JCI table of contents: April 12, 2007

Individuals who inherit two mutant copies of any one of about 12 genes that make the proteins of the Fanconi Anemia (FA) pathway develop FA, which is characterized by increased incidence of cancer and bone marrow failure, among other things. However, individuals with just a single mutant copy of one of these genes are also at increased risk of developing cancer. This occurs when the remaining "good" copy of the gene becomes mutated in a specific cell type, allowing that cell type to form a tumor. However, hope of a new treatment for these cancers has now been provided by researchers from the Dana-Farber Cancer Institute in Boston who suggest that inhibiting the protein ATM might kill these cancer cells.

In the study, which appears online on April 12 in advance of publication in the May print issue of the Journal of Clinical Investigation, Alan D'Andrea and colleagues show that loss of ATM function in human cell lines with a dysfunctional FA pathway caused the cells to die. The dying cells were characterized by high levels of DNA breakage, which is consistent with the fact that FA pathway proteins and ATM are important regulators of two distinct DNA repair pathways. It therefore seems that the ATM pathway of DNA repair keeps the FA pathway–deficient tumor cells alive and that loss of this pathway results in tumor cell death. As FA pathway–deficient tumor cells were shown to be sensitive to an inhibitor of ATM, the authors suggest that ATM might provide a therapeutic target for the treatment of individuals with FA pathway–deficient tumors.

TITLE: Fanconi anemia pathway–deficient tumor cells are hypersensitive to inhibition of ataxia telangiectasia mutated

AUTHOR CONTACT:
Alan D. D'Andrea
Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Phone: (617) 632-2112; Fax: (617) 632-5757; E-mail: alan_dandrea@dfci.harvard.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=31245

The acid form of vitamin A (retinoic acid; RA) is used to treat a type of leukemia known as acute promyleocytic leukemia (APL). It works by binding to its receptors (retinoic acid receptors, RARs) and driving the leukemic cells to mature and die, rather than remain blocked at a highly proliferative immature stage of development. Researchers from the Fred Hutchinson Cancer Research Center in Seattle have now shown that a protein complex known as CaMKII inhibits RAR activity and that CaMKII inhibitors drive leukemic cells to mature and die, thereby identifying a potential alternative treatment for individuals with RA-sensitive APL.

In the study, which appears online on April 12 in advance of publication in the May print issue of the Journal of Clinical Investigation, Steven Collins and colleagues show that in human myeloid leukemia cell lines the CaMKII CaMKII-gamma interacts with RAR and inhibits its function by phosphorylating RAR-alpha, thereby enhancing the interaction between RAR-alpha and transcriptional corepressors. Furthermore, an inhibitor of CaMKs, KN62, induced myeloid leukemia cell lines to mature, leading the authors to suggest that CaMKII-gamma might provide a new target for the treatment of individuals with RA-sensitive myeloid leukemias.

TITLE: CaMK II regulates retinoic acid receptor transcriptional activity and the differentiation of myeloid leukemia cells

AUTHOR CONTACT:
Steven J. Collins
Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
Phone: (206) 667-4389; Fax: (206) 667-6523; E-mail: scollins@fhcrc.org.

View the PDF of this article at: https://www.the-jci.org/article.php?id=30779

Familial Alzheimer disease (FAD) is an inherited early-onset form of Alzheimer disease. Mutations in the genes that make the proteins presenilin-1 and presenilin-2 have been identified in a substantial proportion of individuals with FAD, but the molecular effects of these mutations have not been clearly defined.

In a study that appears online on April 12 in advance of publication in the May print issue of the Journal of Clinical Investigation, Ilya Bezprozvanny and colleagues from the University of Texas Southwestern, Dallas, used in vitro assays to show that, unlike normal presenilin-1, five of the six FAD-associated mutant forms of presenilin-1 analyzed do not allow calcium to passively leak into the main body of a cell from a compartment known as the ER. For one mutant, the initial observations were corroborated by the observation that fibroblasts from an individual with FAD who expressed this mutant form of presenilin-1 did not passively leak calcium from the ER. As mutant forms of presenilin-1 associated with a distinct neurological disorder, frontal temporal dementia, did not affect calcium leakage from the ER, the authors conclude that the molecular effects of mutant forms of presenilin-1 are disease specific. However, further studies are required to determine whether altered calcium leakage actually causes FAD or is just associated with it.

TITLE: Familial Alzheimer disease–linked mutations specifically disrupt Ca2+ leak function of presenilin 1

AUTHOR CONTACT:
Ilya Bezprozvanny
University of Texas Southwestern Medical Center, Dallas, Texas, USA
Phone: (214) 645-6017; Fax: (214) 645-6018; E-mail: Ilya.Bezprozvanny@UTSouthwestern.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=30447

Mutations in the gene that makes the protein RyR2 have been associated with several forms of aberrant heart function in humans. However, the molecular reasons why these mutations are associated with impaired heart function have not been determined and many questions remain about how this protein is regulated. For example, in vitro studies have shown that a protein known as calmodulin (CaM) inhibits RyR2 function, but the physiological significance of this was not known.

In a study that appears online on April 12, in advance of publication in the May print issue of the Journal of Clinical Investigation, Gerhard Meissner and colleagues from the University of North Carolina at Chapel Hill, found that mice expressing only a mutant form of RyR2 that cannot bind CaM showed signs of cardiac hypertrophy (thickening of the walls of the heart) as early as 1 day after birth and died within 16 days of birth. Further analysis indicated that cardiac muscle cells from these mice showed abnormal release of calcium from a cellular compartment known as the sarcoplasmic reticulum and that the heartbeat of these mice was substantially slower than the heartbeat of normal mice. This study indicates that CaM inhibition of RyR2 is crucial for normal cardiac function in mice, but it will be important to determine whether impaired CaM inhibition of RyR2 is associated with the human heart diseases linked to mutations in the gene that makes RyR2.

TITLE: Early cardiac hypertrophy in mice with impaired calmodulin regulation of cardiac muscle Ca2+ release channel

AUTHOR CONTACT:
Gerhard Meissner
University of North Carolina, Chapel Hill, North Carolina, USA.
Phone: (919) 966-5021; Fax: (919) 966-2852; E-mail: meissner@med.unc.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=29515

The amount of energy available to a cell is controlled by the protein AMPK, which senses when a cell has low levels of energy and triggers the cell to generate more. Mutations in one of the AMPK subunits (gamma-2) leading to increased AMPK activity are associated with heart failure characterized by the accumulation of high levels of the energy source glycogen in heart muscle cells. However, the mechanisms by which these mutations lead to heart failure have not been defined.

In a study that appears online on April 12 in advance of publication in the May print issue of the Journal of Clinical Investigation, Rong Tian and colleagues from Brigham and Women's Hospital, Boston, used mice expressing one of the mutant forms of the gamma-2 AMPK subunit in heart muscle cells to show that increased AMPK activity is associated with altered metabolism in the heart muscle cells. The cells were found to take up an increased amount of glucose and to store this as glycogen, leading to increased amounts of glycogen in the heart muscle cells. This effect of AMPK is of clinical relevance since it suggests that activation of AMPK, which is being considered as a potential treatment for type 2 diabetes, might lead to heart failure.

TITLE: Aberrant activation of AMP-activated protein kinase remodels metabolic network in favor of cardiac glycogen storage

AUTHOR CONTACT:
Rong Tian
Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Phone: (617) 732-6994; Fax: (617) 732-6990; E-mail: rtian@rics.bwh.harvard.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=30658