PMID- 16243918
OWN - NLM
STAT- MEDLINE
DCOM- 20060502
LR  - 20200930
IS  - 0363-6135 (Print)
IS  - 0363-6135 (Linking)
VI  - 290
IP  - 4
DP  - 2006 Apr
TI  - Contribution of p16INK4a and p21CIP1 pathways to induction of premature 
      senescence of human endothelial cells: permissive role of p53.
PG  - H1575-86
AB  - We have previously found that nonenzymatically glycated collagen I (GC), 
      mimicking diabetic microenvironment, can induce senescent phenotype in early 
      passage human umbilical vein endothelial cells (HUVECs). In the present study, we 
      explored the functional involvement of cell cycle checkpoint pathways in 
      initiating GC-induced premature endothelial cell senescence. When compared with 
      native collagen, early passage HUVECs showed increased p53, p21(CIP1) (p21), and 
      p16(INK4a) (p16) mRNA expression after exposure to GC. Twenty-four hours after 
      transfection of p16, p21, and p53-enhanced green fluorescent protein (EGFP) 
      recombinant plasmids, HUVECs entered G(1)-phase cell cycle arrest. By days 3 and 
      5, HUVECs transfected with p16-EGFP showed an increased proportion of senescent 
      cells, and this increase was more prominent in the GFP-positive cell population, 
      which exhibited 68% of senescent cells. Transfection of p21 also induced 
      senescence but only by day 5. Cotransfection of p16 and p21 showed no additive 
      effect. Transfection of p21 or p53 induced apoptosis in HUVECs. Next, we 
      suppressed endogenous p53, p21, p16, or retinoblastoma (Rb) gene expression 
      through small interference RNA strategy and investigated their influence in p16- 
      and p21-initiated endothelial cell senescence. Analysis indicated that 
      suppression of p53 expression can abolish senescence induced by p16 
      overexpression. Paradoxically, this effect was not observed when p21 was 
      suppressed. On the other hand, suppression of Rb eliminated senescence initiated 
      by either p16 or p21 overexpression. In summary, the p53/p21 pathway is mainly 
      responsible for GC-induced apoptosis, but the coordinated activation of the 
      p53/p21 and p16 pathway is responsible for GC-induced endothelial cell senescence 
      through a Rb-dependent mechanism.
FAU - Chen, Jun
AU  - Chen J
AD  - Department of Medicine, New York Medical College, Valhalla, NY 10595, USA. 
      jun_chen@nymc.edu
FAU - Huang, Xuan
AU  - Huang X
FAU - Halicka, Dorota
AU  - Halicka D
FAU - Brodsky, Sergey
AU  - Brodsky S
FAU - Avram, Ari
AU  - Avram A
FAU - Eskander, Jonathan
AU  - Eskander J
FAU - Bloomgarden, Noah A
AU  - Bloomgarden NA
FAU - Darzynkiewicz, Zbigniew
AU  - Darzynkiewicz Z
FAU - Goligorsky, Michael S
AU  - Goligorsky MS
LA  - eng
GR  - R01 CA028704/CA/NCI NIH HHS/United States
GR  - DK-064863/DK/NIDDK NIH HHS/United States
GR  - R01 CA028704-27/CA/NCI NIH HHS/United States
GR  - DK-45462/DK/NIDDK NIH HHS/United States
GR  - DK-52738/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20051021
PL  - United States
TA  - Am J Physiol Heart Circ Physiol
JT  - American journal of physiology. Heart and circulatory physiology
JID - 100901228
RN  - 0 (Cdkn1a protein, mouse)
RN  - 0 (Cdkn2a protein, mouse)
RN  - 0 (Collagen Type I)
RN  - 0 (Cyclin-Dependent Kinase Inhibitor p16)
RN  - 0 (Cyclin-Dependent Kinase Inhibitor p21)
RN  - 0 (Recombinant Proteins)
RN  - 0 (TP53 protein, human)
RN  - 0 (Tumor Suppressor Protein p14ARF)
RN  - 0 (Tumor Suppressor Protein p53)
SB  - IM
MH  - Animals
MH  - Cells, Cultured
MH  - Cellular Senescence/drug effects/*physiology
MH  - Collagen Type I/*pharmacology
MH  - Cyclin-Dependent Kinase Inhibitor p16
MH  - Cyclin-Dependent Kinase Inhibitor p21/*metabolism
MH  - Endothelial Cells/drug effects/*metabolism
MH  - Humans
MH  - Mice
MH  - Recombinant Proteins/metabolism
MH  - Signal Transduction/*physiology
MH  - Tumor Suppressor Protein p14ARF/*metabolism
MH  - Tumor Suppressor Protein p53/*metabolism
EDAT- 2005/10/26 09:00
MHDA- 2006/05/04 09:00
CRDT- 2005/10/26 09:00
PHST- 2005/10/26 09:00 [pubmed]
PHST- 2006/05/04 09:00 [medline]
PHST- 2005/10/26 09:00 [entrez]
AID - 00364.2005 [pii]
AID - 10.1152/ajpheart.00364.2005 [doi]
PST - ppublish
SO  - Am J Physiol Heart Circ Physiol. 2006 Apr;290(4):H1575-86. doi: 
      10.1152/ajpheart.00364.2005. Epub 2005 Oct 21.