p53 Family Members Regulate the Expression of the Apolipoprotein D Gene*
p53 Family Members Regulate the Expression of the Apolipoprotein D Gene*
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DOI：
10.1074/jbc.m807185200
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发表时间：
2009-01
影响因子：
4.8
通讯作者：
Y. Sasaki;H. Negishi;Ryota Koyama;Naoki Anbo;Kana Ohori;M. Idogawa;H. Mita;M. Toyota;K. Imai;Y. Shinomura;T. Tokino
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文献类型：
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作者：
Y. Sasaki;H. Negishi;Ryota Koyama;Naoki Anbo;Kana Ohori;M. Idogawa;H. Mita;M. Toyota;K. Imai;Y. Shinomura;T. Tokino
p73和p63是p53基因家族的成员，其主要通过调节多种基因的转录而在发育和稳态中发挥重要作用。我们在这里报告，载脂蛋白D（apoD），脂质运载蛋白超家族的脂质转运蛋白的成员，是p53家族成员基因的直接转录靶点。我们发现apoD的表达被TAp 73或TAp 63特异性上调，但p53没有显著上调。此外，apoD转录激活顺铂的方式依赖于内源性p73。通过使用靶向p73的小干扰RNA，我们证明了沉默内源性p73废除顺铂治疗后apoD转录的诱导。我们还确定了一个p73/p63结合位点的apoD基因的启动子，是响应p53家族成员。TAp 73的异位表达以及添加重组人apoD到培养基中诱导人骨肉瘤细胞系Saos-2的成骨细胞分化，如通过碱性磷酸酶活性评估的。重要的是，apoD敲低废除p73介导的碱性磷酸酶诱导。此外，TAp 73介导的apoD表达能够诱导人神经母细胞瘤细胞系SH-SY 5 Y中的形态分化以及神经元标记物的表达。这些结果表明，apoD诱导可能介导的p73活性在正常发育。
p73 and p63 are members of the p53 gene family that play an important role in development and homeostasis, mainly by regulating transcription of a variety of genes. We report here that apolipoprotein D (apoD), a member of the lipocalin superfamily of lipid transport proteins, is a direct transcriptional target of the p53 family member genes. We found that the expression of apoD was specifically up-regulated by either TAp73 or TAp63 but not significantly by p53. In addition, apoD transcription is activated in response to cisplatin in a manner dependent on endogenous p73. By using small interference RNA designed to target p73, we demonstrated that silencing endogenous p73 abolishes induction of apoD transcription following cisplatin treatment. We also identified a p73/p63-binding site in the promoter of the apoD gene that is responsive to the p53 family members. The ectopic expression of TAp73 as well as the addition of recombinant human apoD to culture medium induced the osteoblastic differentiation of the human osteosarcoma cell line Saos-2, as assessed by alkaline phosphatase activity. Importantly, apoD knockdown abrogated p73-mediated alkaline phosphatase induction. Moreover, TAp73-mediated apoD expression was able to induce morphological differentiation, as well as expression of neuronal markers, in the human neuroblastoma cell line SH-SY5Y. These results suggest that apoD induction may mediate the activity of p73 in normal development.