Modulation of purinergic signaling by NPP-type ectophosphodiesterases

Extracellular nucleotides can elicit a wide array of cellular responses by binding to specific purinergic receptors. The level of ectonucleotides is dynamically controlled by their release from cells, synthesis by ectonucleoside diphosphokinases and ectoadenylate kinases, and hydrolysis by ectonucleotidases. One of the four structurally unrelated families of ectonucleotidases is represented by the NPP-type ectophosphodiesterases. Three of the seven members of the NPP family, namely NPP1–3, are known to hydrolyze nucleotides. The enzymatic action of NPP1–3 (in)directly results in the termination of nucleotide signaling, the salvage of nucleotides and/or the generation of new messengers like ADP, adenosine or pyrophosphate. NPP2 is unique in that it hydrolyzes both nucleotides and lysophospholipids and, thereby, generates products that could synergistically promote cell motility. We review here the enzymatic properties of NPPs and analyze current evidence that links their nucleotide-hydrolyzing capability to epithelial and neural functions, the immune response and cell motility

Decreased Expression of Bmi1 Is Closely Associated with Cellular Senescence in Small Bile Ducts in Primary Biliary Cirrhosis

Cellular senescence of biliary epithelial cells with p16(INK4a) and p21(WAF1/Cip) expression in damaged small bile ducts may be critical for progressive bile duct loss in primary biliary cirrhosis. We investigated the involvement of bmi1, a polycomb group gene repressing p16(INK4a) expression, in the pathogenesis of biliary cellular senescence. Bmi1 expression was examined immunohistochemically in livers taken from the patients with primary biliary cirrhosis (n = 18) and other diseased (n = 19) and normal livers (n = 16). We examined the effect of oxidative stress and a short interference RNA (siRNA) targeting bmi1 on cellular senescence in cultured mouse biliary epithelial cells. Bmi1 was widely expressed in the nuclei of biliary epithelial cells in the control livers. In contrast, bmi1 expression was significantly decreased in damaged small bile ducts in 43% of livers with primary biliary cirrhosis of stage 1/2, coordinating with the increased p16(INK4a) expression. In cultured biliary epithelial cells, oxidative stress by H(2)O(2) treatment significantly decreased bmi1 expression, followed by increased P16(INK4a) expression. A knockdown of bmi1 induced increased p16(INK4a) expression, decreased cell proliferation, and increased cellular senescence. In conclusion, the decreased bmi1 expression caused by oxidative stress may be involved in the pathogenesis of cellular senescence of biliary epithelial cells in primary biliary cirrhosis