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PMID: 12045187 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Nuclear and cytoplasmic shuttling of TRADD induces apoptosis via different mechanisms.

The Journal of cell biology ·Vol. 157 ·No. 6 ·2002-06-10 ·Pages 975-84

Morgan M, Thorburn J, Pandolfi PP, Thorburn A

Abstract

The adapter protein tumor necrosis factor receptor (TNFR)1-associated death domain (TRADD) plays an essential role in recruiting signaling molecules to the TNFRI receptor complex at the cell membrane. Here we show that TRADD contains a nuclear export and import sequence that allow shuttling between the nucleus and the cytoplasm. In the absence of export, TRADD is found within nuclear structures that are associated with promyelocytic leukemia protein (PML) nuclear bodies. In these structures, the TRADD death domain (TRADD-DD) can activate an apoptosis pathway that is mechanistically distinct from its action at the membrane-bound TNFR1 complex. Apoptosis by nuclear TRADD-DD is promyelocytic leukemia protein dependent, involves p53, and is inhibited by Bcl-xL but not by caspase inhibitors or dominant negative FADD (FADD-DN). Conversely, apoptosis induced by TRADD in the cytoplasm is resistant to Bcl-xL, but sensitive to caspase inhibitors and FADD-DN. These data indicate that nucleocytoplasmic shuttling of TRADD leads to the activation of distinct apoptosis mechanisms that connect the death receptor apparatus to nuclear events.

MeSH Terms
Amino Acid Sequence Animals Apoptosis/drug effects Cell Nucleus/metabolism Cytoplasm/metabolism Fatty Acids, Unsaturated/pharmacology Female Humans Mice/embryology Mice, Knockout Molecular Sequence Data Proteins/chemistry,genetics,metabolism Receptors, Tumor Necrosis Factor/metabolism Sequence Alignment Signal Transduction TNF Receptor-Associated Death Domain Protein TNF Receptor-Associated Factor 1 Tumor Cells, Cultured Tumor Necrosis Factor Receptor-Associated Peptides and Proteins Tumor Suppressor Protein p53/metabolism
Chemicals
Fatty Acids, Unsaturated Proteins Receptors, Tumor Necrosis Factor TNF Receptor-Associated Death Domain Protein TNF Receptor-Associated Factor 1 Tradd protein, mouse Tumor Necrosis Factor Receptor-Associated Peptides and Proteins Tumor Suppressor Protein p53 leptomycin B
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Morgan Michael
Department of Cancer Biology and Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
Thorburn Jacqueline
Pandolfi Pier Paolo
Thorburn Andrew
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Article Info
Journal
The Journal of cell biology
Abbr.
J Cell Biol
ISSN
0021-9525
DOI
10.1083/jcb.200204039
Published
2002-06-10
Epub
2002-00-03
Pages
975-84
Language
English
Region
United States
NLM ID
0375356
PMCID
PMC2174032
Subset
IM
Grants
NINDS NIH HHS · NS42662 · United States
External Links
PubMed source DOI: 10.1083/jcb.200204039 PMC Full Text View journal details
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