Critical role of presenilin-dependent γ-secretase activity in DNA damage-induced promyelocytic leukemia protein expression and apoptosis

Abstract

Promyelocytic leukemia (PML) is a major component of macromolecular multiprotein complexes called PML nuclear-bodies (PML-NBs). These PML-NBs recruit numerous proteins including CBP, p53 and HIPK2 in response to DNA damage, senescence and apoptosis. In this study, we investigated the effect of presenilin (PS), the main component of the c-secretase complex, in PML/p53 expression and downstream consequences during DNA damage-induced cell death using camptothecin (CPT). We found that the loss of PS in PS knockout (KO) MEFs (mouse embryonic fibroblasts) results in severely blunted PML expression and attenuated cell death upon CPT exposure, a phenotype that is fully reversed by re-expression of PS1 in PS KO cells and recapitulated by c-secretase inhibitors in hPS1 MEFs. Interestingly, the g-secretase cleavage product, APP intracellular domain (AICD), together with Fe65-induced PML expression at the protein and transcriptional levels in PS KO cells. PML and p53 reciprocally positively regulated each other during CPT-induced DNA damage, both of which were dependent on PS. Finally, elevated levels of PML-NB, PML protein and PML mRNA were detected in the brain tissues from Alzheimer's disease (AD) patients, where g-secretase activity is essential for pathogenesis. Our data provide for the first time, a critical role of the PS/AICD-PML/p53 pathway in DNA damage-induced apoptosis, and implicate this pathway in AD pathogenesis. Cell Death and Differentiation (2013) 20, 639-648; doi:10.1038/cdd.2012.162; published online 11 January 2012Promyelocytic leukemia (PML) protein is a well-known tumor suppressor, which functions by its association with PML-nuclear bodies (PML-NBs).1,2 PML regulates a variety of cellular processes such as induction of apoptosis, cellular senescence, inhibition of proliferation, transcription, response to DNA-damage and antiviral response.1,2 PML-NBs, which are spherical shape with a diameter of 0.2-1.0 mm, possess dynamic and heterogeneous structures.1 PML-NBs are present in most mammalian cells' nuclei, numbers that typically range from 5-15 bodies per nucleus depending on the cell type, cell cycle and differentiation stage of the cell. 1As PML KO mice are resistant to proapoptotic stimuli 3 and overexpression of PML prohibits tumor formation in nude mice, 4 the tumor suppressive and pro-apoptotic roles of these structures are well established. Indeed, PML KO cells are protected against both p53-dependent and -independent apoptotic stimuli, such as infrared, interferon, TNF-a and ceramide.5 Moreover, PML has been found to physically associate with critical apoptosis regulators including p53, pRb, c-Jun and Daxx. 6 Our previous studies have shown that genotoxic stressors such as camptothecin (CPT) and etoposide enhance g-secretase activity and Ab generation, 7,8 suggesting that modulation of g-secretase activity is a component of the genotoxic cell death pathway. As presenilin (PS) contains the core catalytic activity within the g-secretase complex, we hypothesized that PS has a key role in mediating...

The Role of Presenilin-1 in the Excitotoxicity of Ethanol Withdrawal

“…PS1 has also been implicated in cell death: the deletion of PS1 in mouse embryonic cells mitigated the cytotoxicity of a DNA-damaging reagent (Song et al, 2013). This phenotype was reversed by re-expression of PS1 (Song et al, 2013), which leads to the assumption that PS1 contributes to cell death. Being a main component of g-secretase, the reduced cell viability associated with PS1 may be attributed to g-secretase.…”

Association of Long Runs of Homozygosity With Alzheimer Disease Among African American Individuals

“…Both loci contain good functional gene candidates. For instance, the locus on Chr15q24.1 includes PML , which is involved in the pathway of presenilin-APP-PML-p53 and overexpressed in AD brain, 33 while the Chr4q31.3 region includes SH3D19 , which is implicated in the regulation of the ADAM family of metalloproteins responsible for α-secretase activity in the amyloid pathway. 34-37 Potentially damaging variations reported in public databases within both consensus regions are presented in eTable 6 in the Supplement.…”

Structural Neuroimaging Genetics Interactions in Alzheimer’s Disease

“…According to previous reports [59], loss of PML appears to affect neurogenesis – it is possible to hypothesize that PML might regulate plasticity and behavior in normal brain function. PML protein and PML mRNA level are upregulated in human AD brains [61]. Recent findings suggest that γ-secretase activity might be upregulated in human AD brains [62].…”

“…p53 could be an important mediator of PS function in apoptotic cell death induced by DNA damage. Increased level of PML protein is also detected in neurons of the temporal cortex of AD brains, where γ-secretase activity is essential for pathogenesis [61]. It may be reasonable to hypothesize that PML expression is elevated in dementia patients.…”