PMID- 22497928
OWN - NLM
STAT- MEDLINE
DCOM- 20121218
LR  - 20181201
IS  - 1878-5875 (Electronic)
IS  - 1357-2725 (Linking)
VI  - 44
IP  - 7
DP  - 2012 Jul
TI  - Exchange protein activated by cyclic adenosine monophosphate regulates the switch 
      between adipogenesis and osteogenesis of human mesenchymal stem cells through 
      increasing the activation of phosphatidylinositol 3-kinase.
PG  - 1106-20
LID - 10.1016/j.biocel.2012.03.019 [doi]
AB  - Epac, exchange protein activated by cyclic adenosine monophosphate (cAMP), could 
      regulate the trans-differentiation between adipogenesis and osteogenesis of human 
      mesenchymal stem cells (hMSCs). Epac activated by 8-pCPT-2'-O-Me-cAMP, a cAMP 
      analog preferentially activating Epac, resulted in the increase of adipogenic 
      gene expression and the decrease of osteogenic gene expression. The 
      pro-adipogenic and anti-osteogenic effect of 8-pCPT-2'-O-Me-cAMP was attributed 
      to that 8-pCPT-2'-O-Me-cAMP led to the activation of protein kinase B (PKB) and 
      cAMP response element-binding protein (CREB) as well as the inhibition of Ras 
      homolog gene family member A (RhoA), focal adhesion kinase (FAK), 
      extracellular-signal-regulated kinase (ERK) and runt-related transcription factor 
      2 (Runx2) activities. Inhibition of Epac by a dominant-negative form of Epac1 
      resulted in the decrease of phosphatidylinositol 3-kinase (PI3K), PKB and CREB 
      activities as well as down-regulation of peroxisome proliferator activated 
      receptor-gamma (PPARgamma) expression. Inhibition of PI3K by a specific inhibitor or 
      inhibition of Arf and Rho GAP adapter protein 3 (ARAP3, a phosphatidylinositol 
      (PtdIns)(3,4,5)P(3) binding protein) by ARAP3 siRNA led to the recovery of RhoA 
      and FAK activities. RhoA-V14, a constitutively active form of RhoA, could 
      activate the MEK/ERK/Runx2 signaling. Therefore, we conclude that PI3K activated 
      by Epac leads to the activation of PKB/CREB signaling and the up-regulation of 
      PPARgamma expression, which in turn activate the transcription of adipogenic genes; 
      whereas osteogenesis is driven by Rho/FAK/MEK/ERK/Runx2 signaling, which can be 
      inhibited by Epac via PI3K. These results should be helpful to provide new 
      targets for treatment of osteoporosis and related bone-wasting diseases.
CI  - Crown Copyright (c) 2012. Published by Elsevier Ltd. All rights reserved.
FAU - Tang, Zihua
AU  - Tang Z
AD  - Institute of Cell and Development Biology, College of Life Sciences, Zhejiang 
      University, Hangzhou 310058, PR China.
FAU - Shi, Dongyan
AU  - Shi D
FAU - Jia, Bingbing
AU  - Jia B
FAU - Chen, Jiarong
AU  - Chen J
FAU - Zong, Chen
AU  - Zong C
FAU - Shen, Dan
AU  - Shen D
FAU - Zheng, Qiang
AU  - Zheng Q
FAU - Wang, Jinfu
AU  - Wang J
FAU - Tong, Xiangming
AU  - Tong X
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120403
PL  - Netherlands
TA  - Int J Biochem Cell Biol
JT  - The international journal of biochemistry & cell biology
JID - 9508482
RN  - 0 (8-(4-chloro-phenylthio)-2'-O-methyladenosine-3'-5'-cyclic monophosphate)
RN  - 0 (Guanine Nucleotide Exchange Factors)
RN  - 0 (RAPGEF3 protein, human)
RN  - E0399OZS9N (Cyclic AMP)
RN  - EC 2.7.1.137 (Phosphatidylinositol 3-Kinase)
SB  - IM
MH  - Adipogenesis
MH  - Cell Differentiation
MH  - Cells, Cultured
MH  - Cyclic AMP/analogs & derivatives/pharmacology
MH  - Enzyme Activation
MH  - Gene Expression
MH  - Guanine Nucleotide Exchange Factors/*metabolism
MH  - Humans
MH  - Mesenchymal Stem Cells/*cytology/*metabolism
MH  - Osteogenesis
MH  - Phosphatidylinositol 3-Kinase/*metabolism
MH  - Phosphorylation
MH  - Signal Transduction
MH  - Transfection
EDAT- 2012/04/14 06:00
MHDA- 2012/12/19 06:00
CRDT- 2012/04/14 06:00
PHST- 2011/12/11 00:00 [received]
PHST- 2012/03/24 00:00 [revised]
PHST- 2012/03/26 00:00 [accepted]
PHST- 2012/04/14 06:00 [entrez]
PHST- 2012/04/14 06:00 [pubmed]
PHST- 2012/12/19 06:00 [medline]
AID - S1357-2725(12)00111-2 [pii]
AID - 10.1016/j.biocel.2012.03.019 [doi]
PST - ppublish
SO  - Int J Biochem Cell Biol. 2012 Jul;44(7):1106-20. doi: 
      10.1016/j.biocel.2012.03.019. Epub 2012 Apr 3.