The p75{sup NTR} mediates a bifurcated signal transduction cascade through the NF{kappa}B and JNK pathways to inhibit cell survival
- Department of Cell Biology, Georgetown University Medical School, 202 Med-Dent Building, 3900 Reservoir Road, NW, Washington, DC 20057-1436 (United States)
- Department of Cell Biology, Georgetown University Medical School, 202 Med-Dent Building, 3900 Reservoir Road, NW, Washington, DC 20057-1436 (United States) Vincent T. Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057-1436 (United States)
p75{sup NTR} 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, p75{sup NTR} functions as an inhibitory protein capable of slowing proliferation and inducing apoptosis. It has been shown that p75{sup NTR} is expressed in the normal prostate, progressively lost from malignant tumor cells in vivo, and largely absent from prostate cancer cell lines derived from metastases. Although the role of p75{sup NTR} in prostate cancer has been well established, the signal transduction pathway that mediates its inhibitory activity has only been partially elucidated. This study demonstrates that exogenous expression of p75{sup NTR} down-regulates, in a dose-dependent manner, a bifurcated signaling cascade that results in reduced expression of potent transcription effectors. This two-arm signal transduction cascade was directly linked to the upstream receptor by using dominant-negative deletion constructs of p75{sup NTR} that rescued tumor cells from p75{sup NTR}-induced loss of survival and promotion of apoptosis. Furthermore, the dominant negatives rescued alterations in the levels of signal transduction intermediates. Conversely, the use of kinase-inactive intermediates that are downstream of the receptor further reduced expression of involved transcription effectors and reduced survival of the cells. These results provide a definitive link between the proximate p75{sup NTR} and signal transduction intermediates leading to the transcription effectors NF{kappa}B and JNK, with associated growth suppression and induction of apoptosis.
- OSTI ID:
- 20717548
- Journal Information:
- Experimental Cell Research, Vol. 304, Issue 1; Other Information: DOI: 10.1016/j.yexcr.2004.10.020; PII: S0014-4827(04)00654-8; Copyright (c) 2004 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); ISSN 0014-4827
- Country of Publication:
- United States
- Language:
- English
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