PMID- 24057571
OWN - NLM
STAT- MEDLINE
DCOM- 20140930
LR  - 20211203
IS  - 1432-0738 (Electronic)
IS  - 0340-5761 (Linking)
VI  - 88
IP  - 2
DP  - 2014 Feb
TI  - PI3K signaling mediates diverse regulation of ATF4 expression for the survival of 
      HK-2 cells exposed to cadmium.
PG  - 403-14
LID - 10.1007/s00204-013-1129-y [doi]
AB  - Cadmium exposure causes endoplasmic reticulum (ER) stress and accumulation of 
      activating transcription factor 4 (ATF4), an ER stress marker. To elucidate the 
      role of phosphatidylinositol-3-kinase (PI3K) signaling in this process, we 
      examined the effects of PI3K signaling on cadmium chloride (CdCl2) 
      exposure-induced ATF4 expression in HK-2 human renal proximal tubular cells. ATF4 
      knockdown by siRNA enhanced CdCl2-induced cellular damage, indicating a 
      cytoprotective function of ATF4. Treatment with LY294002, a PI3K inhibitor, 
      suppressed CdCl2-induced ATF4 expression and Akt phosphorylation at Thr308 with 
      little effect on phosphorylation of eukaryotic translation initiation factor 2 
      subunit alpha at Ser51. Activation of PI3K signaling with epidermal growth factor 
      treatment enhanced CdCl2-induced Akt phosphorylation and ATF4 expression. 
      Suppression of CdCl2-induced ATF4 expression by LY294002 treatment was markedly 
      blocked by cycloheximide, a translation inhibitor, but not by MG-132, a 
      proteasome inhibitor, or actinomycin D, a transcription inhibitor. CdCl2 exposure 
      also induced phosphorylation of mammalian target of rapamycin (mTOR) at Ser2448, 
      glycogen synthase kinase-3alpha (GSK-3alpha) at Ser21, GSK-3beta at Ser9, and 90 kDa 
      ribosomal S6 kinase 2 (RSK2) at Ser227 in HK-2 cells. Treatment with rapamycin, 
      an mTOR inhibitor, MK2206, an Akt inhibitor, and BI-D1870, a RSK inhibitor, 
      partially suppressed CdCl2-induced ATF4 expression. Conversely, SB216763, a GSK-3 
      inhibitor, markedly inhibited the potency of LY294002 to suppress CdCl2-induced 
      ATF4 expression. These results suggest that PI3K signaling diversely regulates 
      the expression of ATF4 in a translation-dependent manner via downstream 
      molecules, including mTOR, GSK-3alpha/beta, and RSK2, and plays a role in protecting 
      HK-2 cells from cadmium-induced damage.
FAU - Fujiki, Kota
AU  - Fujiki K
AD  - Department of Hygiene and Public Health I, Tokyo Women's Medical University, 
      Tokyo, 162-8666, Japan.
FAU - Inamura, Hisako
AU  - Inamura H
FAU - Matsuoka, Masato
AU  - Matsuoka M
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130922
PL  - Germany
TA  - Arch Toxicol
JT  - Archives of toxicology
JID - 0417615
RN  - 0 (ATF4 protein, human)
RN  - 0 (Chromones)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Morpholines)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 00BH33GNGH (Cadmium)
RN  - 145891-90-3 (Activating Transcription Factor 4)
RN  - 31M2U1DVID (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one)
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 (Ribosomal Protein S6 Kinases, 90-kDa)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (ribosomal protein S6 kinase, 90kDa, polypeptide 3)
RN  - EC 2.7.11.26 (Glycogen Synthase Kinase 3)
RN  - J6K4F9V3BA (Cadmium Chloride)
SB  - IM
MH  - Activating Transcription Factor 4/genetics/*metabolism
MH  - Cadmium/*toxicity
MH  - Cadmium Chloride/toxicity
MH  - Cell Line/drug effects
MH  - Chromones/pharmacology
MH  - Enzyme Inhibitors/pharmacology
MH  - Gene Knockdown Techniques
MH  - Glycogen Synthase Kinase 3/metabolism
MH  - Humans
MH  - Kidney Tubules, Proximal/cytology/*drug effects/metabolism
MH  - Morpholines/pharmacology
MH  - Phosphatidylinositol 3-Kinases/*metabolism
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Ribosomal Protein S6 Kinases, 90-kDa/metabolism
MH  - Signal Transduction/drug effects
MH  - TOR Serine-Threonine Kinases/metabolism
EDAT- 2013/09/24 06:00
MHDA- 2014/10/01 06:00
CRDT- 2013/09/24 06:00
PHST- 2013/06/25 00:00 [received]
PHST- 2013/09/11 00:00 [accepted]
PHST- 2013/09/24 06:00 [entrez]
PHST- 2013/09/24 06:00 [pubmed]
PHST- 2014/10/01 06:00 [medline]
AID - 10.1007/s00204-013-1129-y [doi]
PST - ppublish
SO  - Arch Toxicol. 2014 Feb;88(2):403-14. doi: 10.1007/s00204-013-1129-y. Epub 2013 
      Sep 22.