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July 3rd, 2025
Version: 2
Cajal Institute (CSIC)
neuroscience
biorxiv

Resistance of E2F4DN to p38MAPK phosphorylation attenuates DNA damage-induced neuronal death via Cited2

Llabres-Mas, A. M.Open in Google Scholar•Lopez-Sanchez, N.Open in Google Scholar•Garrido-Garcia, A.Open in Google Scholar•Cano-Daganzo, V.Open in Google Scholar•Frade, J. M.Open in Google Scholar

E2F4 is a transcription factor that supports cellular homeostasis and serves as a substrate for the stress-activated kinase p38MAPK, which phosphorylates it at a conserved Thr248/Thr250 motif. A non-phosphorylatable mutant, E2F4DN (Thr248Ala/Thr250Ala), has shown therapeutic efficacy in a murine model of Alzheimer's disease (AD). We hypothesized that phosphorylation of E2F4 disrupts its protective function, whereas E2F4DN retains this activity during cellular stress. To test this hypothesis, we treated N2a-derived neurons with camptothecin (CPT) to induce genotoxic stress. CPT activated p38MAPK within 8 hours, leading to E2F4 phosphorylation at the Thr248/Thr250 site. We then overexpressed E2F4DN or a phosphomimetic variant, E2F4CA (Thr248Glu/Thr250Glu), and assessed apoptosis by procaspase-3 cleavage. E2F1, used as a pro-apoptotic control, strongly induced caspase-3 activation. This effect was partially mimicked by E2F4CA, whereas E2F4DN markedly suppressed caspase-3 cleavage. Notably, E2F4DN but not E2F4CA upregulated the antiapoptotic factor Cited2, and Cited2 knockdown abolished the protective effect of E2F4DN. These findings suggest that p38MAPK-mediated phosphorylation of E2F4 promotes neuronal apoptosis, while E2F4DN maintains homeostatic function via Cited2, offering mechanistic insight into its neuroprotective role in AD.

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