PMID- 28186502
OWN - NLM
STAT- MEDLINE
DCOM- 20180129
LR  - 20181113
IS  - 1476-5403 (Electronic)
IS  - 1350-9047 (Print)
IS  - 1350-9047 (Linking)
VI  - 24
IP  - 4
DP  - 2017 Apr
TI  - STAT1 mediates transmembrane TNF-alpha-induced formation of death-inducing 
      signaling complex and apoptotic signaling via TNFR1.
PG  - 660-671
LID - 10.1038/cdd.2016.162 [doi]
AB  - Tumor necrosis factor-alpha (TNF-alpha) exists in two forms: secretory TNF-alpha (sTNF-alpha) 
      and transmembrane TNF-alpha (tmTNF-alpha). Although both forms of TNF-alpha induce tumor cell 
      apoptosis, tmTNF-alpha is able to kill tumor cells that are resistant to 
      sTNF-alpha-mediated cytotoxicity, indicating their differences in signal 
      transduction. Here, we demonstrate that internalization of TNFR1 is crucial for 
      sTNF-alpha- but not for tmTNF-alpha-induced apoptosis. sTNF-alpha induces binding of tumor 
      necrosis factor receptor type 1-associated death domain protein (TRADD) to the 
      death domain (DD) of TNFR1 and subsequent activation of nuclear factor kappa B 
      (NF-kappaB), and the formation of death-inducing signaling complexes (DISCs) in the 
      cytoplasm after internalization. In contrast, tmTNF-alpha induces DISC formation on 
      the membrane in a DD-independent manner. It leads to the binding of signal 
      transducer and activator of transcription 1 (STAT1) to a region spanning amino 
      acids 319-337 of TNFR1 and induces phosphorylation of serine at 727 of STAT1. The 
      phosphorylation of STAT1 promotes its binding to TRADD, and thus recruits 
      Fas-associated protein with DD (FADD) and caspase 8 to form DISC complexes. This 
      STAT1-dependent signaling results in apoptosis but not NF-kappaB activation. 
      STAT1-deficiency in U3A cells counteracts tmTNF-alpha-induced DISC formation and 
      apoptosis. Conversely, reconstitution of STAT1 expression restores 
      tmTNF-alpha-induced apoptotic signaling in the cell line. Consistently, tmTNF-alpha 
      suppresses the growth of STAT1-containing HT1080 tumors, but not of 
      STAT1-deficient U3A tumors in vivo. Our data reveal an unappreciated molecular 
      mechanism of tmTNF-alpha-induced apoptosis and may provide a new clue for cancer 
      therapy.
FAU - Jiang, Yaping
AU  - Jiang Y
AD  - Department of Immunology, Basic Medical School, Tongji Medical College, Huazhong 
      University of Science and Technology, Wuhan 430030, PR China.
FAU - Yu, Min
AU  - Yu M
AD  - Department of Immunology, Basic Medical School, Tongji Medical College, Huazhong 
      University of Science and Technology, Wuhan 430030, PR China.
AD  - Department of General Surgery, Xinqiao Hospital, Third Military Medical 
      University, Chongqing, PR China.
FAU - Hu, Xuena
AU  - Hu X
AD  - Department of Immunology, Basic Medical School, Tongji Medical College, Huazhong 
      University of Science and Technology, Wuhan 430030, PR China.
FAU - Han, Lu
AU  - Han L
AD  - Department of Immunology, Basic Medical School, Tongji Medical College, Huazhong 
      University of Science and Technology, Wuhan 430030, PR China.
FAU - Yang, Kun
AU  - Yang K
AD  - Department of Immunology, Basic Medical School, Tongji Medical College, Huazhong 
      University of Science and Technology, Wuhan 430030, PR China.
FAU - Ba, Hongping
AU  - Ba H
AD  - Department of Immunology, Basic Medical School, Tongji Medical College, Huazhong 
      University of Science and Technology, Wuhan 430030, PR China.
FAU - Zhang, Zunyue
AU  - Zhang Z
AD  - Department of Immunology, Basic Medical School, Tongji Medical College, Huazhong 
      University of Science and Technology, Wuhan 430030, PR China.
FAU - Yin, Bingjiao
AU  - Yin B
AD  - Department of Immunology, Basic Medical School, Tongji Medical College, Huazhong 
      University of Science and Technology, Wuhan 430030, PR China.
FAU - Yang, Xiang-Ping
AU  - Yang XP
AD  - Department of Immunology, Basic Medical School, Tongji Medical College, Huazhong 
      University of Science and Technology, Wuhan 430030, PR China.
FAU - Li, Zhuoya
AU  - Li Z
AD  - Department of Immunology, Basic Medical School, Tongji Medical College, Huazhong 
      University of Science and Technology, Wuhan 430030, PR China.
FAU - Wang, Jing
AU  - Wang J
AD  - Department of Immunology, Basic Medical School, Tongji Medical College, Huazhong 
      University of Science and Technology, Wuhan 430030, PR China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20170210
PL  - England
TA  - Cell Death Differ
JT  - Cell death and differentiation
JID - 9437445
RN  - 0 (Amino Acid Chloromethyl Ketones)
RN  - 0 (Death Domain Receptor Signaling Adaptor Proteins)
RN  - 0 (Fas-Associated Death Domain Protein)
RN  - 0 (NF-kappa B)
RN  - 0 (Receptors, Tumor Necrosis Factor, Type I)
RN  - 0 (STAT1 Transcription Factor)
RN  - 0 (TNF Receptor-Associated Death Domain Protein)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 0 (benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone)
RN  - EC 3.4.22.- (Caspase 8)
RN  - I9N81SC5HD (monodansylcadaverine)
RN  - L90BEN6OLL (Cadaverine)
SB  - IM
MH  - Amino Acid Chloromethyl Ketones/pharmacology
MH  - Animals
MH  - Apoptosis/drug effects
MH  - Cadaverine/analogs & derivatives/pharmacology
MH  - Caspase 8/metabolism
MH  - Cell Line
MH  - Death Domain Receptor Signaling Adaptor Proteins/*metabolism
MH  - Fas-Associated Death Domain Protein/antagonists & inhibitors/genetics/metabolism
MH  - HEK293 Cells
MH  - Humans
MH  - Mice
MH  - NF-kappa B/metabolism
MH  - NIH 3T3 Cells
MH  - Phosphorylation/drug effects
MH  - Protein Binding
MH  - Receptors, Tumor Necrosis Factor, Type I/antagonists & 
      inhibitors/genetics/*metabolism
MH  - STAT1 Transcription Factor/genetics/*metabolism
MH  - Signal Transduction/drug effects
MH  - TNF Receptor-Associated Death Domain Protein/metabolism
MH  - Tumor Necrosis Factor-alpha/genetics/*metabolism/toxicity
PMC - PMC5384023
COIS- The authors declare that they have no conflict of interest.
EDAT- 2017/02/12 06:00
MHDA- 2018/01/30 06:00
PMCR- 2018/04/01
CRDT- 2017/02/11 06:00
PHST- 2016/06/10 00:00 [received]
PHST- 2016/11/22 00:00 [revised]
PHST- 2016/12/12 00:00 [accepted]
PHST- 2017/02/12 06:00 [pubmed]
PHST- 2018/01/30 06:00 [medline]
PHST- 2017/02/11 06:00 [entrez]
PHST- 2018/04/01 00:00 [pmc-release]
AID - cdd2016162 [pii]
AID - 10.1038/cdd.2016.162 [doi]
PST - ppublish
SO  - Cell Death Differ. 2017 Apr;24(4):660-671. doi: 10.1038/cdd.2016.162. Epub 2017 
      Feb 10.