PMID- 35378512
OWN - NLM
STAT- MEDLINE
DCOM- 20220422
LR  - 20220524
IS  - 1945-4589 (Electronic)
IS  - 1945-4589 (Linking)
VI  - 14
IP  - 7
DP  - 2022 Apr 4
TI  - Downregulation of IGFBP5 contributes to replicative senescence via ERK2 
      activation in mouse embryonic fibroblasts.
PG  - 2966-2988
LID - 10.18632/aging.203999 [doi]
AB  - Insulin-like growth factor (IGF)-binding proteins (IGFBPs) are secretory proteins 
      that regulate IGF signaling. In this study, we investigated the role of IGFBP5 in 
      replicative senescence in embryonic mouse fibroblasts (MEFs). During passages 
      according to the 3T3 method, MEFs underwent senescence after the 5th passage (P5) 
      based on cell growth arrest, an increase in the number of cells positive for 
      senescence-associated beta-galactosidase (SA-beta-GAL) staining, and upregulation of 
      p16 and p19. In P8 MEFs, IGFBP5 mRNA level was markedly reduced compared with 
      that in P2 MEFs. Downregulation of IGFBP5 via siRNA in P2 MEFs increased the 
      number of SA-beta-GAL-positive cells, upregulated p16 and p19, and inhibited cell 
      growth. Incubation of MEFs with IGFBP5 during serial passage increased the 
      cumulative population doubling and decreased SA-beta-GAL positivity compared with 
      those in vehicle-treated cells. IGFBP5 knockdown in P2 MEFs increased 
      phosphorylation levels of ERK1 and ERK2. Silencing of ERK2, but not that of ERK1, 
      blocked the increase in the number of SA-beta-GAL-positive cells in IGFBP5-knockdown 
      cells. The reduction in the cell number and upregulation of p16 and p21 in 
      IGFBP5-knockdown cells were attenuated by ERK2 knockdown. Our results suggest 
      that downregulation of IGFBP5 during serial passage contributes to replicative 
      senescence via ERK2 in MEFs.
FAU - Nojima, Iyori
AU  - Nojima I
AD  - Department of Pharmacology, Sapporo Medical University School of Medicine, 
      Sapporo, Japan.
FAU - Hosoda, Ryusuke
AU  - Hosoda R
AD  - Department of Pharmacology, Sapporo Medical University School of Medicine, 
      Sapporo, Japan.
FAU - Toda, Yuki
AU  - Toda Y
AD  - Department of Pharmacology, Sapporo Medical University School of Medicine, 
      Sapporo, Japan.
FAU - Saito, Yoshiki
AU  - Saito Y
AD  - Department of Pharmacology, Sapporo Medical University School of Medicine, 
      Sapporo, Japan.
FAU - Ueda, Naohiro
AU  - Ueda N
AD  - Department of Pharmacology, Sapporo Medical University School of Medicine, 
      Sapporo, Japan.
FAU - Horimoto, Kouhei
AU  - Horimoto K
AD  - Department of Pharmacology, Sapporo Medical University School of Medicine, 
      Sapporo, Japan.
FAU - Iwahara, Naotoshi
AU  - Iwahara N
AD  - Department of Pharmacology, Sapporo Medical University School of Medicine, 
      Sapporo, Japan.
FAU - Horio, Yoshiyuki
AU  - Horio Y
AD  - Department of Pharmacology, Sapporo Medical University School of Medicine, 
      Sapporo, Japan.
FAU - Kuno, Atsushi
AU  - Kuno A
AD  - Department of Pharmacology, Sapporo Medical University School of Medicine, 
      Sapporo, Japan.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220404
PL  - United States
TA  - Aging (Albany NY)
JT  - Aging
JID - 101508617
SB  - IM
MH  - Animals
MH  - Cell Proliferation
MH  - *Cellular Senescence/genetics
MH  - Down-Regulation
MH  - *Fibroblasts/metabolism
MH  - Mice
MH  - Phosphorylation
PMC - PMC9037271
OTO - NOTNLM
OT  - ERK1
OT  - ERK2
OT  - IGFBP5
OT  - mouse embryonic fibroblasts
OT  - replicative senescence
COIS- CONFLICTS OF INTEREST: The authors declared no potential conflicts of interest 
      with respect to the research, authorship, and/or publication of this article.
EDAT- 2022/04/05 06:00
MHDA- 2022/04/23 06:00
PMCR- 2022/04/15
CRDT- 2022/04/04 20:17
PHST- 2021/07/01 00:00 [received]
PHST- 2022/03/23 00:00 [accepted]
PHST- 2022/04/05 06:00 [pubmed]
PHST- 2022/04/23 06:00 [medline]
PHST- 2022/04/04 20:17 [entrez]
PHST- 2022/04/15 00:00 [pmc-release]
AID - 203999 [pii]
AID - 10.18632/aging.203999 [doi]
PST - ppublish
SO  - Aging (Albany NY). 2022 Apr 4;14(7):2966-2988. doi: 10.18632/aging.203999. Epub 
      2022 Apr 4.