Enhanced deacetylation of p53 by the anti-apoptotic protein HSCO in association with histone deacetylase 1
Enhanced deacetylation of p53 by the anti-apoptotic protein HSCO in association with histone deacetylase 1
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DOI：
10.1074/jbc.m609751200
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发表时间：
2007-05-04
影响因子：
4.8
通讯作者：
Fujita, Jun
中科院分区：
文献类型：
--
作者：
Higashitsuji, Hisako;Higashitsuji, Hiroaki;Fujita, Jun
HSCO（hepatoma subtracted- cDNA library clone one，也称为ETHE 1）最初通过其在肝细胞癌中的频繁过表达来鉴定。HSCO通过与RelA结合并加速其从细胞核输出来抑制NF-κ B B的功能。我们发现HSCO通过抑制p53的转录活性在暴露于DNA损伤剂的细胞中表现出抗凋亡活性。在过表达HSCO的细胞中，促凋亡基因Noxa、Perp、PIG 3和Bax的诱导受到抑制。通过增加p53的泛素化和降解，HSCO降低p53蛋白水平。HSCO与组蛋白脱乙酰酶1（HDAC 1）特异性结合，独立于Mdm 2，并通过HDAC 1促进p53在Lys-373/382处的脱乙酰化。HSCO中的金属-β-内酰胺酶家族共有序列对于其对p53脱乙酰化的作用是重要的。免疫共沉淀和免疫荧光研究表明，HSCO，HDAC 1和p53在细胞核中形成复合物。因此，HSCO是增加HDAC 1对p53的脱乙酰酶活性的辅因子，导致细胞凋亡的抑制。用抗HSCO药物治疗保留野生型p53和过表达HSCO的肝细胞癌可能会重新建立p53反应并逆转化疗耐药性。
HSCO ( hepatoma subtracted- cDNA library clone one, also called ETHE1) was originally identified by its frequent overexpression in hepatocellular carcinomas. HSCO inhibits function of NF-kappa B by binding to RelA and accelerating its export from the nucleus. We show here that HSCO exhibits anti-apoptotic activity in cells exposed to DNA-damaging agents by suppressing transcriptional activity of p53. Induction of pro-apoptotic genes, Noxa, Perp, PIG3, and Bax were suppressed in cells overexpressing HSCO. By increasing ubiquitylation and degradation of p53, HSCO reduces p53 protein levels. HSCO specifically associates with histone deacetylase 1 (HDAC1) independently of Mdm2 and facilitates deacetylation of p53 at Lys-373/382 by HDAC1. The metallo-beta-lactamase family consensus sequence in HSCO is important for its effect on p53 deacetylation. Co-immunoprecipitation and immunofluorescence studies suggested that HSCO, HDAC1, and p53 form a complex in the nucleus. Thus, HSCO is a cofactor that increases the deacetylase activity of HDAC1 toward p53, leading to suppression of apoptosis. Treatment of hepatocellular carcinomas that retain wildtype p53 and overexpress HSCO with anti-HSCO agents might re-establish the p53 response and revert chemoresistance.