Regulation of p53 family member isoform DeltaNp63alpha by the nuclear factor-kappaB targeting kinase IkappaB kinase beta.
Regulation of p53 family member isoform DeltaNp63alpha by the nuclear factor-kappaB targeting kinase IkappaB kinase beta.
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DOI：
10.1158/0008-5472.can-09-2613
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发表时间：
2010-02-15
期刊：
影响因子：
11.2
通讯作者：
Sidransky D
中科院分区：
文献类型：
--
作者：
Chatterjee A;Chang X;Sen T;Ravi R;Bedi A;Sidransky D
p53家族（p53、p73、p63）在细胞应激反应中起重要作用，包括响应于DNA损伤诱导细胞周期停滞和凋亡。除了能够反式激活下游靶基因表达的p63和p73同种型（TA同种型）外，这两种基因还表达显性负抑制同种型，如Δ Np 63 α。Δ Np 63 α响应于DNA损伤剂而降解，从而使细胞对遗传毒性剂产生有效反应。在这里，我们确定了一个关键的分子机制，调节Δ Np 63 α表达的外部刺激，如化疗药物或TNF-α。我们发现Δ Np 63 α与IκB激酶（IKK）相互作用，IKK是一种多亚基蛋白激酶，由两个催化亚基IKKα和IKKβ以及一个调节亚基IKKγ（NEMO-NF-κB必需修饰物）组成。我们发现IKKβ激酶促进泛素介导的Δ Np 63 α蛋白酶体降解，而激酶缺陷突变体IKKβ-K44 A则不能。细胞因子或化疗诱导的IKKβ刺激导致Δ Np 63 α降解，并增强参与DNA损伤细胞反应的p53家族诱导基因的反式激活。相反，用NEMO结合肽或siRNA介导的IKKβ表达沉默抑制IKK β可减弱细胞因子或化疗诱导的Δ Np 63 α降解。这些数据表明，IKKβ在调节Δ Np 63 α对外界刺激的反应中起重要作用。我们的研究结果表明，IKK的激活可能是Δ Np 63 α水平降低的一种机制，从而使细胞在面对细胞应激或DNA损伤时易于死亡。
The p53 family (p53, p73, p63) plays an instrumental role in the cellular stress response, including induction of cell cycle arrest and apoptosis in response to DNA damage. In addition to p63 and p73 isotypes capable of transactivating downstream target gene expression (TA isotypes), both genes also express dominant negative inhibitory isoforms, such as ΔNp63α. ΔNp63α is degraded in response to DNA damaging agents, thereby enabling an effective cellular response to genotoxic agents. Here, we identify a key molecular mechanism underlying the regulation of ΔNp63α expression in response to extrinsic stimuli, such as chemotherapeutic agents or TNF-α. We show that ΔNp63α interacts with IκB kinase (IKK), a multisubunit protein kinase that consists of two catalytic subunits, IKKα and IKKβ, and a regulatory subunit, IKKγ (NEMO-NF-κB essential modifier). We find that IKKβ kinase promotes ubiquitin-mediated proteasomal degradation of ΔNp63α, whereas a kinase-deficient mutant IKKβ-K44A fails to do so. Cytokine- or chemotherapy-induced stimulation of IKKβ leads to degradation of ΔNp63α and augments trans-activation of p53 family-induced genes involved in the cellular response to DNA damage. Conversely, inhibition of IKKβ with a NEMO-binding peptide or siRNA-mediated silencing IKKβ expression attenuates cytokine- or chemotherapy induced degradation of ΔNp63α. These data demonstrate that IKKβ plays an essential role in regulating ΔNp63α in response to extrinsic stimuli. Our findings suggest that the activation of IKK may be a mechanism by which levels of ΔNp63α are reduced, thereby rendering the cells susceptible to cell death in the face of cellular stress or DNA damage.