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J. Biol. Chem., Vol. 277, Issue 16, 13952-13958, April 19, 2002
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From the Caspase-associated recruitment domains (CARD) are
protein-protein interaction modules found extensively in proteins that
play important roles in apoptosis, NF The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EBI Data Bank with accession number(s) AF322184.
CARD-8 Protein, a New CARD Family Member That Regulates
Caspase-1 Activation and Apoptosis*
,
§,
,
, and
**
Center for Apoptosis Research and the
Department of Microbiology and Immunology, Kimmel Cancer Institute,
Thomas Jefferson University, Philadelphia, Pennsylvania 19107 and
¶ Millennium Pharmaceuticals, Inc.,
Cambridge, Massachusetts 02139
B activation, and cytokine
regulation. In this study we identified a novel human protein, CARD-8,
which contains a C-terminal CARD domain with high similarity to the CARD domain of caspase-1/ICE. We demonstrate that CARD-8 interacts physically with caspase-1 and negatively regulates
caspase-1-dependent IL-1
generation in the THP-1
monocytic cell line. CARD-8 binds also to ICEBERG and pseudo-ICE, two
other recently identified proteins, which bind to the CARD domain of
caspase-1 and negatively regulate its activity. Reverse
transcriptase-PCR analysis revealed that CARD-8 is expressed mainly in
monocytes, placenta, lymph nodes, and spleen. This pattern of
expression is consistent with caspase-1 expression in the same cells
and tissues. CARD-8 was also found to negatively regulate NF-
B
activation by TNF-
stimulation and by ectopically expressed
RICK, suggesting that this protein may control cell survival.
Consistent with these results, stable expression of CARD-8 in U937 or
THP-1 cells sensitizes the cells to differentiation-induced apoptosis.
Overexpression of CARD-8 can also induce apoptosis in transfected
cells. The results suggest that CARD-8 represents a new signaling
molecule involved in the regulation of caspase-1 and NF-
B activation.
*
This work was supported by National Institutes of Health
Grants CA85421 and AG14357 (to E. S. A.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence may be addressed: Millennium
Pharmaceuticals, Inc., 640 Memorial Dr., Cambridge, MA 02139. Tel.:
617-679-7215; Fax: 617-679-7071; E-mail: bertin@mpi.com.
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