Identification of dihydropyrimidinase-related protein 4 as a novel target of the p53 tumor suppressor in the apoptotic response to DNA damage
Identification of dihydropyrimidinase-related protein 4 as a novel target of the p53 tumor suppressor in the apoptotic response to DNA damage
复制标题
DOI：
10.1002/ijc.25475
复制
发表时间：
2011-04-01
影响因子：
6.4
通讯作者：
Yoshida, Kiyotsugu
中科院分区：
文献类型：
--
作者：
Kimura, Junko;Kudoh, Takuya;Yoshida, Kiyotsugu
p53肿瘤抑制基因在多种肿瘤中经常发生突变，在维持基因组完整性方面发挥着重要作用。基因毒性损伤后，p53 的蛋白水平增加，p53 作为序列特异性转录因子发挥作用，调节细胞周期停滞、DNA 修复或凋亡所需的下游靶基因的表达。然而，p53 诱导细胞凋亡的机制仍不清楚。为了寻找 p53 影响细胞凋亡的新下游靶标，我们进行了微阵列分析。我们鉴定了二氢嘧啶酶相关蛋白 (DPYSL) 4 基因，该基因通过在 p53 缺陷细胞中过度表达 p53 而上调。 DPYSL4 的 mRNA 和蛋白表达均由抗癌药物在 p53 熟练细胞中特异性诱导。进一步的分析表明 DPYSL4 是 p53 的直接靶标。我们还发现，在 DPYSL4 沉默的细胞中，基因毒性诱导的细胞凋亡受到抑制。这些发现表明 DPYSL4 是一种由 p53 控制的新型细胞凋亡诱导因子，以响应 DNA 损伤。
The p53 tumor suppressor gene, which is frequently mutated in a wide variety of tumors, plays an important role in maintaining genomic integrity. Following genotoxic insults, the protein level of p53 is increased, and p53 functions as a sequence-specific transcription factor that regulates the expression of downstream target genes required for cell cycle arrest, DNA repair or apoptosis. However, the mechanism for p53-inducible apoptosis remains largely unclear. To search novel downstream targets of p53 on apoptosis, we had carried out microarray analysis. We identified dihydropyrimidinase-related protein (DPYSL) 4 gene, which was upregulated by overexpressing p53 in p53-deficient cells. Both mRNA and protein expressions of DPYSL4 were specifically induced by anticancer agents in p53-proficient cells. Further analyses demonstrated that DPYSL4 was a direct target for p53. We also found that genotoxic-induced apoptosis was repressed in cells silenced for DPYSL4. These findings indicate that DPYSL4 is a novel apoptosis-inducible factor controlled by p53 in response to DNA damage.