A Genetic Screen for Anchorage-Independent Proliferation in Mammalian Cells Identifies a Membrane-Bound Neuregulin

Anchorage-independent proliferation is a hallmark of oncogenic transformation and is thought to be conducive to proliferation of cancer cells away from their site of origin. We have previously reported that primary Schwann cells expressing the SV40 Large T antigen (LT) are not fully transformed in that they maintain a strict requirement for attachment, requiring a further genetic change, such as oncogenic Ras, to gain anchorage-independence. Using the LT-expressing cells, we performed a genetic screen for anchorage-independent proliferation and identified Sensory and Motor Neuron Derived Factor (SMDF), a transmembrane class III isoform of Neuregulin 1. In contrast to oncogenic Ras, SMDF induced enhanced proliferation in normal primary Schwann cells but did not trigger cellular senescence. In cooperation with LT, SMDF drove anchorage-independent proliferation, loss of contact inhibition and tumourigenicity. This transforming ability was shared with membrane-bound class III but not secreted class I isoforms of Neuregulin, indicating a distinct mechanism of action. Importantly, we show that despite being membrane-bound signalling molecules, class III neuregulins transform via a cell intrinsic mechanism, as a result of constitutive, elevated levels of ErbB signalling at high cell density and in anchorage-free conditions. This novel transforming mechanism may provide new targets for cancer therapy

Vigorous physical activity and vagal modulation in young adults

Background: Aerobic exercise leads to reduced sympathetic and increased cardiac vagal modulation, providing an antiarrhythmic effect. The optimal exercise intensity to promote this adaptation remains undefined. The aims of the present investigation were twofold. First, to examine differences in heart rate variability (HRV) measures in participants with different levels of objectively measured physical activity (PA). Second, to identify the characteristic of PA which most influences the cardiac autonomic nervous system (cANS) function in young adults. METHODS: Cross-sectional evaluation of 84 adults examining relationships between PA amount and intensities, measured by accelerometry, cANS function derived from HRV. Groups were created based on tertiles of PA and analysis of covariance was used to assess between-group differences in HRV. Stepwise regression analysis was used to determine the characteristic of PA, which best predicted vagal HRV indices. Results: There were significantly higher levels of vagal HRV indices in the most active group compared with the least active group. Regression analysis revealed that the number of bouts of vigorous PA undertaken was the best predictor of the vagal HRV indices assessed. Conclusion: This study suggests that vagal modulation is enhanced with high levels of PA and that it is the number of bouts of vigorous PA that is most closely associated with cANS function. © 2009 The European Society of Cardiology