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Archive - Feb 22, 2010


It’s Not Magic—Merlin Works in Nucleus

According to previous models, the tumor suppressor protein Merlin, encoded by the neurofibromatosis type 2 (NF2) gene, inhibits mitotic signaling at or near the cell membrane. However, in the cover story of the February 19, 2010 issue of Cell, researchers present evidence supporting the proposal that Merlin actually suppresses tumorigenesis by translocating to the nucleus where it binds to the E3 ubiquitin ligase CRL4DCAF1 and inhibits its ability to ubiquitylate target proteins. The researchers stated that multiple converging lines of evidence now indicate that Merlin's inhibition of CRL4DCAF1 activity is required to induce growth arrest and suppress tumorigenesis. Notably, the scientists showed that the tumor-derived mutations in NF2 that they examined invariably disrupted Merlin’s ability to interact with or inhibit CRL4DCAF1. This represents a new mechanism for the production of certain tumors in the brain. These tumors occur in a range of cell types, including Schwann cells. Schwann cells produce the sheaths that surround and insulate neurons. The tumors most often occur spontaneously, but can also occur in significant numbers as part of the inherited disease NF2. In NF2, the sheer number of tumors can overwhelm a patient, often leading to severe disability and eventually death. Patients can suffer from 20 to 30 tumors at any one time, and the condition typically affects older children and young adults. No therapy, other than invasive (radio) surgery which is aimed at a single tumor and which may not eradicate the full extent of the tumors, exists. NF2 is estimated to affect one in every 2,500 people worldwide. It can affect any family, regardless of past history, through gene mutation, and currently there is no cure. Dr.

Calcineurin Critical to Healthy Heart Function

Researchers have reported the first-ever data to show that the enzyme calcineurin is critical to controlling normal development and function of heart cells, and that loss of the protein leads to heart problems and death in genetically modified mice. The near total absence of calcineurin in these experimental mice led to heart arrhythmia, failure, and death, according to the research team. This report was selected as the paper of the week for the February 26, 2010 issue of the Journal of Biological Chemistry and was published online on February 19. Calcineurin is a protein phosphatase that is uniquely regulated by sustained increases in intracellular calcium ions following signal transduction events. Calcineurin is known to control cellular proliferation, differentiation, apoptosis, and inducible gene expression following stress and neuroendocrine stimulation. In the adult heart, calcineurin has earlier been shown to regulate hypertrophic growth of cardiomyocytes in response to pathologic insults that are associated with altered Ca2+ handling. It was previously known that calcineurin is important to heart function, but the extent of its role had not been defined prior to the current study. Although the current research involved mice, it nevertheless offers important insights for future studies that could lead to new approaches in diagnosis and treatment of heart patients, said Dr. Marjorie Maillet, the study's lead author and a researcher in the laboratory of senior author Dr. Jeffery Molkentin, at the Cincinnati Children’s Hospital Medical Center. In their work, the researches determined that calcineurin signaling is directly linked to the proper control of cardiac contractility, rhythm, and the expression of Ca2+-handling genes in the heart.