PMID- 28316325
OWN - NLM
STAT- MEDLINE
DCOM- 20171116
LR  - 20211204
IS  - 1945-4589 (Electronic)
IS  - 1945-4589 (Linking)
VI  - 9
IP  - 3
DP  - 2017 Mar 17
TI  - Silencing of the small GTPase DIRAS3 induces cellular senescence in human white 
      adipose stromal/progenitor cells.
PG  - 860-879
LID - 10.18632/aging.101197 [doi]
AB  - Inhibition of Akt-mTOR signaling protects from obesity and extends life span in 
      animals. In the present study, we analyse the impact of the small GTPase, 
      GTP-binding RAS-like 3 (DIRAS3), a recently identified weight-loss target gene, 
      on cellular senescence in adipose stromal/progenitor cells (ASCs) derived from 
      human subcutaneous white adipose tissue (sWAT). We demonstrate that DIRAS3 
      knock-down (KD) in ASCs induces activation of Akt-mTOR signaling and 
      proliferation arrest. DIRAS3 KD ASCs lose the potential to form colonies and are 
      negative for Ki-67. Moreover, silencing of DIRAS3 results in a premature 
      senescence phenotype. This is characterized by senescence-associated 
      beta-galactosidase positive enlarged ASCs containing increased p16(INK4A) level and 
      activated retinoblastoma protein. DIRAS3 KD ASCs form senescence-associated 
      heterochromatic foci as shown by increased level of gamma-H2A.X positive foci. 
      Furthermore, these cells express a senescence-associated secretory phenotype 
      characterized by increased interleukin-8 secretion. Human DIRAS3 KD ASCs develop 
      also a senescence phenotype in sWAT of SCID mice. Finally, we show that DIRAS3 KD 
      in ASCs stimulates both adipogenic differentiation and premature senescence. In 
      conclusion, our data suggest that silencing of DIRAS3 in ASCs and subsequently 
      hyper-activation of Akt-mTOR drives adipogenesis and premature senescence. 
      Moreover, differentiating ASCs and/or mature adipocytes may acquire features of 
      cellular senescence.
FAU - Ejaz, Asim
AU  - Ejaz A
AD  - Division of Cell Metabolism and Differentiation Research, Institute for 
      Biomedical Aging Research, University of Innsbruck, A-6020 Innsbruck, Austria.
FAU - Mattesich, Monika
AU  - Mattesich M
AD  - Department of Plastic and Reconstructive Surgery, Innsbruck Medical University, 
      A-6020 Innsbruck, Austria.
FAU - Zwerschke, Werner
AU  - Zwerschke W
AD  - Division of Cell Metabolism and Differentiation Research, Institute for 
      Biomedical Aging Research, University of Innsbruck, A-6020 Innsbruck, Austria.
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Aging (Albany NY)
JT  - Aging
JID - 101508617
RN  - 0 (Cyclin-Dependent Kinase Inhibitor p16)
RN  - 0 (DIRAS3 protein, human)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.2.1.23 (beta-Galactosidase)
RN  - EC 3.6.5.2 (rho GTP-Binding Proteins)
SB  - IM
MH  - Adipocytes/*cytology/metabolism
MH  - Adipogenesis/genetics
MH  - Adipose Tissue, White/*cytology/metabolism
MH  - Cell Proliferation/genetics
MH  - Cellular Senescence/*genetics
MH  - Cyclin-Dependent Kinase Inhibitor p16/metabolism
MH  - Female
MH  - Gene Silencing
MH  - Humans
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Signal Transduction/genetics
MH  - Stem Cells/*cytology/metabolism
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - beta-Galactosidase/metabolism
MH  - rho GTP-Binding Proteins/*genetics/metabolism
PMC - PMC5391236
OTO - NOTNLM
OT  - DIRAS3
OT  - adipocyte
OT  - adipogenesis
OT  - adipose stem cell
OT  - adipose stromal/progenitor cell
OT  - aging
OT  - mTOR
OT  - obesity
OT  - senescence
COIS- CONFLICTS OF INTEREST The authors declare no conflict of interest.
EDAT- 2017/03/21 06:00
MHDA- 2017/11/29 06:00
PMCR- 2017/03/01
CRDT- 2017/03/21 06:00
PHST- 2016/11/02 00:00 [received]
PHST- 2017/03/03 00:00 [accepted]
PHST- 2017/03/21 06:00 [pubmed]
PHST- 2017/11/29 06:00 [medline]
PHST- 2017/03/21 06:00 [entrez]
PHST- 2017/03/01 00:00 [pmc-release]
AID - 101197 [pii]
AID - 10.18632/aging.101197 [doi]
PST - ppublish
SO  - Aging (Albany NY). 2017 Mar 17;9(3):860-879. doi: 10.18632/aging.101197.