PMID- 21813711
OWN - NLM
STAT- MEDLINE
DCOM- 20111227
LR  - 20211020
IS  - 1522-1563 (Electronic)
IS  - 0363-6143 (Print)
IS  - 0363-6143 (Linking)
VI  - 301
IP  - 5
DP  - 2011 Nov
TI  - Expression of a naturally occurring angiotensin AT(1) receptor cleavage fragment 
      elicits caspase-activation and apoptosis.
PG  - C1175-85
LID - 10.1152/ajpcell.00040.2011 [doi]
AB  - Several transmembrane receptors are documented to accumulate in nuclei, some as 
      holoreceptors and others as cleaved receptor products. Our prior studies indicate 
      that a population of the 7-transmembrane angiotensin type-1 receptor (AT(1)R) is 
      cleaved in a ligand-augmented manner after which the cytoplasmic, 
      carboxy-terminal cleavage fragment (CF) traffics to the nucleus. In the present 
      report, we determine the precise cleavage site within the AT(1)R by mass 
      spectrometry and Edman sequencing. Cleavage occurs between Leu(305) and Gly(306) 
      at the junction of the seventh transmembrane domain and the intracellular 
      cytoplasmic carboxy-terminal domain. To evaluate the function of the CF distinct 
      from the holoreceptor, we generated a construct encoding the CF as an in-frame 
      yellow fluorescent protein fusion. The CF accumulates in nuclei and induces 
      apoptosis in CHO-K1 cells, rat aortic smooth muscle cells (RASMCs), MCF-7 human 
      breast adenocarcinoma cells, and H9c2 rat cardiomyoblasts. All cell types show 
      nuclear fragmentation and disintegration, as well as evidence for 
      phosphotidylserine displacement in the plasma membrane and activated caspases. 
      RASMCs specifically showed a 5.2-fold increase (P < 0.001) in CF-induced active 
      caspases compared with control and a 7.2-fold increase (P < 0.001) in cleaved 
      caspase-3 (Asp174). Poly(ADP-ribose)polymerase was upregulated 4.8-fold (P < 
      0.001) in CF expressing cardiomyoblasts and colocalized with terminal 
      deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL). CF 
      expression also induces DNA laddering, the gold-standard for apoptosis in all 
      cell types studied. CF-induced apoptosis, therefore, appears to be a general 
      phenomenon as it is observed in multiple cell types including smooth muscle cells 
      and cardiomyoblasts.
FAU - Cook, Julia L
AU  - Cook JL
AD  - Laboratory of Molecular Genetics, Department of Research, Ochsner Clinic 
      Foundation, New Orleans, LA 70121, USA. jcook@ochsner.org
FAU - Singh, Akannsha
AU  - Singh A
FAU - DeHaro, Dawn
AU  - DeHaro D
FAU - Alam, Jawed
AU  - Alam J
FAU - Re, Richard N
AU  - Re RN
LA  - eng
GR  - HL-072795/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20110803
PL  - United States
TA  - Am J Physiol Cell Physiol
JT  - American journal of physiology. Cell physiology
JID - 100901225
RN  - 0 (Receptor, Angiotensin, Type 1)
RN  - EC 2.4.2.30 (Poly(ADP-ribose) Polymerases)
RN  - EC 3.4.22.- (Caspases)
SB  - IM
MH  - Amino Acid Sequence
MH  - Animals
MH  - *Apoptosis
MH  - Caspases/*metabolism
MH  - Cell Line
MH  - Cell Nucleus/metabolism
MH  - Cells, Cultured
MH  - Humans
MH  - In Situ Nick-End Labeling
MH  - Molecular Sequence Data
MH  - Poly(ADP-ribose) Polymerases/metabolism
MH  - Rats
MH  - Receptor, Angiotensin, Type 1/*metabolism
MH  - Up-Regulation
PMC - PMC3213909
EDAT- 2011/08/05 06:00
MHDA- 2011/12/28 06:00
PMCR- 2012/11/01
CRDT- 2011/08/05 06:00
PHST- 2011/08/05 06:00 [entrez]
PHST- 2011/08/05 06:00 [pubmed]
PHST- 2011/12/28 06:00 [medline]
PHST- 2012/11/01 00:00 [pmc-release]
AID - ajpcell.00040.2011 [pii]
AID - C-00040-2011 [pii]
AID - 10.1152/ajpcell.00040.2011 [doi]
PST - ppublish
SO  - Am J Physiol Cell Physiol. 2011 Nov;301(5):C1175-85. doi: 
      10.1152/ajpcell.00040.2011. Epub 2011 Aug 3.