887; Fax: 81-6-6879-2890; E-mail: rikonisi@dent.osaka-u.ac.jp
View the PDF of this article at: https://www.the-jci.org/press/19657.pdf
ACCOMPANYING COMMENTARY: RANKing c-Jun in osteoclast development
AUTHOR CONTACT:
Steven L. Teitelbaum Washington University School of Medicine, 660 South Euclid Ave., St.
Louis, MO 63110, USA
Phone: (314) 454-8463; Fax: (314) 454-5505; E-mail: teitelbs@path.wustl.edu
View the PDF of this article at: https://www.the-jci.org/press/22644.pdf
Spontaneity in Arthritis
TITLE: Distinct contribution of IL-6, TNF-alpha, IL-1, and IL-10 to T cell–mediated spontaneous autoimmune arthritis in mice
AUTHOR CONTACT:
Shimon Sakaguchi Kyoto University, 53 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan Phone: 81-75-751-3888; Fax: 81-75-751-3820; E-mail: shimon@frontier.kyoto-u.ac.jp
View the PDF of this article at: https://www.the-jci.org/press/21795.pdf
ACCOMPANYING COMMENTARY: The T cell cometh: interplay between adaptive immunity and cytokine networks in rheumatoid arthritis
AUTHOR CONTACT:
Gary S. Firestein University of California San Diego School of Medicine, 9500 Gilman Dr., La Jolla, CA 92093-0656, USA
Phone: (858) 822-0480; Fax: (858) 534-2359; E-mail: gfirestein@ucsd.edu
View the PDF of this article at: https://www.the-jci.org/press/22651.pdf
Instability in Immunogenicity
TITLE: Poor immunogenicity of a self/tumor antigen derives from peptide–MHC-I instability and is independent of tolerance
AUTHOR CONTACT:
Nicholas P. Restifo National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA Phone: (301) 496-4904; Fax: (301) 496-0011; E-mail: Nicholas_Restifo@nih.gov
View the PDF of this article at: https://www.the-jci.org/press/21695.pdf
ACCOMPANYING COMMENTARY: Immune recognition of self in immunity against cancer
AUTHOR CONTACT:
Alan N. Houghton Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10021, USA
Phone: (212) 639-7595; Fax: (212) 794-4352; E-mail: a-houghton@ski.mskcc.org
View the PDF of this article at: https://www.the-jci.org/press/22685.pdf
Galling Gallstones
TITLE: Targeted disruption of the murine cholecystokinin-1 receptor promotes intestinal cholesterol absorption and susceptibility to cholesterol cholelithiasis
AUTHOR CONTACT:
Martin C. Carey Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA
Phone: (617) 732-5822; Fax: (617) 730-5807; E-mail: mccarey@rics.bwh.harvard.edu
View the PDF of this article at: https://www.the-jci.org/press/16801.pdf
Targeting Cardiovascular Disease
TITLE: Apolipoprotein A-I is a selective target for myeloperoxidase-catalyzed oxidation and functional impairment in subjects with cardiovascular disease
AUTHOR CONTACT:
Stanley L. Hazen Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, OH 44195, USA
Phone: (216) 445-9763; Fax: (216) 444-9404; E-mail: hazens@ccf.org
View the PDF of this article at: https://www.the-jci.org/press/21109.pdf
For Sonic Hedgehog, Timing is Everything
TITLE: Temporal perturbations in sonic hedgehog signaling elicit the spectrum of holoprosencephaly phenotypes
AUTHOR CONTACT:
Jill A. Helms Stanford University, 257 Campus Dr., Stanford, CA 94305, USA
Phone: (650) 736-0919; Fax: (650) 736-4374; E-mail: jhelms@stanford.edu
View the PDF of this article at: https://www.the-jci.org/press/19596.pdf
The Fox in the Insulin Coop
TITLE: Foxa2 regulates multiple pathways of insulin secretion
AUTHOR CONTACT:
Klaus H. Kaestner University of Pennsylvania Medical School, 415 Curie Blvd., Philadelphia, PA 19104, USA
Phone: (215) 898-8759; Fax: (215) 573-5892; E-mail: kaestner@mail.med.upenn.edu
View the PDF of this article at: https://www.the-jci.org/press/21149.pdf
Getting Specific with Burkitt Lymphoma
TITLE: Critical role of EBNA1-specific CD4+ T cells in the control of mouse Burkitt lymphoma in vivo
AUTHOR CONTACT:
Rong-Fu Wang Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
Phone: (713) 798-1244; Fax: (713) 798-1263; E-mail: rongfuw@bcm.tmc.edu
View the PDF of this article at: https://www.the-jci.org/press/22053.pdf
Warning: This document and the Journal of Clinical Investigation papers to which it refers, may contain information that is price sensitive with respect to publicly quoted companies. Anyone dealing in securities using information contained within this document or within advance copies of the JCI, may be guilty of insider trading under the US Securities Exchange Act of 1934.
Journal
Journal of Clinical Investigation