Up-regulation of Siah1 by ethanol triggers apoptosis in neural crest cells through p38 MAPK-mediated activation of p53 signaling pathway

Abstract

Seven in absentia homolog 1 (SIAH1) is one of the E3 ubiquitin ligases and plays a key role in regulating target protein degradation. This study was designed to test the hypothesis that Siah1 mediates ethanol-induced apoptosis in NCCs through p38 MAPK-mediated activation of the p53 signaling pathway. We found that exposure of NCCs to ethanol resulted in the increases in the total protein levels of p53 and the phosphorylation of p53 at serine 15. Ethanol exposure also resulted in a significant increase in the phosphorylation of p38 MAPK. Knock-down of Siah1 dramatically reduced the ethanol-induced increase in the phosphorylation of p38 MAPK. Knock-down of Siah1 by siRNA or down-regulation of p38 MAPK by either siRNA or inhibitor significantly diminished ethanol-induced accumulations of p53 and the phosphorylation of p53. In addition, ethanol exposure resulted in a significant increase in the expression of p53 downstream targets and apoptosis in NCCs, which can be significantly diminished by down-regulation of Siah1 with siRNA. Knock-down of p38 MAPK by siRNA also dramatically reduced the ethanol-induced apoptosis. These results demonstrate that Siah1 plays a crucial role in ethanol-induced apoptosis in NCCs and that the up-regulation of Siah1 by ethanol can trigger apoptosis through p38 MAPK-mediated activation of the p53 signaling pathway.

Iron overload induces G1 phase arrest and autophagy in murine preosteoblast cells

“…Additionally, our results showed that expression of p53 was elevated under iron overload (Figure a). When DNA is damaged, activated p38 up‐regulates the transcription of p53 and mediates apoptosis (Yuan et al, ). Furthermore, the activation of p38, up‐regulation of p53, down‐regulation of p‐ERK1/2, and silencing of the mTOR pathway induced autophagy (Figure b).…”

Alcohol‐mediated calcium signals dysregulate pro‐survival Snai2/PUMA/Bcl2 networks to promote p53‐mediated apoptosis in avian neural crest progenitors

“…Normally, Snai2 suppresses PUMA to repress p53 activity, but in this model alcohol overrode any such protections and instead activated p53 to induce these cells' apoptosis. In mouse, alcohol induces p53 and its downstream target PUMA to induce NC apoptosis (Chen et al, ; Yuan et al, ). Although we could not independently validate a role for PUMA, the p53‐mediated apoptosis and dysregulated Snai2/p53 interactions described here are consistent with and extend that work.…”

“…It was surprising that these cells were vulnerable to alcohol‐induced apoptosis, given their elevated Snai2 content, and this could be explained because p53 remained elevated and was not down‐regulated when migration commenced (Rinon et al, ). P53 is a transcriptional effector that promotes apoptosis in response to cellular stress, and alcohol induces p53 in diverse cell lineages including developing neurons (Anthony, Zhou, Ogawa, Goodlett, & Ruiz, ; Derdak et al, ; Pani et al, ) and mouse NC (Chen et al, ; Yuan et al, ). The elevated p53 protein documented here is consistent with those reports.…”

“…In summary, we report here that alcohol disrupts the regulatory loop between Snai2 and p53 that normally provides tight control on NC expansion, survival, and migration. Alcohol's effects on NC are complex, and in addition to its suppression of sonic hedgehog signaling during head process formation (Lipinski et al, ), this dysregulation contributes to the facial deficits caused by PAE through the activation of p53 (Chen et al, ; Yuan et al, ). As Snai2, p53, and MDM2 are also oncogenes with crucial roles in transformation and metastasis, alcohol's dysregulation of these signals across multiple cell lineages (Elamin et al, ; Forsyth et al, ; Ward et al, , and herein) have larger implications for the mechanisms underlying alcohol‐related pathologies and tumor progression.…”

“…Snai1/2 promotes delamination and cell cycle withdrawal through repression of the cell‐adhesion protein E‐cadherin (Thiery et al, ) and CyclinD1/D2 (Vega et al, ), respectively. Because delamination normally promotes p53‐mediated apoptosis in nonmigratory populations, Snai1/2 promotes cell survival during EMT by controlling proteins that govern p53 activity and Bcl2 stability, such as PUMA, ATM, and PTEN (Kim et al, ; Kurrey et al, ; Wu et al, ), several of these are dysregulated by alcohol (Chen, Liu, Feng, Wu, & Chen, ; Derdak et al, ; Yuan et al, ). For NC, targeted Snai1/2 overexpression promotes their specification and cellular expansion (Aybar, Nieto, & Mayor, ; Del Barrio & Nieto, ; LaBonne & Bronner‐Fraser, ), whereas Snai2 loss‐of‐function reduces both NC numbers and migration (Aybar et al, ; Carl, Dufton, Hanken, & Klymkowsky, ; LaBonne & Bronner‐Fraser, ).…”