XIAP-associating factor 1, a transcriptional target of BRD7, contributes to endothelial cell senescence.
XIAP-associating factor 1, a transcriptional target of BRD7, contributes to endothelial cell senescence.
复制标题
DOI：
10.18632/oncotarget.6962
复制
发表时间：
2016-02-02
期刊：
影响因子：
--
通讯作者：
Kim KS
中科院分区：
文献类型：
--
作者：
Heo JI;Kim W;Choi KJ;Bae S;Jeong JH;Kim KS
X连锁凋亡抑制因子1(XAF1)是XIAP介导的半胱氨酸天冬氨酸氨基转移酶抑制的拮抗剂。虽然XAF1是一种肿瘤抑制基因，但XAF1在细胞衰老中的作用尚不清楚。我们发现在阿霉素和电离辐射等遗传毒性药物作用下，XAF1在肺微血管内皮细胞中的表达增加，从而导致肺微血管内皮细胞过早衰老。相反，XAF1在早衰细胞中的下调部分克服了内皮细胞的衰老。P53基因敲除，而不是p16基因敲除，可消除XAF1诱导的衰老表型。XAF1的表达受溴结构域7(BRD7)转录调控。干扰素-γ可阻断干扰素诱导的小鼠衰老。在肺癌细胞中，BRD7基因被敲除后，XAF1的抑癌活性降低，而在BRD7缺失的异种移植瘤中，干扰素-γ对肿瘤的生长没有抑制作用。这些数据表明，XAF1参与了BRD7相关的衰老，并通过P53依赖的途径在内皮细胞衰老的调节中发挥重要作用。此外，对BRD7/XAF1系统的调节可能有助于组织或组织的衰老和防止细胞转化。
X-linked inhibitor of apoptosis (XIAP)-associated factor 1 (XAF1) is well known as an antagonist of XIAP-mediated caspase inhibition. Although XAF1 serves as a tumor-suppressor gene, the role of XAF1 in cellular senescence remains unclear. We found that XAF1 expression was increased by genotoxic agents, such as doxorubicin and ionizing radiation in pulmonary microvascular endothelial cells, consequently leading to premature senescence. Conversely, downregulation of XAF1 in premature senescent cells partially overcame endothelial cell senescence. p53 knockdown, but not p16 knockdown, abolished senescence phenotypes caused by XAF1 induction. XAF1 expression was transcriptionally regulated by Bromodomain 7 (BRD7). XAF1 induction with interferon-gamma (IFN-γ) treatment was abrogated by BRD7 knockdown, which resulted in blocking interferon-induced senescence. In lung cancer cells, XAF1 tumor suppressor activity was decreased by BRD7 knockdown, and inhibition of tumor growth by IFN-γ did not appear in BRD7-depleted xenograft tumors. These data suggest that XAF1 is involved in BRD7-associated senescence and plays an important role in the regulation of endothelial senescence through a p53-dependent pathway. Furthermore, regulation of the BRD7/XAF1 system might contribute to tissue or organismal aging and protection against cellular transformation.