PMID- 16354677
OWN - NLM
STAT- MEDLINE
DCOM- 20060329
LR  - 20220330
IS  - 0270-7306 (Print)
IS  - 1098-5549 (Electronic)
IS  - 0270-7306 (Linking)
VI  - 26
IP  - 1
DP  - 2006 Jan
TI  - Inhibition of SIRT1 catalytic activity increases p53 acetylation but does not 
      alter cell survival following DNA damage.
PG  - 28-38
AB  - Human SIRT1 is an enzyme that deacetylates the p53 tumor suppressor protein and 
      has been suggested to modulate p53-dependent functions including DNA 
      damage-induced cell death. In this report, we used EX-527, a novel, potent, and 
      specific small-molecule inhibitor of SIRT1 catalytic activity to examine the role 
      of SIRT1 in p53 acetylation and cell survival after DNA damage. Treatment with 
      EX-527 dramatically increased acetylation at lysine 382 of p53 after different 
      types of DNA damage in primary human mammary epithelial cells and several cell 
      lines. Significantly, inhibition of SIRT1 catalytic activity by EX-527 had no 
      effect on cell growth, viability, or p53-controlled gene expression in cells 
      treated with etoposide. Acetyl-p53 was also increased by the histone deacetylase 
      (HDAC) class I/II inhibitor trichostatin A (TSA). EX-527 and TSA acted 
      synergistically to increase acetyl-p53 levels, confirming that p53 acetylation is 
      regulated by both SIRT1 and HDACs. While TSA alone reduced cell survival after 
      DNA damage, the combination of EX-527 and TSA had no further effect on cell 
      viability and growth. These results show that, although SIRT1 deacetylates p53, 
      this does not play a role in cell survival following DNA damage in certain cell 
      lines and primary human mammary epithelial cells.
FAU - Solomon, Jonathan M
AU  - Solomon JM
AD  - Elixir Pharmaceuticals, Inc., One Kendall Square, Cambridge, MA 02139, USA.
FAU - Pasupuleti, Rao
AU  - Pasupuleti R
FAU - Xu, Lei
AU  - Xu L
FAU - McDonagh, Thomas
AU  - McDonagh T
FAU - Curtis, Rory
AU  - Curtis R
FAU - DiStefano, Peter S
AU  - DiStefano PS
FAU - Huber, L Julie
AU  - Huber LJ
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Mol Cell Biol
JT  - Molecular and cellular biology
JID - 8109087
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Histone Deacetylase Inhibitors)
RN  - 0 (Hydroxamic Acids)
RN  - 0 (Tumor Suppressor Protein p53)
RN  - 3X2S926L3Z (trichostatin A)
RN  - 9007-49-2 (DNA)
RN  - EC 3.5.1.- (SIRT1 protein, human)
RN  - EC 3.5.1.- (Sirtuin 1)
RN  - EC 3.5.1.- (Sirtuins)
SB  - IM
MH  - Acetylation
MH  - Catalysis/drug effects
MH  - Cell Line
MH  - Cell Survival
MH  - DNA/drug effects
MH  - *DNA Damage
MH  - Enzyme Inhibitors/pharmacology
MH  - Gene Expression Regulation
MH  - *Histone Deacetylase Inhibitors
MH  - Humans
MH  - Hydroxamic Acids/pharmacology
MH  - Sirtuin 1
MH  - Sirtuins/*antagonists & inhibitors
MH  - Tumor Suppressor Protein p53/*metabolism
PMC - PMC1317617
EDAT- 2005/12/16 09:00
MHDA- 2006/03/30 09:00
PMCR- 2006/05/01
CRDT- 2005/12/16 09:00
PHST- 2005/12/16 09:00 [pubmed]
PHST- 2006/03/30 09:00 [medline]
PHST- 2005/12/16 09:00 [entrez]
PHST- 2006/05/01 00:00 [pmc-release]
AID - 26/1/28 [pii]
AID - 0899-05 [pii]
AID - 10.1128/MCB.26.1.28-38.2006 [doi]
PST - ppublish
SO  - Mol Cell Biol. 2006 Jan;26(1):28-38. doi: 10.1128/MCB.26.1.28-38.2006.