PMID- 21044953
OWN - NLM
STAT- MEDLINE
DCOM- 20110209
LR  - 20211122
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 285
IP  - 53
DP  - 2010 Dec 31
TI  - ERK/ribosomal S6 kinase (RSK) signaling positively regulates death receptor 5 
      expression through co-activation of CHOP and Elk1.
PG  - 41310-9
LID - 10.1074/jbc.M110.153775 [doi]
AB  - Death receptor 5 (DR5) is a death domain-containing transmembrane receptor that 
      triggers apoptosis upon binding to its ligand or when overexpressed. Its 
      expression is induced by certain small molecule drugs, including celecoxib, 
      through mechanisms that have not been fully elucidated. The current study has 
      revealed a novel ERK/ribosomal S6 kinase (RSK)-dependent mechanism that regulates 
      DR5 expression primarily using celecoxib as a DR5 inducer. Both C/EBP homologous 
      protein (CHOP) and Elk1 are required for celecoxib-induced DR5 expression based 
      on promoter deletion and mutation analysis and siRNA-mediated gene silencing 
      results. Co-expression of both CHOP and Elk1 exhibited enhanced effects on 
      increasing DR5 promoter activity and DR5 expression, indicating that CHOP and 
      Elk1 co-operatively regulate DR5 expression. Because Elk1 is an ERK-regulated 
      protein, we accordingly found that celecoxib increased the levels of 
      phosphorylated ERK1/2, RSK2, and Elk1. Inhibition of either ERK signaling with a 
      MEK inhibitor or ERK1/2 siRNA, or RSK2 signaling with an RSK2 inhibitor or RSK2 
      siRNA abrogated DR5 up-regulation by celecoxib as well as other agents. Moreover, 
      these inhibitions suppressed celecoxib-induced CHOP up-regulation. Thus, 
      ERK/RSK-dependent, CHOP and Elk1-mediated mechanisms are critical for DR5 
      induction. Additionally, celecoxib increased CHOP promoter activity in an 
      ATF4-dependent manner, and siRNA-mediated blockade of ATF4 abrogated both CHOP 
      induction and DR5 up-regulation, indicating that ATF4 is involved in 
      celecoxib-induced CHOP and DR5 expression. Collectively, we conclude that small 
      molecules such as celecoxib induce DR5 expression through activating ERK/RSK 
      signaling and subsequent Elk1 activation and ATF4-dependent CHOP induction.
FAU - Oh, You-Take
AU  - Oh YT
AD  - Department of Hematology and Medical Oncology, Emory University School of 
      Medicine and Winship Cancer Institute, Atlanta, Georgia 30322, USA.
FAU - Liu, Xiangguo
AU  - Liu X
FAU - Yue, Ping
AU  - Yue P
FAU - Kang, Sumin
AU  - Kang S
FAU - Chen, Jing
AU  - Chen J
FAU - Taunton, Jack
AU  - Taunton J
FAU - Khuri, Fadlo R
AU  - Khuri FR
FAU - Sun, Shi-Yong
AU  - Sun SY
LA  - eng
GR  - P50 CA128613/CA/NCI NIH HHS/United States
GR  - CA128613/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20101102
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (ATF4 protein, human)
RN  - 0 (Cyclooxygenase 2 Inhibitors)
RN  - 0 (DDIT3 protein, human)
RN  - 0 (ELK1 protein, human)
RN  - 0 (Pyrazoles)
RN  - 0 (Receptors, TNF-Related Apoptosis-Inducing Ligand)
RN  - 0 (Sulfonamides)
RN  - 0 (ets-Domain Protein Elk-1)
RN  - 145891-90-3 (Activating Transcription Factor 4)
RN  - 147336-12-7 (Transcription Factor CHOP)
RN  - EC 2.7.11.1 (RPS6KA1 protein, human)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 90-kDa)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
RN  - JCX84Q7J1L (Celecoxib)
SB  - IM
MH  - Activating Transcription Factor 4/*metabolism
MH  - Apoptosis
MH  - Celecoxib
MH  - Cell Line, Tumor
MH  - Cyclooxygenase 2 Inhibitors/*pharmacology
MH  - Extracellular Signal-Regulated MAP Kinases/metabolism
MH  - *Gene Expression Regulation, Enzymologic
MH  - *Gene Expression Regulation, Neoplastic
MH  - Gene Silencing
MH  - Humans
MH  - Pyrazoles/*pharmacology
MH  - Receptors, TNF-Related Apoptosis-Inducing Ligand/*metabolism
MH  - Ribosomal Protein S6 Kinases, 90-kDa/*metabolism/*physiology
MH  - Signal Transduction
MH  - Sulfonamides/*pharmacology
MH  - Transcription Factor CHOP/*metabolism
MH  - ets-Domain Protein Elk-1/*genetics/*metabolism
PMC - PMC3009856
EDAT- 2010/11/04 06:00
MHDA- 2011/02/10 06:00
PMCR- 2011/12/31
CRDT- 2010/11/04 06:00
PHST- 2010/11/04 06:00 [entrez]
PHST- 2010/11/04 06:00 [pubmed]
PHST- 2011/02/10 06:00 [medline]
PHST- 2011/12/31 00:00 [pmc-release]
AID - S0021-9258(19)76114-6 [pii]
AID - M110.153775 [pii]
AID - 10.1074/jbc.M110.153775 [doi]
PST - ppublish
SO  - J Biol Chem. 2010 Dec 31;285(53):41310-9. doi: 10.1074/jbc.M110.153775. Epub 2010 
      Nov 2.