Abstract
The transcription factor p53 mediates the apoptosis of post-mitotic neurons exposed to a wide range of stress stimuli. The apoptotic activity of p53 is tightly regulated by the apoptosis-stimulating proteins of p53 (ASPP) family members: ASPP1, ASPP2 and iASPP. We previously showed that the pro-apoptotic members ASPP1 and ASPP2 contribute to p53-dependent death of retinal ganglion cells (RGCs). However, the role of the p53 inhibitor iASPP in the central nervous system (CNS) remains to be elucidated. To address this, we asked whether iASPP contributes to the survival of RGCs in an in vivo model of acute optic nerve damage. We demonstrate that iASPP is expressed by injured RGCs and that iASPP phosphorylation at serine residues, which increase iASPP affinity towards p53, is significantly reduced following axotomy. We show that short interference RNA (siRNA)-induced iASPP knockdown exacerbates RGC death, whereas adeno-associated virus (AAV)-mediated iASPP expression promotes RGC survival. Importantly, our data also demonstrate that increasing iASPP expression in RGCs downregulates p53 activity and blocks the expression of pro-apoptotic targets PUMA and Fas/CD95. This study demonstrates a novel role for iASPP in the survival of RGCs, and provides further evidence of the importance of the ASPP family in the regulation of neuronal loss after axonal injury.
Highlights
IASPP is the most evolutionarily conserved member of the ‘Ankyrin-repeat, SH3-domain, and Proline-rich-region containing Protein’ (ASPP) family [1], comprised of ASPP1, ASPP2, and Inhibitor of Apoptosis-Stimulating Protein of p53 (iASPP)
Results iASPP is abundantly expressed by injured retinal ganglion cells (RGCs) but its activity decreases after axonal damage
All RNA binding protein with multiple splicing (RBPMS)-positive neurons were immunoreactive for iASPP (Fig. 1B–F), indicating that adult RGCs are endowed with high levels of constitutive iASPP protein
Summary
IASPP is the most evolutionarily conserved member of the ‘Ankyrin-repeat, SH3-domain, and Proline-rich-region containing Protein’ (ASPP) family [1], comprised of ASPP1, ASPP2, and iASPP. The full-length isoform of iASPP, which is the predominant form of this molecule expressed in cells, was later discovered and shown to carry a C-terminus identical to RAI [3]. ASPP family members have attracted much attention since their implication in a novel mechanism of p53 apoptotic regulation was identified in cancer cells. IASPP was shown to be encoded by the Protein Phosphatase 1 Regulatory Subunit 13-Like (PPP1R13L) gene, which is overexpressed in many tumors including acute leukemia [12], breast cancer [1], glioblastoma [13], ovarian cancer [14], and head and neck squamous cell carcinoma [15]. Due to its potent inhibitory role of p53 apoptotic activity, iASPP function has been studied primarily in cancer cells or in the context of tumor biology. The role of iASPP in neuronal survival and neurodegeneration is not well understood
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