Cell competition is a cell-cell interaction by which a cell compares its fitness to that of neighboring cells. The cell with the relatively lower fitness level is the “loser” and actively eliminated, while the cell with the relatively higher fitness level is the “winner” and survives. Recent studies have shown that cells with high Yes-associated protein (YAP) activity win cell competitions but the mechanism is unknown. Here, we report the unexpected finding that cells overexpressing constitutively active YAP undergo apical extrusion and are losers, rather than winners, in competitions with normal mammalian epithelial cells. Inhibitors of metabolism-related proteins such as phosphoinositide-3-kinase (PI3K), mammalian target of rapamycin (mTOR), or p70S6 kinase (p70S6K) suppressed this apical extrusion, as did knockdown of vimentin or filamin in neighboring cells. Interestingly, YAP-overexpressing cells switched from losers to winners when co-cultured with cells expressing K-Ras (G12V) or v-Src. Thus, the role of YAP in deciding cell competitions depends on metabolic factors and the status of neighboring cells.

We've previously shown that high levels of selenoprotein P (SeP), a major selenoprotein in plasma, can be a risk factor of type 2 diabetes. It was also thought that inhibition of insulin secretion caused by over-supplementation of selenium by SeP to pancreatic β cells contributed to the progress of diabetes. On the other hand, methylmercury, which is an environmental pollutant, is known to cancel the action of selenium via the covalent modification. Therefore, we thought that the interaction between selenium and methylmercury could be associated with the pathogenesis of diabetes. To address the hypothesis, MIN6 cells, a mouse pancreatic β-cell line, were treated with selenocystine (as a selenium donner) and methylmercury then examined insulin release from the cells. Selenocystine (400-1200 nM), which corresponds to the concentration of selenium in SeP of diabetic patients, shows cytotoxicity and inhibited glucose-driven insulin secretion. Methylmercury rescued the cytotoxicity that induced by selenocystine, however it affected the insulin secretion that is depressed by selenocystine at little intense. These data indicate that the mechanisms underlying inhibition of insulin secretion by selenocystine are independent of cytotoxicity, and methylmercury cannot be expected to restore insulin secretion or suppress diabetes as selenium neutlizer.