舒红兵很不简单的，不算他以前在国外的工作，在国内发的文章也有20来篇了，多数是JBC分以上的文章。
1: Proc Natl Acad Sci U S A. 2007 Jun 28; [Epub ahead of print]
Negative regulation of MDA5- but not RIG-I-mediated innate antiviral signaling by
the dihydroxyacetone kinase.
Diao F, Li S, Tian Y, Zhang M, Xu LG, Zhang Y, Wang RP, Chen D, Zhai Z, Zhong B,
Tien P, Shu HB.
College of Life Sciences, Peking University, Beijing 100871, China; College of
Life Sciences, State Key Laboratory of Virology, Wuhan University, Wuhan 430072,
China.
Viral infection leads to activation of the transcription factors interferon
regulatory factor-3 and NF-kappaB, which collaborate to induce type I IFNs. The
RNA helicase proteins RIG-I and MDA5 were recently identified as two cytoplasmic
viral RNA sensors that recognize different species of viral RNAs produced during
viral replication. In this study, we identified DAK, a functionally unknown
dihydroacetone kinase, as a specific MDA5-interacting protein. DAK was associated
with MDA5, but not RIG-I, under physiological conditions. Overexpression of DAK
inhibited MDA5- but not RIG-I- or TLR3-mediated IFN-beta induction.
Overexpression of DAK also inhibited cytoplasmic dsRNA and SeV-induced activation
of the IFN-beta promoter, whereas knockdown of endogenous DAK by RNAi activated
the IFN-beta promoter, and increased cytoplasmic dsRNA- or SeV-triggered
activation of the IFN-beta promoter. In addition, overexpression of DAK inhibited
MDA5- but not RIG-I-mediated antiviral activity, whereas DAK RNAi increased
cytoplasmic dsRNA-triggered antiviral activity. These findings suggest that DAK
is a physiological suppressor of MDA5 and specifically inhibits MDA5- but not
RIG-I-mediated innate antiviral signaling.
PMID: 17600090 [PubMed - as supplied by publisher]
2: J Biol Chem. 2007 Jun 8;282(23):16776-82. Epub 2007 Apr 20.
RBCK1 negatively regulates tumor necrosis factor- and interleukin-1-triggered
NF-kappaB activation by targeting TAB2/3 for degradation.
Tian Y, Zhang Y, Zhong B, Wang YY, Diao FC, Wang RP, Zhang M, Chen DY, Zhai ZH,
Shu HB.
College of Life Sciences, Peking University, Beijing 100871, China.
Inflammation is a homeostatic mechanism that limits the effects of infectious
agents. Tumor necrosis factor (TNF) and interleukin (IL)-1 are two cytokines that
induce inflammation through activation of the transcription factor NF-kappaB.
Various studies have suggested that two homologous and structurally related
adapter proteins TAB2 and TAB3 play redundant roles in TNF- and IL-1-mediated
NF-kappaB activation pathways. Both TAB2 and TAB3 contain CUE, coiled-coil, and
nuclear protein localization 4 zinc finger (NZF) domains. The NZF domains of
TAB2/3 are critical for TAB2/3 to bind to Lys(63)-linked polyubiquitin chains of
other adaptor proteins, such as receptor-interacting protein and TRAF6, which are
two signaling proteins essential for TNF- and IL-1-induced NF-kappaB activation,
respectively. In a search for proteins containing NZF domains conserved with
those of TAB2/3, we identified RBCK1, which has been shown to act as an E3
ubiquitin ligase in iron metabolism. Overexpression of RBCK1 negatively regulates
TAB2/3-mediated and TNF- and IL-1-induced NF-kappaB activation, whereas knockdown
of RBCK1 by RNA interference potentiates TNF- and IL-1-induced NF-kappaB
activation. RBCK1 physically interacts with TAB2/3 and facilitates degradation of
TAB2/3 through a proteasome-dependent process. Taken together, our findings
suggest that RBCK1 is involved in negative regulation of inflammatory signaling
triggered by TNF and IL-1 through targeting TAB2/3 for degradation.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 17449468 [PubMed - in process]
3: Cell Mol Life Sci. 2007 Mar;64(5):632-40.
TTDN1 is a Plk1-interacting protein involved in maintenance of cell cycle
integrity.
Zhang Y, Tian Y, Chen Q, Chen D, Zhai Z, Shu HB.
College of Life Sciences, Peking University, Beijing, 100871, China.
Polo-like kinase 1 (Plk1) is a highly conserved serine/threonine kinase that
plays critical roles in many cell cycle events, especially in mitosis. In the
present study, we identified TTDN1 as a potential interacting partner of Plk1 in
yeast two-hybrid screens. Sequence analysis indicates that TTDN1 contains a
consensus Plk1-binding motif at its C terminus. TTDN1 colocalizes with Plk1 at
the centrosome in mitosis and the midbody during cytokinesis. TTDN1 is
phosphorylated by Cdk1 in mitosis, and this is required for its interaction with
Plk1. Site-directed mutagenesis indicates that TTDN1 is phosphorylated at
multiple residues, including Ser93 and Ser104. Mutation of Thr120 of TTDN1
abolishes its interaction with Plk1, suggesting phosphorylation of Thr120 in the
consensus Plk1-binding motif is required for its interaction with Plk1.
Overexpression of TTDN1 or its knockdown by siRNA causes multi-polar spindles and
multiple nuclei, suggesting that TTDN1 plays a role in regulating mitosis and
cytokinesis.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 17310276 [PubMed - indexed for MEDLINE]
4: Virology. 2006 Aug 15;352(1):14-21. Epub 2006 Jun 6.
Innate immune responses: crosstalk of signaling and regulation of gene
transcription.
Zhong B, Tien P, Shu HB.
College of Life Sciences, Wuhan University, Wuhan 430072, China.
Innate immune responses to pathogens such as bacteria and viruses are triggered
by recognition of specific structures of invading pathogens called
pathogen-associated molecular patterns (PAMPs) by cellular pattern recognition
receptors (PRRs) that are located at plasma membrane or inside cells. Stimulation
of different PAMPs activates Toll-like receptor (TLR)-dependent and -independent
signaling pathways that lead to activation of transcription factors nuclear
factor-kappaB (NF-kappaB), interferon regulatory factor 3/7 (IRF3/7) and/or
activator protein-1 (AP-1), which collaborate to induce transcription of a large
number of downstream genes. This review focuses on the rapid progress that has
recently improved our understanding of the crosstalk among the pathways and the
precise regulation of transcription of the downstream genes.
Publication Types:
Review
PMID: 16753195 [PubMed - indexed for MEDLINE]
5: FEBS Lett. 2006 Feb 6;580(3):940-7. Epub 2006 Jan 18.
The p53-inducible E3 ubiquitin ligase p53RFP induces p53-dependent apoptosis.
Huang J, Xu LG, Liu T, Zhai Z, Shu HB.
Department of Cell Biology and Genetics, College of Life Sciences, Peking
University, Beijing 100871, China.
Recently, it has been shown that really interesting new gene (RING)-in between
ring finger (IBR)-RING domain-containing proteins, such as Parkin and Parc, are
E3 ubiquitin ligases and are involved in regulation of apoptosis. In this report,
we show that p53-inducible RING-finger protein (p53RFP), a p53-inducible E3
ubiquitin ligase, induces p53-dependent but caspase-independent apoptosis. p53RFP
contains an N-terminal RING-IBR-RING domain and an uncharacterized, evolutionally
highly conserved C-terminal domain. p53RFP interacts with E2
ubiquitin-conjugating enzymes UbcH7 and UbcH8 but not with UbcH5, and this
interaction is mediated through the RING-IBR-RING domain of p53RFP.
Interestingly, the conserved C-terminal domain of p53RFP is required and
sufficient for p53RFP-mediated apoptosis, suggesting p53RFP-mediated apoptosis
does not require its E3 ubiquitin ligase activity. Together with a recent report
showing that p53RFP is involved in ubiquitination and degradation of p21, a p53
downstream protein promoting growth arrest and antagonizing apoptosis, our
findings suggest that p53RFP is involved in switching a cell from p53-mediated
growth arrest to apoptosis.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 16427630 [PubMed - indexed for MEDLINE]
6: J Immunol. 2006 Jan 15;176(2):1072-80.
The Ret finger protein inhibits signaling mediated by the noncanonical and
canonical IkappaB kinase family members.
Zha J, Han KJ, Xu LG, He W, Zhou Q, Chen D, Zhai Z, Shu HB.
Department of Cell Biology and Genetics, College of Life Sciences, Peking
University, Beijing, China;
IFN regulatory factor-3 is a transcription factor that is required for the rapid
induction of type I IFNs in the innate antiviral response. Two noncanonical
IkappaB kinase (IKK) family members, IKKepsilon and TRAF family-associated
NF-kappaB activator-binding kinase-1, have been shown to phosphorylate IFN
regulatory factor-3 and are critically involved in virus-triggered and
TLR3-mediated signaling leading to induction of type I IFNs. In yeast two-hybrid
screens for potential IKKepsilon-interacting proteins, we identified Ret finger
protein (RFP) as an IKKepsilon-interacting protein. Coimmunoprecipitation
experiments indicated that RFP interacted with IKKepsilon and TRAF
family-associated NF-kappaB activator-binding kinase-1 as well as the two
canonical IKK family members, IKKbeta and IKKalpha. RFP inhibited activation of
the IFN-stimulated response element and/or NF-kappaB mediated by the IKK family
members and triggered by TNF, IL-1, polyinosinic-polycytidylic acid (ligand for
TLR3), and viral infection. Moreover, knockdown of RFP expression by RNA
interference-enhanced activation of IFN-stimulated response element and/or
NF-kappaB triggered by polyinosinic-polycytidylic acid, TNF, and IL-1. Taken
together, our findings suggest that RFP negatively regulates signaling involved
in the antiviral response and inflammation by targeting the IKKs.
Publication Types:
In Vitro
Research Support, Non-U.S. Gov't
PMID: 16393995 [PubMed - indexed for MEDLINE]
7: Eur J Immunol. 2006 Jan;36(1):199-206.
TNF receptor-associated factor-1 (TRAF1) negatively regulates Toll/IL-1 receptor
domain-containing adaptor inducing IFN-beta (TRIF)-mediated signaling.
Su X, Li S, Meng M, Qian W, Xie W, Chen D, Zhai Z, Shu HB.
College of Life Sciences, Peking University, Beijing, China.
Toll-like receptor 3 (TLR3) plays an important role in antiviral responses
through recognizing viral double-stranded RNA produced during viral infection and
mediating induction of type I IFN. TRIF is a Toll/IL-1 receptor (TIR)
domain-containing adaptor protein that is associated with TLR3 and critically
involved in TLR3-mediated signaling. In yeast two-hybrid screens, we identified
TNF receptor-associated factor (TRAF)1 as a TRIF-interacting protein. The TRAF-C
domain of TRAF1 and the TIR domain of TRIF were responsible for their
interaction. Overexpression of TRAF1 inhibited TRIF- and TLR3-mediated activation
of NF-kappaB, IFN-stimulated response element and the IFN-beta promoter.
Overexpression of TRIF caused caspase-dependent cleavage of TRAF1. The cleaved
N-terminal but not C-terminal fragment of TRAF1 was responsible for inhibiting
TRIF signaling. Mutation of the caspase cleavage site of TRAF1 or addition of the
caspase inhibitor crmA inhibited TRAF1 cleavage and abolished the ability of
TRAF1 to inhibit TRIF signaling, suggesting that TRIF-induced cleavage of TRAF1
is required for its inhibition of TRIF signaling. Our findings provide a novel
mechanism for negative regulation of TRIF-mediated signaling.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 16323247 [PubMed - indexed for MEDLINE]
8: EMBO J. 2005 Dec 7;24(23):4018-28. Epub 2005 Nov 10.
SIKE is an IKK epsilon/TBK1-associated suppressor of TLR3- and virus-triggered
IRF-3 activation pathways.
Huang J, Liu T, Xu LG, Chen D, Zhai Z, Shu HB.
College of Life Sciences, Peking University, Beijing, China.
Viral infection or TLR3 engagement causes activation of the transcription factors
IRF-3 and NF-kappaB, which collaborate to induce transcription of type I IFN
genes. IKKepsilon and TBK1 are two IKK-related kinases critically involved in
virus- and TLR3-triggered activation of IRF-3. We identified a protein termed
SIKE (for Suppressor of IKKepsilon) that interacts with IKKepsilon and TBK1. SIKE
is associated with TBK1 under physiological condition and dissociated from TBK1
upon viral infection or TLR3 stimulation. Overexpression of SIKE disrupted the
interactions of IKKepsilon or TBK1 with TRIF, RIG-I and IRF-3, components in
virus- and TLR3-triggered IRF-3 activation pathways, but did not disrupt the
interactions of TRIF with TRAF6 and RIP, components in TLR3-triggered NF-kappaB
activation pathway. Consistently, overexpression of SIKE inhibited virus- and
TLR3-triggered interferon-stimulated response elements (ISRE) but not NF-kappaB
activation. Knockdown of SIKE potentiated virus- and TLR3-triggered ISRE but not
NF-kappaB activation. Moreover, overexpression of SIKE inhibited IKKepsilon- and
TBK1-mediated antiviral response. These findings suggest that SIKE is a
physiological suppressor of IKKepsilon and TBK1 and plays an inhibitory role in
virus- and TLR3-triggered IRF-3 but not NF-kappaB activation pathways.
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
PMID: 16281057 [PubMed - indexed for MEDLINE]
9: J Cell Sci. 2005 Feb 1;118(Pt 3):555-63. Epub 2005 Jan 18.
TRIP6 is a RIP2-associated common signaling component of multiple NF-kappaB
activation pathways.
Li L, Bin LH, Li F, Liu Y, Chen D, Zhai Z, Shu HB.
Department of Cell Biology and Genetics, College of Life Sciences, Peking
University, Beijing 100871, China.
Receptor-interacting protein 2 (RIP2) is a member of the RIP kinase family that
has been shown to be crucially involved in inflammation, innate and adaptive
immune responses. The physiological and pathological roles of RIP2 are mediated
through its involvement in multiple NF-kappaB activation pathways, including
those triggered by tumor necrosis factor (TNF), interleukin 1 (IL-1), Toll-like
receptor 2 (TLR2), TLR3, TLR4 and Nod1. In this report, we identified the
LIM-domain-containing protein TRIP6 as a RIP2-interacting protein in yeast
two-hybrid screens. In mammalian cells, TRIP6 interacts with RIP2 in a TNF- or
IL-1-dependent manner. Overexpression of TRIP6 potentiates RIP2-mediated
NF-kappaB activation in a dose-dependent manner. The LIM domains of TRIP6 are
responsible for its interaction with RIP2. TRIP6 also interacts with TRAF2, a
protein that is crucially involved in TNF signaling, as well as the IL-1
receptor, TLR2 and Nod1. Overexpression of TRIP6 potentiates NF-kappaB activation
by TNF, IL-1, TLR2 or Nod1, whereas a dominant negative mutant or
RNA-interference construct of TRIP6 inhibits NF-kappaB activation by TNF, IL-1,
TLR2 or Nod1. Moreover, TRIP6 also potentiates RIP2- and Nod1-mediated ERK
activation. These data have established a physical and functional association
between TRIP6 and RIP2, and suggest that RIP2's involvement in multiple NF-kappaB
and ERK activation pathways is mediated through TRIP6.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 15657077 [PubMed - indexed for MEDLINE]
10: FEBS Lett. 2004 Oct 8;576(1-2):86-90.
A20 is a potent inhibitor of TLR3- and Sendai virus-induced activation of
NF-kappaB and ISRE and IFN-beta promoter.
Wang YY, Li L, Han KJ, Zhai Z, Shu HB.
Department of Cell Biology and Genetics, College of Life Sciences, Peking
University, Beijing 100871, China.
Toll-like receptor 3 (TLR3) recognizes dsRNA generated during viral infection and
activation of TLR3 results in induction of type I interferons (IFNs) and cellular
anti-viral response. TLR3 is associated with a TIR domain-containing adapter
protein TRIF, which activates distinct downstream pathways leading to activation
of NF-kappaB and ISRE sites in the promoters of type I IFNs. We show here that
A20, a NF-kappaB-inducible zinc finger protein that has been demonstrated to be
an inhibitor of TNF-induced NF-kappaB activation and a physiological suppressor
of inflammatory response, potently inhibited TLR3- and Sendai virus-mediated
activation of ISRE and NF-kappaB and IFN-beta promoter in reporter gene assays.
A20 also inhibited TRIF-, but not its downstream signaling components TBK1-,
IKKbeta-, and IKKepsilon-mediated activation of ISRE and NF-kappaB and IFN-beta
promoter. Moreover, A20 interacted with TRIF in co-immunoprecipitation
experiments. Finally, expression of A20 could be induced at protein level by
Sendai virus infection. These data suggest that A20 targets TRIF to inhibit
TLR3-mediated induction of IFN-beta transcription and functions as a feedback
negative regulator for TLR3 signaling and cellular anti-viral response. Copyright
2004 Federation of European Biochemical Societies
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 15474016 [PubMed - indexed for MEDLINE]
11: Oncogene. 2004 Sep 2;23(40):6815-9.
AMID is a p53-inducible gene downregulated in tumors.
Wu M, Xu LG, Su T, Tian Y, Zhai Z, Shu HB.
Department of Cell Biology and Genetics, College of Life Sciences, Peking
University, Beijing 100871, PR China.
AMID, also called PRG3, is an AIF-homologous and mitochondria-associated protein
that has been implicated in caspase-independent apoptosis. In this report, we
demonstrated that human AMID gene promoter was activated by p53 in reporter gene
assays. Chromatin immunoprecipitation experiments indicated that p53 could bind
to human AMID promoter. Deletion mutagenesis indicated that human AMID promoter
contains two p53-responsive elements. Furthermore, expression array analysis
indicated that human AMID mRNA expression was downregulated in a majority of
human tumors. Our findings point to the possibility that AMID is a p53-downstream
gene involved in tumorigenesis.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 15273740 [PubMed - indexed for MEDLINE]
12: Biochem Biophys Res Commun. 2004 Jun 25;319(2):298-303.
RIP5 is a RIP-homologous inducer of cell death.
Zha J, Zhou Q, Xu LG, Chen D, Li L, Zhai Z, Shu HB.
Department of Cell Biology and Genetics, College of Life Sciences, Peking
University, Beijing 100871, China.
Members of the RIP serine/threonine kinase family are involved in activation of
NF-kappaB, JNK, and p38, and induction of apoptosis. Here we report the
identification of a novel RIP-homologous protein designated as RIP5. The
C-terminus of RIP5 contains a kinase domain, which is mostly homologous with the
kinase domain of RIP. RIP5 also contains a large unconserved N-terminal domain.
Overexpression of RIP5 induces cell death with characteristic apoptotic
morphology. Overexpression of RIP5 also induces DNA fragmentation and this is
blocked by the caspase inhibitor crmA. However, RIP5-induced apoptotic morphology
is not blocked by crmA. These findings suggest that RIP5 may induce both
caspase-dependent apoptosis and caspase-independent cell death.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 15178406 [PubMed - indexed for MEDLINE]
13: J Biol Chem. 2004 Apr 16;279(16):16847-53. Epub 2004 Jan 30.
ZNF216 Is an A20-like and IkappaB kinase gamma-interacting inhibitor of NFkappaB
activation.
Huang J, Teng L, Li L, Liu T, Li L, Chen D, Xu LG, Zhai Z, Shu HB.
Department of Cell Biology and Genetics, College of Life Sciences, Peking
University, Beijing 100871, China.
The transcription factor NFkappaB plays important roles in immune regulation,
inflammatory responses, and anti-apoptosis. Activation of NFkappaB requires the
activity of IkappaB kinase, a kinase complex that contains two catalytic
subunits, IKKalpha and IKKbeta, and a non-enzymatic regulatory subunit, IKKgamma.
To understand how NFkappaB activation is regulated at the IKKgamma level, we
searched for IKKgamma-interacting proteins by the yeast two-hybrid system. This
search identified ZNF216, a zinc finger protein with unknown biological
functions. ZNF216 contains an A20-like zinc finger domain (ZnF-A20) at its N
terminus and an AN1-like domain (ZnF-AN1) at its C terminus. Similar to A20,
ZNF216 interacted with IKKgamma, RIP, and TRAF6 in co-immunoprecipitation
experiments. Domain mapping experiments indicated that the ZnF-A20 domain was
responsible for interacting with IKKgamma and RIP, whereas the ZnF-AN1 domain
interacted with TRAF6. ZNF216 inhibited NFkappaB activation triggered by
overexpression of RIP and TRAF6 but not of p65. ZNF216 also inhibited tumor
necrosis factor (TNF)-, interleukin-1-, and Toll-like receptor 4-induced NFkappaB
activation in a dose-dependent manner. The ZnF-A20 domain was essential for
ZNF216-mediated inhibition of NFkappaB activation. The ZnF-A20 and ZnF-AN1
domains of ZNF216 could interact with each other, whereas ZNF216 could form
homo-oligomers or hetero-oligomers with A20. Unlike A20, which inhibits
TNF-induced apoptosis, overexpression of ZNF216 sensitized cells to TNF-induced
apoptosis. Our findings suggest that ZNF216 and A20 have redundant and distinct
roles in regulating NFkappaB activation and apoptosis.
Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
PMID: 14754897 [PubMed - indexed for MEDLINE]
14: Biochem Biophys Res Commun. 2003 Oct 24;310(3):720-4.
Identification of a nuclear protein that promotes NF-kappaB activation.
Chen D, Li Z, Yang Q, Zhang J, Zhai Z, Shu HB.
Department of Cell Biology and Genetics, College of Life Sciences, Peking
University, Beijing, China.
Receptor-interacting protein (RIP) is a serine/threonine protein kinase that is
critically involved in tumor necrosis factor receptor-1 (TNF-R1)-induced
NF-kappaB activation. In a yeast two-hybrid screening for potential
RIP-interacting proteins, we identified a novel protein designated as NKAP.
Although NKAP interacts with RIP in yeast, NKAP does not interact with RIP in
mammalian cells in co-immunoprecipitation experiments. When overexpressed in 293
cells, NKAP activated NF-kappaB in a dose-dependent manner. Moreover,
down-regulation of NKAP by antisense RNA significantly inhibited TNF- and
IL-1-induced NF-kappaB activation. Immunofluorescent staining indicated that NKAP
was localized in the nucleus. Our findings suggest that NKAP is a novel nuclear
regulator of TNF- and IL-1-induced NF-kappaB activation.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 14550261 [PubMed - indexed for MEDLINE]
15: Biochem Biophys Res Commun. 2003 Oct 3;309(4):980-5.
Casper/c-FLIP is physically and functionally associated with NF-kappaB1 p105.
Li Z, Zhang J, Chen D, Shu HB.
Department of Cell Biology, Institute of Basic Medical Sciences, Chinese Academy
of Medical Sciences, Beijing 10005, China.
Casper/c-FLIP is a caspase-8-related molecule critically involved in regulation
of death receptor-induced apoptosis. It has been shown that Casper can either
promote or antagonize apoptosis and can activate the transcription factor
NF-kappaB. The exact functions of Casper are controversial. To further understand
how Casper signals, we searched Casper-interacting proteins by yeast two-hybrid
screening. This effort identified NF-kappaB1 (p105), an atypical IkappaB molecule
and the precursor of NF-kappaB subunit p50. Co-immunoprecipitation experiments
indicated that Casper interacted with p105 in 293 cells and this interaction was
mediated through the C-terminal IkappaB-like domain (IkappaBgamma).
Overexpression of p105 and IkappaBgamma inhibited Casper-induced NF-kappaB
activation and potentiated Casper-induced apoptosis. Furthermore, Casper and its
C-terminal caspase-like domain inhibited p105 processing into p50. Our findings
suggest that p105 is involved in Casper-mediated regulation of apoptosis and
NF-kappaB activation.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 13679070 [PubMed - indexed for MEDLINE]
16: Biochem Biophys Res Commun. 2003 Oct 3;309(4):774-8.
Identification of a novel serine/threonine kinase that inhibits TNF-induced
NF-kappaB activation and p53-induced transcription.
Huang J, Teng L, Liu T, Li L, Chen D, Li F, Xu LG, Zhai Z, Shu HB.
Department of Cell Biology and Genetics, College of Life Sciences, Peking
University, Beijing 100871, China.
SINK is a p65-interacting protein that inhibits PKAc-induced phosphorylation of
p65 and NF-kappaB transcriptional competence. We identified a SINK-homologous
serine/threonine kinase SHIK. SHIK is ubiquitously expressed and is localized in
the cytoplasm. Overexpression of SHIK inhibits TNF-triggered NF-kappaB activation
in reporter gene assays. Overexpression of SHIK also inhibits p53-mediated
transcription in reporter gene assays, while a point mutant (D197-->I) of SHIK
potentiates p53-mediated transcription. Our findings suggest that SHIK is a
negative regulator of NF-kappaB- and p53-mediated gene transcription.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 13679039 [PubMed - indexed for MEDLINE]
17: Oncogene. 2003 Jul 10;22(28):4348-55.
NIK is a component of the EGF/heregulin receptor signaling complexes.
Chen D, Xu LG, Chen L, Li L, Zhai Z, Shu HB.
Department of Cell Biology and Genetics, College of Life Sciences, Peking
University, Beijing 100871, China.
Nuclear factor kappaB-inducing kinase (NIK) is a member of the MAP kinase kinase
kinase family that was first identified as a component of the TNF-R1-induced
NF-kappaB activation pathway (TNF, tumor necrosis factor; nuclear factor kappaB,
NF-kappaB). Gene knockout study, however, suggests that NIK is dispensable for
TNF-R1- but required for lymphotoxin-beta receptor-induced NF-kappaB activation.
A NIK kinase inactive mutant is a potent inhibitor of NF-kappaB activation
triggered by various stimuli, suggesting that NIK is involved in a broad range of
NF-kappaB activation pathways. To unambiguously identify signaling pathways that
NIK participates in, we screened antibody arrays for proteins that are associated
with NIK. This effort identified ErbB4, one of the EGF/heregulin receptors, and
Grb7, an adapter protein associated with ErbB4 (ErbB, epidermal growth factor
receptor family protein; EGF, epidermal growth factor; Grb, growth factor
receptor bound). Coimmunoprecipitation experiments demonstrated that NIK
interacted with Grb7, as well as Grb10 and Grb14, but not Grb2. Domain mapping
experiments indicated that the central GM domain of Grb7 was sufficient for its
interaction with NIK. Coimmunoprecipitation experiments also indicated that Grb7
and NIK could be simultaneously recruited into signaling complexes of all known
EGF/heregulin receptors, including EGFR, ErbB2, ErbB3, and ErbB4. In reporter
gene assays, NIK could potentiate Grb7, ErbB2/ErbB4, and EGF-induced NF-kappaB
activation. A NIK kinase inactive mutant could block ErbB2/ErbB4 and EGF-induced
NF-kappaB activation. Moreover, EGF/heregulin receptors activated NF-kappaB in
wild-type, but not NIK-/- embryonic fibroblasts. Our findings suggest that NIK is
a component of the EGF/heregulin receptor signaling complexes and involved in
NF-kappaB activation triggered by these receptors.
Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
PMID: 12853971 [PubMed - indexed for MEDLINE]
18: J Biol Chem. 2003 Jul 18;278(29):27072-9. Epub 2003 May 7.
SINK is a p65-interacting negative regulator of NF-kappaB-dependent
transcription.
Wu M, Xu LG, Zhai Z, Shu HB.
Department of Cell Biology and Genetics, College of Life Sciences, Peking
University, Beijing 100871, China.
The transcription factor NF-kappaB plays important roles in inflammation and cell
survival. In this study, we identified SINK, an NF-kappaB-inducible protein.
Overexpression of SINK inhibited NF-kappaB-dependent transcription induced by
tumor necrosis factor (TNF) stimulation or its downstream signaling proteins but
did not inhibit NF-kappaB translocation to the nucleus and binding to DNA.
Co-immunoprecipitation and in vitro kinase assays indicated that SINK
specifically interacted with the NF-kappaB transactivator p65 and inhibited p65
phosphorylation by the catalytic subunit of protein kinase A, which has
previously been shown to regulate NF-kappaB activation. Consistent with its role
in inhibition of NF-kappaB-dependent transcription, SINK also sensitized cells to
apoptosis induced by TNF and TRAIL (TNF-related apoptosis-inducing ligand). Taken
together, these data suggest that SINK is critically involved in a novel negative
feedback control pathway of NF-kappaB-induced gene expression.
Publication Types:
In Vitro
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
PMID: 12736262 [PubMed - indexed for MEDLINE]
19: J Biol Chem. 2002 Jul 12;277(28):25617-23. Epub 2002 Apr 29.
AMID, an apoptosis-inducing factor-homologous mitochondrion-associated protein,
induces caspase-independent apoptosis.
Wu M, Xu LG, Li X, Zhai Z, Shu HB.
Department of Cell Biology and Genetics, College of Life Sciences, Peking
University, Beijing 100871, China.
Apoptosis-inducing factor (AIF) is a mitochondrial flavoprotein that triggers
caspase-independent apoptosis. We describe here the cloning and characterization
of a novel AIF-homologous molecule designated AMID (AIF-homologous
mitochondrion-associated inducer of death). AMID lacks a mitochondrial
localization sequence but shares significant homology with AIF and NADH
oxidoreductases from bacteria to mammalian species. Immunofluorescent staining
and biochemical experiments indicated that AMID was co-localized with
mitochondria. Overexpression of AMID induced cell death with characteristic
apoptotic morphology. Furthermore, AMID-induced apoptosis was independent of
caspase activation and p53 and was not inhibited by Bcl-2. These findings suggest
that AMID induces a novel caspase-independent apoptotic pathway.
Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
PMID: 11980907 [PubMed - indexed for MEDLINE]
20: J Biol Chem. 2002 May 3;277(18):15985-91. Epub 2002 Feb 19.
A novel zinc finger protein interacts with receptor-interacting protein (RIP) and
inhibits tumor necrosis factor (TNF)- and IL1-induced NF-kappa B activation.
Chen D, Li X, Zhai Z, Shu HB.
Department of Cell Biology and Genetics, College of Life Sciences, Peking
University, Beijing 100871, China.
Receptor-interacting protein (RIP) is a serine/threonine protein kinase that is
critically involved in tumor necrosis factor receptor-1 (TNF-R1)-induced NF-kappa
B activation. In a yeast two-hybrid screening for potential RIP-interacting
proteins, we identified ZIN (zinc finger protein inhibiting NF-kappa B), a novel
protein that specifically interacts with RIP. ZIN contains four RING-like zinc
finger domains at the middle and a proline-rich domain at the C terminus.
Overexpression of ZIN inhibits RIP-, IKK beta-, TNF-, and IL1-induced NF-kappa B
activation in a dose-dependent manner in 293 cells. Domain mapping experiments
indicate that the RING-like zinc finger domains of ZIN are required for its
interaction with RIP and inhibition of RIP-mediated NF-kappa B activation.
Overexpression of ZIN also potentiates RIP- and TNF-induced apoptosis. Moreover,
immunofluorescent staining indicates that ZIN is a cytoplasmic protein and that
it colocalizes with RIP. Our findings suggest that ZIN is an inhibitor of TNF-
and IL1-induced NF-kappa B activation pathways.
Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
PMID: 11854271 [PubMed - indexed for MEDLINE]
