Vincent Bruno, Sunyach Claire, Orzechowski Hans-Dieter, St George-Hyslop Peter, Checler Frédéric
Institut de Pharmacologie Moléculaire et Cellulaire, Unité Mixte de Recherche 6097 Centre National de la Recherche Scientifique/Université de Nice-Sophia-Antipolis, 06560 Valbonne, France.
J Neurosci. 2009 May 20;29(20):6752-60. doi: 10.1523/JNEUROSCI.0789-09.2009.
The presenilin-dependent gamma-secretase processing of the beta-amyloid precursor protein (betaAPP) conditions the length of the amyloid beta peptides (Abeta) that accumulate in the senile plaques of Alzheimer's disease-affected brains. This, together with an additional presenilin-mediated epsilon-secretase cleavage, generates intracellular betaAPP-derived fragments named amyloid intracellular domains (AICDs) that regulate the transcription of several genes. We establish that presenilins control the transcription of cellular prion protein (PrP(c)) by a gamma-secretase inhibitor-sensitive and AICD-mediated process. We demonstrate that AICD-dependent control of PrP(c) involves the tumor suppressor p53. Thus, p53-deficiency abolishes the AICD-mediated control of PrP(c) transcription. Furthermore, we show that p53 directly binds to the PrP(c) promoter and increases its transactivation. Overall, our study unravels a transcriptional regulation of PrP(c) by the oncogene p53 that is directly driven by presenilin-dependent formation of AICD. Furthermore, it adds support to previous reports linking secretase activities involved in betaAPP metabolism to the physiology of PrP(c).
β-淀粉样前体蛋白（βAPP）的早老素依赖性γ-分泌酶加工决定了在阿尔茨海默病患者大脑老年斑中积累的淀粉样β肽（Aβ）的长度。这与早老素介导的额外的ε-分泌酶切割一起，产生了名为淀粉样细胞内结构域（AICD）的细胞内βAPP衍生片段，这些片段调节多个基因的转录。我们证实，早老素通过γ-分泌酶抑制剂敏感且由AICD介导的过程控制细胞朊蛋白（PrP(c)）的转录。我们证明，AICD对PrP(c)的依赖性控制涉及肿瘤抑制因子p53。因此，p53缺陷消除了AICD介导对PrP(c)转录的控制。此外，我们表明p53直接结合到PrP(c)启动子上并增强其反式激活。总体而言，我们的研究揭示了癌基因p53对PrP(c)的转录调控，该调控由早老素依赖性AICD的形成直接驱动。此外，它为先前将参与βAPP代谢的分泌酶活性与PrP(c)生理学联系起来的报道提供了支持。
