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FRISC: The Faculty Research Interests Science Comparator |
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Assistant Professor of Molecular Biology
Genetics and
Development
Office: (214) 648-1145
FAX: (214) 648-1196
Building: NA, Room: 8.202
Email: jchen@hamon.swmed.edu
Regulation of apoptosis proteins in cancer cells by ubiquitin.
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Score: 0.387 |
NF- k B is a transcription factor
whose activity is regulated primarily by its nuclear translocation. In
unstimulated cells, NF- k B is usually sequestered in
the cytoplasm through its association with the inhibitory protein I k B,
such as I k B a . Stimulation
of cell by a variety of ligands leads to the rapid phosphorylation and
degradation of I k B, thereby allowing NF- k B
to enter the nucleus to turn on a large array of genes involved in immune,
inflammatory and apoptotic responses.
Our laboratory is interested in understanding how I k B
is phosphorylated and degraded in response to signals. In particular, we focus
on the I k B kinase and I k B
ubiquitination enzymes. We have previously identified a multiprotein kinase
complex (~700 kDa) that phosphorylates I k B a
at specific serine residues. Surprisingly, this I k B
kinase (IKK) complex can be activated by a novel ubiquitin-dependent mechanism
that was poorly understood. Recently, we have gained insights into the mechanism
of IKK activation by ubiquitin through the study of the interleukin-1/LPS
signaling pathways. A critical signaling molecule of these pathways is TRAF6,
which activates IKK through an unknown mechanism. We sought to fill in the gap
between TRAF6 and IKK by establishing a cell free system that activates IKK in
response to TRAF6. Fractionation of this system led to the identification of two
factors that link TRAF6 to IKK activation. One of these factors, termed TRIKA1 ( T RAF6- R egulated
IK K A ctivator 1), turns out to be a dimeric ubiquitin conjugating
enzyme complex composed of Ubc13 and a Ubc-like protein Uev1A (Mms2). The other
factor, termed TRIKA2, is a protein kinase complex composed of TAK1, TAB1 and
TAB2. We found that the TAK1 kinase complex is activated by a novel mechanism
involving the synthesis of a unique polyubiquitin chain by Ubc13/Uev1A and
TRAF6, the latter functioning as a ubiquitin ligase. The activated TAK1 complex
then phosphorylates and activates MKK and IKK, leading to the activation of
stress kinase cascades that culminate in gene activation by AP1 and NF- k B.
These findings unveil a novel regulatory function of ubiquitin in protein kinase
activation without involving proteasomal degradation, and provide a mechanism by
which stress kinase cascades are initiated.
In addition to playing a regulatory role in IKK activation,
ubiquitin also targets I k B degradation by the
proteasome following the phosphorylation of this inhibitor by IKK. We have
identified the I k B ubiquitin-conjugating enzyme (I k B-E2)
as a member of the Ubc4/Ubc5 family. Furthermore, we have found that the I k B-ubiquitin
ligase (I k B-E3) is a multiprotein complex composed of
Skp1, Cul1, Roc1, and an F-box protein called Slimb/ b TrCP.
Among these subunits of the I k B-E3 complex, b TrCP
is the substrate-recognition subunit that binds specifically to the
phosphorylated form of I k B, thus establishing the
molecular basis for signal-induced ubiquitination and subsequent degradation of
I k B. We have recently assembled a functional I k B-E3
complex using recombinant subunits, and will use this reconstituted system to
delineate the biochemical mechanisms of I k B
ubiquitination.
Selected
Publications
Wang, C., Deng, L., Hong, M.
Akkaraju, G.R., Inoue, J-i., and Chen, Z. (2001) TAK1 is a ubiquitin-dependent
kinase of MKK and IKK. Nature 412,
346-351.
Yang, J., Lin, Y., Guo, Z.,
Cheng, J., Huang, J., Deng, L., Liao, W., Chen, Z., Liu, Z-g., and Su, B. (2001)
The essential role of MEKK3 in TNF-induced NF- k B
activation. Nature Immunology 2,
620-624.
Haudek, S. B., Spencer, E.,
Bryant, D.D., White, J.D., Maass, D., Horton, J.W., Chen, Z , and Giroir,
B. (2001) Overexpression of cardiac I k B a
prevents endotoxin-induced myocardial dysfunction. Am J Physiol Heart Circ Physiol . 280, H962-968.
Deng, L., Wang, C., Spencer, E., Yang, L., Braun, A., You,
J., Slaughter, C., Pickart, C., and Chen, Z. (2000) Activation of the I k B
kinase complex requires a dimeric ubiquitin conjugating enzyme complex and the
formation of a unique polyubiquitin chain. Cell
103, 351-361.
Li., K., Li, Y., Shelton, J.M.,
Richardson, J.A., Spencer, E., Chen, Z., Wang., X., and Williams,R.S. (2000)
Cytochrome C deficiency causes embryonic lethality and attenuates stress-induced
apoptosis. Cell 101, 389-399.
Spencer, E., Jiang, J., and
Chen, Z. (1999) Signal-induced ubiquitination of I k B a
by the F-box protein, Slimb/ b -TrCP. Genes
& Dev . 13, 284-294.
Chen, Z., and Maniatis, T.
(1998) Role of the ubiquitin-proteasome pathway in NF- k B
activation. In Ubiquitin and the Biology of the Cell, J-M. Peters, J.R.
Harris, and D. Finley, eds. (New York: Plenum Press). pp303-322.
Lee, F. S., Hagler, J., Chen,
Z., and Maniatis, T. (1997) Activation of the I k B a
kinase complex by MEKK1, a kinase of the JNK pathway. Cell
88, 213-222.
Chen, Z., Parent, L., and
Maniatis, T. (1996) Site-specific phosphorylation of I k B a
by a novel ubiquitination-dependent protein kinase activity. Cell
84, 853-862.
Chen, Z., Hagler, J. Palombella,
V. J., Melandri, F., Scherer, D., Ballard, D., and Maniatis, T. (1995)
Signal-induced site-specific phosphorylation targets I k B a
to the ubiquitin-proteasome pathway. Genes & Dev . 9: 1586-1597.
Page maintained by Stephanie
Robertson
Last updated: 26 Sep 2001
Extraction Method: Expand using Medical Synonyms-
Eliminated words list: MedlinePlus List
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Similarity Method: Weighted keyword count
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Database: Medline abstracts (1967 - Present)
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Publication Type: All
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Score Calculation Method: Cosine Similarity Method
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Sort by: Score
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Show: Top 100 hits
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Results computed on: 6/9/2006