M?©jat et al. show that one mechanism involves the disruption of neuromuscular junctions.

The study will appear online on Monday, January 5, 2009 and in the January 12, 2009 print issue of the Journal of Cell Biology.

Muscle fiber cells contain hundreds of nuclei. In normal fibers, several nuclei cluster together under the cell membrane at sites of neuronal contact. These postsynaptic nuclei synthesize the components of the neuromuscular junction that specify the overlying membrane as the target site for innervation. The authors found that LMNA-deficient animals (including those with a point mutation in LMNA that in humans can cause Emery-Dreifuss disease) failed to position nuclei into these postsynaptic clusters. This prevented the proper organization of the neuromuscular junction and disrupted muscle fiber innervation, says author Alexandre M?©jat.

The authors showed that either loss or mutation of LMNA disrupted nuclear positioning by causing the mislocalization of two other proteins: Nesprin-1, which spans the outer nuclear membrane and anchors nuclei to the actin cytoskeleton, and SUN2, which spans the inner nuclear membrane, linking Nesprin to lamin A/C. Although lamin A/C is ubiquitously expressed, LMNA defects specifically affected striated and skeletal muscle because Nesprin-1 and SUN2 are highly expressed in these tissues. Samples from Emery-Dreifuss muscular dystrophy patients exhibit similar hallmarks of skeletal muscle functional denervation, suggesting the authors are on the right track.

rockefeller/RUPress/

AURKA encodes the kinase Aurora A which is dysregulated in multiple types of cancer cells. Interestingly, Aurora A kinase activity was not required for N-Myc stabilization. Instead, elevated Aurora A levels in MYCN-amplified neuroblastoma cells interfered with the PI3-kinase-dependent and mitosis-specific degradation of N-Myc. This suggests that small molecule inhibitors of Aurora A kinase may not be effective at inhibiting the oncogenic functions of Aurora A.

"Our results show that stabilization of N-Myc is a critical oncogenic function of Aurora A in childhood neuroblastoma; the challenge will now be to find ways to interfere with this function in order to find new approaches for the therapy of these tumors," says Dr. Eilers. "The findings also suggest that the current views about why Aurora A is oncogenic may need to be re-evaluated."

cell/Cell/