The P75NTR tumor suppressor mediates a bifurcated signal transduction cascade through the NFkB and JNK pathways to inhibit cell survival

Abstract

4971

The p75 neurotrophin receptor (p75NTR) is most abundantly expressed in the nervous system, but is also widely expressed in many other organs and tissues where it primarily functions as a negative regulator of cell survival. In the prostate, p75NTR functions as a tumor suppressor capable of slowing proliferation and inducing apoptosis. Accordingly, the expression of p75NTR in the normal prostate is progressively lost during pathological progression to adenocarcinoma, thereby relieving the tumor cells of p75NTR dependent loss of viability. Although the role of p75NTR in prostate cancer has been well established, the signal transduction pathway that mediates tumor suppressor activity has only been partially elucidated. In this report, we demonstrate that the mechanism of p75NTR dependent signal transduction occurs via a two armed, divergent pathway. Transgenic expression of p75NTR down regulates, in a dose-dependent manner, a bifurcated signaling cascade that results in the reduced expression of the transcription effectors NFκB and JNK. These two arms of signal transduction were directly linked to the proximate p75NTR by the rescue of p75NTR dependent down regulation of the NFκB and JNK signaling cascades using deletion constructs of p75NTR that lacks either the death domain (ΔDD) or a larger intercellular domain (ΔICD) that function as dominant negative antagonists. Both dominant negative p75NTR deletion constructs also rescued tumor cells from p75NTR dependent loss of survival and apoptosis. Conversly, transfection of downstream signaling intermediates in both arms of the pathway with kinase inactive dnIKKβ and dnMEK-4 further reduced expression of NFκB and JNK, respectively, as well as reduced the potential for proliferation (PCNA) and survival of the tumor cells. These results provide a definative link between the proximate p75NTR and a bifurcated signal transduction pathway involving intermediaries that lead to the transcription effectors NFκB and JNK. Additionally, it links the described pathway with the characteristic growth suppression and induction of apoptosis associated with p75NTR expression.