The p53 homologue DeltaNp63alpha interacts with the nuclear factor-kappaB pathway to modulate epithelial cell growth.
The p53 homologue DeltaNp63alpha interacts with the nuclear factor-kappaB pathway to modulate epithelial cell growth.
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DOI：
10.1158/0008-5472.can-07-6123
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发表时间：
2008-07-01
期刊：
影响因子：
11.2
通讯作者：
Weinberg WC
中科院分区：
文献类型：
--
作者：
King KE;Ponnamperuma RM;Allen C;Lu H;Duggal P;Chen Z;Van Waes C;Weinberg WC
P53同源基因ΔNp63α在人类鳞癌中过表达并抑制细胞凋亡。在这里，我们报道了在过表达ΔNp63α的正常角质形成细胞和人类鳞癌细胞中，ΔNp63α与转录活性的核c-Rel(一种核转录因子-κB家族成员)物理上结合在一起，导致c-Rel核聚集增加。C-Relα或突变体IκBαM的过表达可减弱这种积累和相关的增殖促进作用，这表明含c-Rel的复合体的形成对于升高的ΔNp63α在存在生长抑制信号时维持增殖的能力是至关重要的。在人鳞癌细胞和正常角质形成细胞中，ΔNp63α：C-Rel复合体结合了一个启动子基序并抑制了ΔNp63α高表达的角质形成细胞中的CDK抑制因子p21WAF1，这与其在生长调节中的作用是一致的。ΔNp63α与活化的c-Rel的关系反映在其在原发灶的增殖室中的强烈核染色上。这是首次报道高水平的ΔNp63α与角质形成细胞和鳞癌中激活的c-Rel相互作用，从而促进失控增殖，这是癌症发病机制中的一个关键变化。
The p53 homologueΔNp63α is overexpressed and inhibits apoptosis in a subset of human squamous cell carcinomas (SCC). Here we report that in normal keratinocytes overexpressing ΔNp63α and in human squamous carcinoma cells, ΔNp63α physically associates with phosphorylated, transcriptionally active nuclear c-Rel, a NF-κB family member, resulting in increased c-Rel nuclear accumulation. This accumulation and the associated enhanced proliferation driven by elevated ΔNp63α are attenuated by c-Rel siRNA or overexpression of mutant IκBαM, indicating that c-Rel-containing complex formation is critical to the ability of elevated ΔNp63α to maintain proliferation in the presence of growth arresting signals. Consistent with a role in growth regulation, ΔNp63α:c-Rel complexes bind a promoter motif and repress the CDK inhibitor p21WAF1 in both human squamous carcinoma cells and normal keratinocytes overexpressing ΔNp63α. The relationship between ΔNp63α and activated c-Rel is reflected in their strong nuclear staining in the proliferating compartment of primary HNSCC. This is the first report indicating that high levels of ΔNp63α interact with activated c-Rel in keratinocytes and SCC, thereby promoting uncontrolled proliferation, a key alteration in the pathogenesis of cancers.