Turnover of PPP1R15A mRNA encoding GADD34 controls responsiveness and adaptation to cellular stress.

The integrated stress response (ISR) is a key cellular signaling pathway activated by environmental alterations that represses protein synthesis to restore homeostasis. To prevent sustained damage, the ISR is counteracted by the upregulation of growth arrest and DNA damage-inducible 34 (GADD34), a stress-induced regulatory subunit of protein phosphatase 1 that mediates translation reactivation and stress recovery. Here, we uncover a novel ISR regulatory mechanism that post-transcriptionally controls the stability of PPP1R15A mRNA encoding GADD34. We establish that the 3' untranslated region of PPP1R15A mRNA contains an active AU-rich element (ARE) recognized by proteins of the ZFP36 family, promoting its rapid decay under normal conditions and stabilization for efficient expression of GADD34 in response to stress. We identify the tight temporal control of PPP1R15A mRNA turnover as a component of the transient ISR memory, which sets the threshold for cellular responsiveness and mediates adaptation to repeated stress conditions.

Angiogenesis of Oral Lichen Planus: A possible pathogenetic mechanism

Objective: Oral Lichen Planus (OLP) is a chronic inflammatory disease with an autoimmune inflammatory pathogenesis.The aim of the research is to compare the vascular endothelial growth factor (VEGF) and adhesion ofmolecules in the biopsy samples of patients affected by OLP, in order to research the presence of the angiogeneticphenomenon and to understand its pathogenetic mechanism. Materials and Methods: Thirty OLP patients andthirty healthy subjects were enrolled in a study. The immunohistochemical analysis of the VEGF and vascularendothelialadhesion molecules was carried out by means of primary antibodies and anti-CD34, anti-VEGF, anti-CD106 antigen (VCAM-1) and anti-CD54 antigen (ICAM-1). The statistical significance of the differences waschecked with the Mann-Whitney test (MW test). The level of significance was set to P<0.001. Data analysis wascarried out with StatView 5.0.1 (SAS Institute Inc., Cary, NC). Results: The results reveal the presence of a significantangiogenesis in OLP patients for the VEGF, CD34, CD106 and CD54 (P < 0.001).. The number of vesselsin the biopsies of the patients with OLP (mean±SD: 21.27±4.85), compared with the healthy subjects (mean±SD:4.74±0.97) was significantly more (Mann-Whitney test, P < 0.001). The positive expression rate of VEGF, CD34,VCAM-1 and ICAM-1 in oral lichen samples was 64.2%, 54.3%, 32.5% and 29.7%, respectively. Isolated endothelialcells and newly-formed micro-vessels and endothelial cells with high-immune-positivity to the antibodiesanti-ICAM-1 and anti-VCAM-1 were observed. Conclusions: The results of our immunohistochemical researchshow that a significant neoangiogenesis occurs in oral lichen planus (AU)