2024年6月1日发(作者：仲孙韦)
Inhibition[edit]
In unstimulated cells, the NF-κB dimers are sequestered in the cytoplasm by a
family of inhibitors, called IκBs (Inhibitor of κB), which are proteins that contain
multiple copies of a sequence called ankyrin repeats. By virtue of their ankyrin
repeat domains, the IκB proteins mask the nuclear localization signals(NLS) of
NF-κB proteins and keep them sequestered in an inactive state in the cytoplasm.
[28]
在未刺激的细胞的细胞质中，一种名为IκBs（κB的抑制剂）可以阻断NF-κB二聚体，
IκBs是一种含有多个拷贝名为锚蛋白重复序列的蛋白。由于锚蛋白重复序列的结构域，IκB
蛋白会掩盖NF-κB蛋白核定位信号，并且在细胞质中使它们保持一种未激活的状态。
IκBs are a family of related proteins that have an N-terminal regulatory
domain, followed by six or more ankyrin repeats and a PEST domain near their C
terminus. Although the IκB family consists of IκBα, IκBβ, IκBε, and Bcl-3, the
best-studied and major IκB protein is IκBα. Due to the presence of ankyrin repeats
in their C-terminal halves, p105 and p100 also function as IκB proteins. The
c-terminal half of p100, that is often referred to as IκBδ, also functions as an
inhibitor.
[29][30]
IκBδ degradation in response to developmental stimuli, such as
those transduced through LTβR, potentiate NF-κB dimer activation in a NIK
dependent non-canonical pathway.
[29][31]
IκBs是有着N端基调解域的相关蛋白一个家族，在C端基附近有着6个或者更多锚
蛋白重复序列和PEST结构域。虽然IκB家族包括IκBα, IκBβ, IκBε, and Bcl-3，研究最多
和主要的IκB蛋白就是IκBα。因为它们C端基锚蛋白重复序列的存在，p105和p100起
到了IκB蛋白的功能。p100C端基的一半，就是常称作是IκBδ，也起到了抑制的作用。I
κBδ的下调对刺激有着应答，如通过LTβR的转换信号，以依赖于NIK的非经典通路二增
强NF-κB二聚体的活性。
Activation of the NF-κB is initiated by the signal-induced degradation of IκB
proteins. This occurs primarily via activation of a kinase called the IκB kinase (IKK).
IKK is composed of a heterodimer of the catalytic IKKα and IKKβ subunits and a
"master" regulatory protein termed NEMO (NF-κB essential modulator) or IKK
gamma. When activated by signals, usually coming from the outside of the cell, the
IκB kinase phosphorylates two serine residues located in an IκB regulatory domain.
When phosphorylated on these serines (e.g., serines 32 and 36 in human IκBα), the
IκB inhibitor molecules are modified by a process called ubiquitination, which then
leads them to be degraded by a cell structure called the proteasome.
NF-κB的激活由IκB蛋白信号诱导的降解的发起的。这主要通过一种激酶也就是IκB
激酶（IKK）的激活。IKK由IKKα、IKKβ亚基和一种“主要的”NEMO（NF-κB基本调节
器）或IKKγ调节蛋白组成的异质二聚体。一旦其中的丝氨酸发生磷酸化，例如在人的IκBα
丝氨酸32和36，泛素化的过程起着修饰IκB抑制剂分子。一种细胞结构名为蛋白酶体可
以导致抑制剂发生降解。
With the degradation of IκB, the NF-κB complex is then freed to enter the
nucleus where it can 'turn on' the expression of specific genes that have
DNA-binding sites for NF-κB nearby. The activation of these genes by NF-κB then
leads to the given physiological response, for example, an inflammatory or
immune response, a cell survival response, or cellular proliferation. NF-κB turns on
expression of its own repressor, IκBα. The newly synthesized IκBα then re-inhibits
NF-κB and, thus, forms an auto feedback loop, which results in oscillating levels of
NF-κB activity.
[32]
伴随着IκB降解，NF-κB复合物可以自由进入细胞核，在核中因为NF-κB在附近，
复合物可以启动有着DNA结合位点的特异基因的表达。通过NF-κB激活的基因随后导致
给定的生理反应，举例来说，一个炎症或免疫反应，一个细胞存活反应或者细胞的增殖。
NF-κB启动它自身抑制剂-IκBα的表达。新合成的IκBα然后再抑制NF-κB，因此，组成一
个自动反馈回路，引起NF-κB活力的水平的振荡。
In addition, several viruses, including the AIDS virus HIV, have binding sites for
NF-κB that controls the expression of viral genes, which in turn contribute to viral
replication or viral pathogenicity. In the case of HIV-1, activation of NF-κB may, at
least in part, be involved in activation of the virus from a latent, inactive
state.
[33]
YopP is a factor secreted by Yersinia pestis, the causative agent of plague,
that prevents the ubiquitination of IκB. This causes this pathogen to effectively
inhibit the NF-κB pathway and thus block the immune response of a human
infected with Yersinia.
[34]
另外，有一些病毒，包括AIDS病毒HIV，有着控制病毒基因表达的NF-κB的结合位
点，反过来有助于病毒复制或病毒的病理性。在HIV-1的情况下，NF-κB的活化，至少在
某种程度上，
As a drug target[edit]
Aberrant activation of NF-κB is frequently observed in many cancers.
Moreover, suppression of NF-κB limits the proliferation of cancer cells. In addition,
NF-κB is a key player in the inflammatory response. Hence methods of inhibiting
NF-κB signaling has potential therapeutic application in cancer and inflammatory
diseases.
[71][72]
The discovery that activation of NF-κB nuclear translocation can be separated
from the elevation of oxidant stress
[73]
gives an important hint to the development
of strategies for NF-κB inhibition.
A new drug called denosumab acts to raise bone mineral density and reduce
fracture rates in many patient sub-groups by inhibiting RANKL. RANKL acts
through its receptor RANK, which in turn promotes NF-κB,
[74]
RANKL normally
works by enabling the differentiation of osteoclasts from monocytes.
Disulfiram, olmesartan and dithiocarbamates can inhibit the nuclear factor-κB
(NF-κB) signaling cascade.
[75]
Anatabine's antiinflammatory effects are claimed to result from modulation of
NF-κB activity.
[76]
However the studies purporting its benefit use abnormally high
doses in the millimolar range (similar to the extracellular potassium concentration),
which are unlikely to be achieved in humans.
The IκB kinase (IKK) is an enzyme complex that is involved in propagating the
cellular response to inflammation.
[1]
IKK是一种涉及细胞应对炎症反应的酶复合物
The IκB kinase enzyme complex is part of the upstream NF-κB signal
transduction cascade. The IκBα (inhibitor of kappa B) protein inactivates the
NF-κB transcription factor by masking the nuclear localization signals (NLS) of
NF-κB proteins and keeping them sequestered in an inactive state in the
cytoplasm.
[2][3][4]
IKK specifically, phosphorylates the inhibitory IκBα protein.
[5]
This
phosphorylation results in the dissociation of IκBα from NF-κB. NF-κB, which is
now free migrates into the nucleus and activates the expression of at least 150
genes; some of which are anti-apoptotic.
IκB激酶复合物是NF-κB信号转导级联上游的一部分。IκBα（κB的抑制剂）蛋白使
NF-κB转录因子失活，IκB蛋白会掩盖NF-κB蛋白核定位信号，并且在细胞质中使它们保
持一种未激活的状态。特别地，IKK使抑制的IκBα蛋白磷酸化。这个磷酸化导致IκBα从
NF-κB的分离，自由迁移到细胞核而且激活至少150基因的表达，其中一些是抗凋亡的基
因。
2024年6月1日发(作者：仲孙韦)
Inhibition[edit]
In unstimulated cells, the NF-κB dimers are sequestered in the cytoplasm by a
family of inhibitors, called IκBs (Inhibitor of κB), which are proteins that contain
multiple copies of a sequence called ankyrin repeats. By virtue of their ankyrin
repeat domains, the IκB proteins mask the nuclear localization signals(NLS) of
NF-κB proteins and keep them sequestered in an inactive state in the cytoplasm.
[28]
在未刺激的细胞的细胞质中，一种名为IκBs（κB的抑制剂）可以阻断NF-κB二聚体，
IκBs是一种含有多个拷贝名为锚蛋白重复序列的蛋白。由于锚蛋白重复序列的结构域，IκB
蛋白会掩盖NF-κB蛋白核定位信号，并且在细胞质中使它们保持一种未激活的状态。
IκBs are a family of related proteins that have an N-terminal regulatory
domain, followed by six or more ankyrin repeats and a PEST domain near their C
terminus. Although the IκB family consists of IκBα, IκBβ, IκBε, and Bcl-3, the
best-studied and major IκB protein is IκBα. Due to the presence of ankyrin repeats
in their C-terminal halves, p105 and p100 also function as IκB proteins. The
c-terminal half of p100, that is often referred to as IκBδ, also functions as an
inhibitor.
[29][30]
IκBδ degradation in response to developmental stimuli, such as
those transduced through LTβR, potentiate NF-κB dimer activation in a NIK
dependent non-canonical pathway.
[29][31]
IκBs是有着N端基调解域的相关蛋白一个家族，在C端基附近有着6个或者更多锚
蛋白重复序列和PEST结构域。虽然IκB家族包括IκBα, IκBβ, IκBε, and Bcl-3，研究最多
和主要的IκB蛋白就是IκBα。因为它们C端基锚蛋白重复序列的存在，p105和p100起
到了IκB蛋白的功能。p100C端基的一半，就是常称作是IκBδ，也起到了抑制的作用。I
κBδ的下调对刺激有着应答，如通过LTβR的转换信号，以依赖于NIK的非经典通路二增
强NF-κB二聚体的活性。
Activation of the NF-κB is initiated by the signal-induced degradation of IκB
proteins. This occurs primarily via activation of a kinase called the IκB kinase (IKK).
IKK is composed of a heterodimer of the catalytic IKKα and IKKβ subunits and a
"master" regulatory protein termed NEMO (NF-κB essential modulator) or IKK
gamma. When activated by signals, usually coming from the outside of the cell, the
IκB kinase phosphorylates two serine residues located in an IκB regulatory domain.
When phosphorylated on these serines (e.g., serines 32 and 36 in human IκBα), the
IκB inhibitor molecules are modified by a process called ubiquitination, which then
leads them to be degraded by a cell structure called the proteasome.
NF-κB的激活由IκB蛋白信号诱导的降解的发起的。这主要通过一种激酶也就是IκB
激酶（IKK）的激活。IKK由IKKα、IKKβ亚基和一种“主要的”NEMO（NF-κB基本调节
器）或IKKγ调节蛋白组成的异质二聚体。一旦其中的丝氨酸发生磷酸化，例如在人的IκBα
丝氨酸32和36，泛素化的过程起着修饰IκB抑制剂分子。一种细胞结构名为蛋白酶体可
以导致抑制剂发生降解。
With the degradation of IκB, the NF-κB complex is then freed to enter the
nucleus where it can 'turn on' the expression of specific genes that have
DNA-binding sites for NF-κB nearby. The activation of these genes by NF-κB then
leads to the given physiological response, for example, an inflammatory or
immune response, a cell survival response, or cellular proliferation. NF-κB turns on
expression of its own repressor, IκBα. The newly synthesized IκBα then re-inhibits
NF-κB and, thus, forms an auto feedback loop, which results in oscillating levels of
NF-κB activity.
[32]
伴随着IκB降解，NF-κB复合物可以自由进入细胞核，在核中因为NF-κB在附近，
复合物可以启动有着DNA结合位点的特异基因的表达。通过NF-κB激活的基因随后导致
给定的生理反应，举例来说，一个炎症或免疫反应，一个细胞存活反应或者细胞的增殖。
NF-κB启动它自身抑制剂-IκBα的表达。新合成的IκBα然后再抑制NF-κB，因此，组成一
个自动反馈回路，引起NF-κB活力的水平的振荡。
In addition, several viruses, including the AIDS virus HIV, have binding sites for
NF-κB that controls the expression of viral genes, which in turn contribute to viral
replication or viral pathogenicity. In the case of HIV-1, activation of NF-κB may, at
least in part, be involved in activation of the virus from a latent, inactive
state.
[33]
YopP is a factor secreted by Yersinia pestis, the causative agent of plague,
that prevents the ubiquitination of IκB. This causes this pathogen to effectively
inhibit the NF-κB pathway and thus block the immune response of a human
infected with Yersinia.
[34]
另外，有一些病毒，包括AIDS病毒HIV，有着控制病毒基因表达的NF-κB的结合位
点，反过来有助于病毒复制或病毒的病理性。在HIV-1的情况下，NF-κB的活化，至少在
某种程度上，
As a drug target[edit]
Aberrant activation of NF-κB is frequently observed in many cancers.
Moreover, suppression of NF-κB limits the proliferation of cancer cells. In addition,
NF-κB is a key player in the inflammatory response. Hence methods of inhibiting
NF-κB signaling has potential therapeutic application in cancer and inflammatory
diseases.
[71][72]
The discovery that activation of NF-κB nuclear translocation can be separated
from the elevation of oxidant stress
[73]
gives an important hint to the development
of strategies for NF-κB inhibition.
A new drug called denosumab acts to raise bone mineral density and reduce
fracture rates in many patient sub-groups by inhibiting RANKL. RANKL acts
through its receptor RANK, which in turn promotes NF-κB,
[74]
RANKL normally
works by enabling the differentiation of osteoclasts from monocytes.
Disulfiram, olmesartan and dithiocarbamates can inhibit the nuclear factor-κB
(NF-κB) signaling cascade.
[75]
Anatabine's antiinflammatory effects are claimed to result from modulation of
NF-κB activity.
[76]
However the studies purporting its benefit use abnormally high
doses in the millimolar range (similar to the extracellular potassium concentration),
which are unlikely to be achieved in humans.
The IκB kinase (IKK) is an enzyme complex that is involved in propagating the
cellular response to inflammation.
[1]
IKK是一种涉及细胞应对炎症反应的酶复合物
The IκB kinase enzyme complex is part of the upstream NF-κB signal
transduction cascade. The IκBα (inhibitor of kappa B) protein inactivates the
NF-κB transcription factor by masking the nuclear localization signals (NLS) of
NF-κB proteins and keeping them sequestered in an inactive state in the
cytoplasm.
[2][3][4]
IKK specifically, phosphorylates the inhibitory IκBα protein.
[5]
This
phosphorylation results in the dissociation of IκBα from NF-κB. NF-κB, which is
now free migrates into the nucleus and activates the expression of at least 150
genes; some of which are anti-apoptotic.
IκB激酶复合物是NF-κB信号转导级联上游的一部分。IκBα（κB的抑制剂）蛋白使
NF-κB转录因子失活，IκB蛋白会掩盖NF-κB蛋白核定位信号，并且在细胞质中使它们保
持一种未激活的状态。特别地，IKK使抑制的IκBα蛋白磷酸化。这个磷酸化导致IκBα从
NF-κB的分离，自由迁移到细胞核而且激活至少150基因的表达，其中一些是抗凋亡的基
因。