Ras regulates kinesin 13 family members to control cell migration pathways in transformed human bronchial epithelial cells.

We show that expression of the microtubule depolymerizing kinesin KIF2C is induced by transformation of immortalized human bronchial epithelial cells (HBEC) by expression of K-Ras(G12V) and knockdown of p53. Further investigation demonstrates that this is due to the K-Ras/ERK1/2 MAPK pathway, as loss of p53 had little effect on KIF2C expression. In addition to KIF2C, we also found that the related kinesin KIF2A is modestly upregulated in this model system; both proteins are expressed more highly in many lung cancer cell lines compared to normal tissue. As a consequence of their depolymerizing activity, these kinesins increase dynamic instability of microtubules. Depletion of either of these kinesins impairs the ability of cells transformed with mutant K-Ras to migrate and invade matrigel. However, depletion of these kinesins does not reverse the epithelial to mesenchymal transition (EMT) caused by mutant K-Ras. Our studies indicate that increased expression of microtubule destabilizing factors can occur during oncogenesis to support enhanced migration and invasion of tumor cells.

NeuroD1 regulation of migration accompanies the differential sensitivity of neuroendocrine carcinomas to TrkB inhibition.

The developmental transcription factor NeuroD1 is anomalously expressed in a subset of aggressive neuroendocrine tumors. Previously, we demonstrated that TrkB and neural cell adhesion molecule (NCAM) are downstream targets of NeuroD1 that contribute to the actions of neurogenic differentiation 1 (NeuroD1) in neuroendocrine lung. We found that several malignant melanoma and prostate cell lines express NeuroD1 and TrkB. Inhibition of TrkB activity decreased invasion in several neuroendocrine pigmented melanoma but not in prostate cell lines. We also found that loss of the tumor suppressor p53 increased NeuroD1 expression in normal human bronchial epithelial cells and cancer cells with neuroendocrine features. Although we found that a major mechanism of action of NeuroD1 is by the regulation of TrkB, effective targeting of TrkB to inhibit invasion may depend on the cell of origin. These findings suggest that NeuroD1 is a lineage-dependent oncogene acting through its downstream target, TrkB, across multiple cancer types, which may provide new insights into the pathogenesis of neuroendocrine cancers.

Effects of monensin on ruminal forage degradability and total tract diet digestibility in lactating dairy cows during grain-induced subacute ruminal acidosis.

The effects of monensin premix supplementation on ruminal pH characteristics and forage degradability, and total tract diet digestibility during grain-induced subacute ruminal acidosis (SARA) in lactating dairy cows receiving a total mixed ration were investigated. Six multiparous, rumen-fistulated Holstein cows were used in a 2-treatment, 2-period (5 wk per period) crossover design. During wk 5 (d 29 to 35) of each period, SARA was induced using a grain challenge model, and ruminal pH was measured continuously using indwelling pH probes. Ruminal degradation of corn silage and alfalfa haylage was determined using the in situ (nylon bag) technique, and total tract diet digestibility was determined by total fecal collection during wk 5. Monensin supplementation did not affect dry matter intake, milk yield, and composition, and ruminal pH characteristics under these experimentally induced SARA conditions. Rates of ruminal forage fiber degradability were similar between control and monensin-treated cows; however, monensin supplementation increased total tract fiber digestion. This study indicates that monensin altered total tract nutrient digestion by increasing fiber digestion at postruminal sites.