Role of low-affinity p75 receptor in nerve growth factor-inducible growth arrest of PC12 cells.

Mutant PC12 cell clones (PC84 cells) were obtained by transfection with nerve growth factor (NGF) cDNA. These cells secreted active NGF, extended short processes, and proliferated faster than the parental PC12 cells. These features are of great interest because the parental PC12 cells cease proliferation and extend long processes when transfected with NGF cDNA. PC84 cells expressed a high level of acetylcholinesterase activity and neurofilament M, which indicates that PC84 cells were differentiated. The inhibition of TrkA by K252a diminished the short processes of PC84 cells but had no effect on their fast proliferation. The expression level of TrkA in PC84 cells was comparable to that in PC12 cells; whereas that of another NGF receptor, p75, was significantly lower. These data suggest that the decrease of p75 contributed to the continuous growth of PC84 cells, which was confirmed by suppressing p75 activity of PC12 cells with the antisense oligonucleotide of p75 or with anti-p75 neutralizing antibody. The treated cells did not cease proliferation in the presence of NGF and extended short processes. Our results suggest that NGF signaling via TrkA affects the differentiation characteristics of PC12 cells but that an additional signaling via p75 is necessary for the growth arrest of the cells.

Ito H ，Nomoto H ，Furukawa S 《JOURNAL OF NEUROSCIENCE RESEARCH》

Growth arrest of PC12 cells by nerve growth factor is dependent on the phosphatidylinositol 3-kinase/Akt pathway via p75 neurotrophin receptor.

We recently isolated mutant PC12 cell clones (PC84 cells) by transfection of PC12 cells with nerve growth factor (NGF) cDNA. These cells secreted active NGF and extended short processes, but proliferated faster than the parental PC12 cells. Because the expression level of p75, a low-affinity receptor for NGF, was significantly low, we suspected that NGF signaling via p75 was necessary for the growth arrest of the PC12 cells, and this was shown to be the case by repressing p75 function in PC12 cells. In this study, we examined the downstream signaling of p75, which would ultimately evoke the growth arrest. NGF is known to induce rapid phosphorylation of MAP kinase and Akt in PC12 cells, whereas in PC84 cells, MAP kinase was phosphorylated but the phosphorylation level of Akt was very low under the serum-free condition. This finding suggested that the low expression level of p75 in PC84 cells was the reason for the low Akt activation. Because Akt is known to be activated via phosphatidylinositol (PI) 3-kinase, we treated PC12 cells with a PI3-kinase inhibitor, Wortmannin, and found these cells did not cease proliferation in the presence of NGF. Furthermore, anti-p75 neutralizing antibody reduced NGF-induced phosphorylation of Akt in PC12 cells under the serum-free condition. Because we had already shown that PC12 cells treated with anti-p75 neutralizing antibody did not cease proliferation in the presence of NGF, these results suggest that NGF activates Akt via p75, which is necessary for the NGF-induced growth arrest of PC12 cells.

Ito H ，Nomoto H ，Furukawa S 《JOURNAL OF NEUROSCIENCE RESEARCH》

Cotransfection of TrkA and p75(NTR) in neuroblastoma cell line (IMR-32) promotes differentiation and apoptosis of tumor cells.

Chen J ，Zhe X 《CHINESE MEDICAL JOURNAL》

Nerve growth factor exerts differential effects on the growth of human pancreatic cancer cells.

Zhu ZW ，Friess H ，Wang L ，Bogardus T ，Korc M ，Kleeff J ，Büchler MW ... -  《CLINICAL CANCER RESEARCH》

Expression levels of the nerve growth factor receptors TrkA and p75 in effusions and solid tumors of serous ovarian carcinoma patients.

Davidson B ，Lazarovici P ，Ezersky A ，Nesland JM ，Berner A ，Risberg B ，Tropé CG ，Kristensen GB ，Goscinski M ，van de Putte G ，Reich R ... -  《CLINICAL CANCER RESEARCH》