PMID- 22847439
OWN - NLM
STAT- MEDLINE
DCOM- 20121029
LR  - 20211021
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 109
IP  - 33
DP  - 2012 Aug 14
TI  - Hypoxia suppresses conversion from proliferative arrest to cellular senescence.
PG  - 13314-8
LID - 10.1073/pnas.1205690109 [doi]
AB  - Unlike reversible quiescence, cellular senescence is characterized by a large 
      flat cell morphology, beta-gal staining and irreversible loss of regenerative (i.e., 
      replicative) potential. Conversion from proliferative arrest to irreversible 
      senescence, a process named geroconversion, is driven in part by growth-promoting 
      pathways such as mammalian target of rapamycin (mTOR). During cell cycle arrest, 
      mTOR converts reversible arrest into senescence. Inhibitors of mTOR can suppress 
      geroconversion, maintaining quiescence instead. It was shown that hypoxia 
      inhibits mTOR. Therefore, we suggest that hypoxia may suppress geroconversion. 
      Here we tested this hypothesis. In HT-p21-9 cells, expression of inducible p21 
      caused cell cycle arrest without inhibiting mTOR, leading to senescence. Hypoxia 
      did not prevent p21 induction and proliferative arrest, but instead inhibited the 
      mTOR pathway and geroconversion. Exposure to hypoxia during p21 induction 
      prevented senescent morphology and loss of regenerative potential, thus 
      maintaining reversible quiescence so cells could restart proliferation after 
      switching p21 off. Suppression of geroconversion was p53- and HIF-1-independent, 
      as hypoxia also suppressed geroconversion in cells lacking functional p53 and 
      HIF-1alpha. Also, in normal fibroblasts and retinal cells, hypoxia inhibited the mTOR 
      pathway and suppressed senescence caused by etoposide without affecting DNA 
      damage response, p53/p21 induction and cell cycle arrest. Also hypoxia suppressed 
      geroconversion in cells treated with nutlin-3a, a nongenotoxic inducer of p53, in 
      cell lines susceptible to nutlin-3a-induced senescence (MEL-10, A172, and NKE). 
      Thus, in normal and cancer cell lines, hypoxia suppresses geroconversion caused 
      by diverse stimuli. Physiological and clinical implications of the present 
      findings are discussed.
FAU - Leontieva, Olga V
AU  - Leontieva OV
AD  - Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY 
      14263, USA.
FAU - Natarajan, Venkatesh
AU  - Natarajan V
FAU - Demidenko, Zoya N
AU  - Demidenko ZN
FAU - Burdelya, Lyudmila G
AU  - Burdelya LG
FAU - Gudkov, Andrei V
AU  - Gudkov AV
FAU - Blagosklonny, Mikhail V
AU  - Blagosklonny MV
LA  - eng
PT  - Journal Article
DEP - 20120730
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Cyclin-Dependent Kinase Inhibitor p21)
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Imidazoles)
RN  - 0 (Piperazines)
RN  - 0 (Tumor Suppressor Protein p53)
RN  - 53IA0V845C (nutlin 3)
RN  - 6PLQ3CP4P3 (Etoposide)
SB  - IM
CIN - Aging (Albany NY). 2012 Aug;4(8):523-4. PMID: 22915708
MH  - Cell Hypoxia/drug effects
MH  - Cell Line
MH  - Cell Proliferation/drug effects
MH  - *Cellular Senescence/drug effects
MH  - Cyclin-Dependent Kinase Inhibitor p21/metabolism
MH  - Epithelial Cells/*cytology/drug effects/metabolism
MH  - Etoposide/pharmacology
MH  - Fibroblasts/*cytology/drug effects/metabolism
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
MH  - Imidazoles/pharmacology
MH  - Piperazines/pharmacology
MH  - Tumor Suppressor Protein p53/metabolism
PMC - PMC3421205
COIS- The authors declare no conflict of interest.
EDAT- 2012/08/01 06:00
MHDA- 2012/10/30 06:00
PMCR- 2013/02/14
CRDT- 2012/08/01 06:00
PHST- 2012/08/01 06:00 [entrez]
PHST- 2012/08/01 06:00 [pubmed]
PHST- 2012/10/30 06:00 [medline]
PHST- 2013/02/14 00:00 [pmc-release]
AID - 1205690109 [pii]
AID - 201205690 [pii]
AID - 10.1073/pnas.1205690109 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2012 Aug 14;109(33):13314-8. doi: 
      10.1073/pnas.1205690109. Epub 2012 Jul 30.