Identification of flotillin-2, a major protein on lipid rafts, as a novel target of p53 family members
Identification of flotillin-2, a major protein on lipid rafts, as a novel target of p53 family members
复制标题
DOI：
10.1158/1541-7786.mcr-07-0108
复制
发表时间：
2008-03-01
影响因子：
5.2
通讯作者：
Tokino, Takashi
中科院分区：
文献类型：
--
作者：
Sasaki, Yasushi;Oshima, Yuichiro;Tokino, Takashi
P73和p63是p53基因家族的成员，已被证明主要通过调节多种基因的转录在发育和体内平衡中发挥重要作用。这些基因的一个子集编码分泌的蛋白质和受体，这些蛋白质和受体可能参与相邻细胞之间的交流。我们在这里报道，flotilin -2是生物膜微结构域脂筏上的主要疏水蛋白，是p53家族成员基因的直接转录靶点。这些木筏在许多细胞过程中发挥重要作用，包括信号转导、膜运输、细胞骨架组织和病原体进入。我们发现flotilin -2的表达被TAp73 β或TAp63 γ特异性上调，而不被p53显著上调。此外，flotilin -2转录以依赖内源性p73的方式响应顺铂被激活。通过设计靶向p73的小干扰RNA，我们发现沉默内源性p73可以消除顺铂治疗后对flotilin -2转录的诱导。此外，我们确定了位于flotilin -2基因上游的p73/p63结合位点，该位点对p53家族成员有反应。这种反应因素在人类和啮齿动物之间高度保守。我们还发现，通过评估白细胞介素-6介导的信号转导和转录激活因子3的磷酸化，TAp73和TAp63的异位表达增强了信号转导。因此，除了直接激活外，p53家族成员基因还通过脂质筏增强了一组细胞过程。
p73 and p63 are members of the p53 gene family and have been shown to play an important role in development and homeostasis mainly by regulating the transcription of a variety of genes. A subset of these genes encodes secreted proteins and receptors that may be involved in the communication between adjacent cells. We report here that flotillin-2, a major hydrophobic protein on biomembrane microdomain lipid rafts, is a direct transcriptional target of the p53 family member genes. It has been suggested that such rafts could play an important role in many cellular processes including signal transduction, membrane trafficking, cytoskeletal organization, and pathogen entry. We found that the expression of flotillin-2 was specifically up-regulated by either TAp73 beta or TAp63 gamma, but not significantly by p53. In addition, flotillin-2 transcription is activated in response to cisplatin in a manner dependent on endogenous p73. By using small interference RNA designed to target p73, we showed that silencing endogenous p73 abolishes the induction of flotillin-2 transcription following cisplatin treatment. Furthermore, we identified a p73/p63-binding site located upstream of the flotillin-2 gene that is responsive to the p53 family members. This response element is highly conserved between humans and rodents. We also found that ectopic expression of TAp73 as well as TAp63 enhances signal transduction by assessing the interleukin-6-mediated phosphorylation cif signal transducers and activators of transcription 3. Thus, in addition to direct transactivation, p53 family member genes enhance a set of cellular processes via lipid rafts.