ΔNp63α regulates keratinocyte proliferation by controlling PTEN expression and localization
ΔNp63α regulates keratinocyte proliferation by controlling PTEN expression and localization
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DOI：
10.1038/cdd.2011.73
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发表时间：
2011-12-01
影响因子：
12.4
通讯作者：
Kadakia, M. P.
中科院分区：
文献类型：
--
作者：
Leonard, M. K.;Kommagani, R.;Kadakia, M. P.
Delta Np 63 α，作为一种致癌基因，被激活的Akt上调，这是众所周知的细胞存活途径的一部分。Akt激活被10号染色体上缺失的磷酸酶和张力蛋白同源物（PTEN）抑制，并且在pten启动子中存在推定的p63结合位点，这使我们研究Δ Np 63 α是否调节PTEN表达。Delta Np 63 α的敲低导致PTEN水平增加和活化Akt的损失，而Delta Np 63 α的过表达降低了PTEN水平并升高了活化Akt。Delta Np 63 α对PTEN的抑制与p53状态无关，因为Delta Np 63 α的缺失增加了具有和不具有功能性p53的细胞系中的PTEN表达。此外，Delta Np 63 α水平的降低导致核PTEN的增加。相反地，在表皮的增殖基底层中不存在体内细胞核PTEN，其中Δ Np 63 α表达最高。此外，我们表明，在角质形成细胞中，Δ Np 63 α和PTEN之间的平衡调节Akt激活并维持正常的增殖速率。这种平衡在非黑色素瘤皮肤癌中通过增加Delta Np 63 α水平而被破坏，并且可以增强增殖和随后的肿瘤发展。我们的研究表明，Delta Np 63 alpha负调节PTEN，从而在PTEN，Akt和Delta Np 63 alpha之间提供反馈回路，这在皮肤癌的发展中具有不可或缺的作用。Cell Death and Differentiation（2011）18，1924-1933; doi：10.1038/cdd.2011.73; 2011年6月3日在线发表
Delta Np63 alpha, implicated as an oncogene, is upregulated by activated Akt, part of a well-known cell survival pathway. Inhibition of Akt activation by phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and the presence of putative p63-binding sites in the pten promoter led us to investigate whether Delta Np63 alpha regulates PTEN expression. Knockdown of Delta Np63 alpha led to increases in PTEN levels and loss of activated Akt, while overexpression of Delta Np63 alpha decreased PTEN levels and elevated active Akt. The repression of PTEN by Delta Np63 alpha occurs independently of p53 status, as loss of Delta Np63 alpha increases PTEN expression in cell lines with and without functional p53. In addition, decreased levels of Delta Np63 alpha resulted in an increase in nuclear PTEN. Conversely, in vivo nuclear PTEN was absent in the proliferative basal layer of the epidermis where Delta Np63 alpha expression is highest. Additionally, we show that in keratinocytes a balance between Delta Np63 alpha and PTEN regulates Akt activation and maintains normal proliferation rates. This balance is disrupted in non-melanoma skin cancers through increased Delta Np63 alpha levels, and could enhance proliferation and subsequent neoplastic development. Our studies show that Delta Np63 alpha negatively regulates PTEN, thereby providing a feedback loop between PTEN, Akt and Delta Np63 alpha, which has an integral role in skin cancer development. Cell Death and Differentiation (2011) 18, 1924-1933; doi:10.1038/cdd.2011.73; published online 3 June 2011