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 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.

• Authors: 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
• Journal: Cell death and differentiation (Cell Death Differ) Vol. 20 Issue 4 Pg. 639-48 (Apr 2013) ISSN: 1476-5403 [Electronic] England
• PMID: 23306558 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• Alzheimer Disease (metabolism, pathology)
• Amyloid Precursor Protein Secretases (antagonists & inhibitors, genetics, 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, pathology)
• Mice
• Nuclear Proteins (antagonists & inhibitors, genetics, metabolism)
• Presenilins (deficiency, genetics, metabolism)
• Promyelocytic Leukemia Protein
• RNA Interference
• RNA, Messenger (metabolism)
• RNA, Small Interfering (metabolism)
• Signal Transduction
• Transcription Factors (antagonists & inhibitors, genetics, metabolism)
• Tumor Suppressor Protein p53 (metabolism)
• Tumor Suppressor Proteins (antagonists & inhibitors, genetics, metabolism)
• Up-Regulation