just parking some stuff.......
Science 1999 Jan 22;283(5401):543-6
Prevention of constitutive TNF receptor 1 signaling by silencer of death
domains.
Jiang Y, Woronicz JD, Liu W, Goeddel DV
Tularik, Two Corporate Drive, South San Francisco, CA 94080, USA.
Tumor necrosis factor receptor type 1 (TNF-R1) contains a cytoplasmic death domain that is required for the signaling of TNF
activities such as apoptosis and nuclear factor kappa B (NF-kappaB) activation. Normally, these signals are generated only
after TNF-induced receptor aggregation. However, TNF-R1 self-associates and signals independently of ligand when
overexpressed. This apparent paradox may be explained by silencer of death domains (SODD), a widely expressed
approximately 60-kilodalton protein that was found to be associated with the death domain of TNF-R1. TNF treatment
released SODD from TNF-R1, permitting the recruitment of proteins such as TRADD and TRAF2 to the active TNF-R1
signaling complex. SODD also interacted with death receptor-3 (DR3), another member of the TNF receptor superfamily.
Thus, SODD association may be representative of a general mechanism for preventing spontaneous signaling by death
domain-containing receptors.
Science 1998 Sep 11;281(5383):1680-3
NF-kappaB antiapoptosis: induction of TRAF1 and TRAF2 and c-IAP1
and c-IAP2 to suppress caspase-8 activation.
Wang CY, Mayo MW, Korneluk RG, Goeddel DV, Baldwin AS Jr
Department of Endodontics, School of Dentistry, Lineberger Comprehensive Cancer Center, and Curriculum in Genetics and
Molecular Biology, University of North Carolina, Chapel Hill, NC 27599-7295, USA.
Tumor necrosis factor alpha (TNF-alpha) binding to the TNF receptor (TNFR) potentially initiates apoptosis and activates the
transcription factor nuclear factor kappa B (NF-kappaB), which suppresses apoptosis by an unknown mechanism. The
activation of NF-kappaB was found to block the activation of caspase-8. TRAF1 (TNFR-associated factor 1), TRAF2, and
the inhibitor-of-apoptosis (IAP) proteins c-IAP1 and c-IAP2 were identified as gene targets of NF-kappaB transcriptional
activity. In cells in which NF-kappaB was inactive, all of these proteins were required to fully suppress TNF-induced
apoptosis, whereas c-IAP1 and c-IAP2 were sufficient to suppress etoposide-induced apoptosis. Thus, NF-kappaB activates
a group of gene products that function cooperatively at the earliest checkpoint to suppress TNF-alpha-mediated apoptosis and
that function more distally to suppress genotoxic agent-mediated apoptosis. |
