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

H Song; J Hyun Boo; K Ho Kim; C Kim; Y-E Kim; J-H Ahn; G Sun Jeon; H Ryu; D E Kang; I Mook-Jung

doi:10.1038/cdd.2012.162

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

Cell Death Differ. 2013 Apr;20(4):639-48. doi: 10.1038/cdd.2012.162. Epub 2013 Jan 11.

Authors

H Song¹, J Hyun Boo, K Ho Kim, C Kim, Y-E Kim, J-H Ahn, G Sun Jeon, H Ryu, D E Kang, I Mook-Jung

Affiliation

¹ Department of Biochemistry and Biomedical Sciences, WCU neurocytomics, College of Medicine, Seoul National University, Seoul, Korea.

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 γ-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 γ-secretase inhibitors in hPS1 MEFs. Interestingly, the γ-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 γ-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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease / metabolism
Alzheimer Disease / pathology
Amyloid Precursor Protein Secretases / antagonists & inhibitors
Amyloid Precursor Protein Secretases / genetics
Amyloid Precursor Protein Secretases / metabolism*
Animals
Apoptosis / drug effects*
Brain / metabolism
Camptothecin / toxicity*
Carbamates / pharmacology
Cell Line
DNA Damage / drug effects*
Dipeptides / pharmacology
Gene Expression / drug effects
Gene Knockout Techniques
HEK293 Cells
Humans
Leukemia, Promyelocytic, Acute / metabolism
Leukemia, Promyelocytic, Acute / pathology
Mice
Nuclear Proteins / antagonists & inhibitors
Nuclear Proteins / genetics
Nuclear Proteins / metabolism*
Presenilins / deficiency
Presenilins / genetics
Presenilins / metabolism*
Promyelocytic Leukemia Protein
RNA Interference
RNA, Messenger / metabolism
RNA, Small Interfering / metabolism
Signal Transduction
Transcription Factors / antagonists & inhibitors
Transcription Factors / genetics
Transcription Factors / metabolism*
Tumor Suppressor Protein p53 / metabolism
Tumor Suppressor Proteins / antagonists & inhibitors
Tumor Suppressor Proteins / genetics
Tumor Suppressor Proteins / metabolism*
Up-Regulation

Substances

Carbamates
Dipeptides
L 685458
Nuclear Proteins
Pml protein, mouse
Presenilins
Promyelocytic Leukemia Protein
RNA, Messenger
RNA, Small Interfering
Transcription Factors
Tumor Suppressor Protein p53
Tumor Suppressor Proteins
Amyloid Precursor Protein Secretases
Camptothecin