Hypo-Osmolar Stress Induces p75NTR Expression by Activating Sp1-Dependent Transcription

Abstract

Injury-induced expression of the p75 neurotrophin receptor (p75NTR) in the CNS facilitates neuronal apoptosis and prevents neuronal regrowth, but the mechanisms regulating p75NTR expression are poorly characterized. In this study, we showed that hypo-osmolarity induces p75NTR expression in primary neurons, and, using a comparative genomics approach, we identified conserved elements in the 25 kb upstream sequences of the rat, mouse, and human p75NTR genes. We found that only one of these, a proximal region rich in Sp1 sites, responds to changes in hypo-osmolarity. We then showed that Sp1 DNA binding activity is increased in cells exposed to hypoosmolarity, established that hypo-osmolarity enhanced Sp1 binding to the endogenous p75NTR promoter, and showed that Sp1 is required for p75NTR expression induced by hypo-osmolarity. We examined how Sp1 is regulated to effect these changes and established that Sp1 turnover is strongly inhibited by hypo-osmolarity. We propose that stress-induced Sp1 accumulation that results from reductions in Sp1 turnover rate contributes to injury-induced gene expression.

Neurotrophin receptor p75NTR mediates Huntington’s disease–associated synaptic and memory dysfunction

“…Student's 2-tailed t test was performed; 32 dendrites (AAV-ctl) and 26 dendrites (AAV-p75) from 3 animals per condition were analyzed. that the transcription factor Sp1 drives the expression of p75 NTR upon neuronal injury or distinct stress inducers (32,33). Moreover, Sp1 has been described to be increased in cellular and transgenic models of HD (34).…”

“…We next aimed to determine the molecular mechanism by which mutant huntingtin induces aberrant hippocampal p75 NTR expression. The transcription factor Sp1 has been described to drive expression of p75 NTR under cellular stress conditions (32,33), while upregulation of Sp1 has been described in cellular and mouse models of HD (34). These data prompted us to investigate whether increased p75 NTR expression was related to higher hippocampal Sp1 levels.…”

Nerve growth factor (NGF)-mediated regulation of p75NTR expression contributes to chemotherapeutic resistance in triple negative breast cancer cells

“…For example, p75 NTR expression is induced in neurons after seizure (13,28), ischemia (15,29) and upon hypo-osmolar stress (14,30,31 (30,32), and both of which are activated by NGF (33,34).…”

CASZ1, a candidate tumor-suppressor gene, suppresses neuroblastoma tumor growth through reprogramming gene expression

“…The NGFR promoter constructs were generously provided by Philip Barker. 38 The constructs were transiently transfected into SY5YtetCASZ1 cell line and after 24 h, cells were treated with Tet. After 2 days, cells were harvested, protein isolated and relative luciferase activity assessed using a dual-luciferase reporter assay system (Promega, Madison, WI, USA), the experiments were repeated for three times.…”