Transcriptional Regulation of PIK3CD and PIKFYVE in T-Cell Acute Lymphoblastic Leukemia by IKAROS and Protein Kinase CK2.
Transcriptional Regulation of PIK3CD and PIKFYVE in T-Cell Acute Lymphoblastic Leukemia by IKAROS and Protein Kinase CK2.
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DOI：
10.3390/ijms22020819
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发表时间：
2021-01-15
影响因子：
5.6
通讯作者：
Gowda C
中科院分区：
文献类型：
--
作者：
Dovat E;Song C;Hu T;Rahman MA;Dhanyamraju PK;Klink M;Bogush D;Soliman M;Kane S;McGrath M;Ding Y;Desai D;Sharma A;Gowda C
IKAROS由IKZF 1基因编码，是一种DNA结合蛋白，在T细胞急性淋巴细胞白血病（T-ALL）中起肿瘤抑制作用。最近的研究已经确定IKAROS在T-ALL基因表达的表观遗传调控中的新功能，并发现了许多可能由IKAROS直接调控的基因。在这里，我们报告两个基因，磷脂酰肌醇-4，5-二磷酸3-激酶催化亚基δ（PIK 3CD）和磷酸肌醇激酶，FYVE型锌指（PIKFYVE），IKAROS在T-ALL的转录调控。PIK 3CD编码磷酸肌醇3-激酶（PI 3 K）的蛋白质p110δ亚基。PI 3 K/AKT通路在包括T-ALL在内的癌症中经常失调。IKAROS与PIK 3CD和PIKFYVE的启动子区结合，并降低其在原发性T-ALL中的转录。功能分析表明IKAROS作为PIK 3CD和PIKFYVE的转录阻遏物发挥作用。蛋白激酶CK 2（CK 2）是一种在T-ALL中过表达的原癌激酶。CK 2磷酸化IKAROS，损害IKAROS的DNA结合能力，并作为PIK 3CD和PIKFYVE的阻遏物发挥作用。CK 2抑制导致IKAROS与PIK 3CD和PIKFYVE启动子的结合增加以及这两种基因的转录抑制。总体而言，所提供的数据首次证明，在T-ALL中，CK 2活性亢进至少部分地通过受损的IKAROS PIK 3CD和PIKFYVE转录调控促进PI 3 K信号通路上调。靶向CK 2恢复IKAROS对PI 3 K致癌信号通路的调节作用。
IKAROS, encoded by the IKZF1 gene, is a DNA-binding protein that functions as a tumor suppressor in T cell acute lymphoblastic leukemia (T-ALL). Recent studies have identified IKAROS’s novel function in the epigenetic regulation of gene expression in T-ALL and uncovered many genes that are likely to be directly regulated by IKAROS. Here, we report the transcriptional regulation of two genes, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta (PIK3CD) and phosphoinositide kinase, FYVE-type zinc finger containing (PIKFYVE), by IKAROS in T-ALL. PIK3CD encodes the protein p110δ subunit of phosphoinositide 3-kinase (PI3K). The PI3K/AKT pathway is frequently dysregulated in cancers, including T-ALL. IKAROS binds to the promoter regions of PIK3CD and PIKFYVE and reduces their transcription in primary T-ALL. Functional analysis demonstrates that IKAROS functions as a transcriptional repressor of both PIK3CD and PIKFYVE. Protein kinase CK2 (CK2) is a pro-oncogenic kinase that is overexpressed in T-ALL. CK2 phosphorylates IKAROS, impairs IKAROS’s DNA-binding ability, and functions as a repressor of PIK3CD and PIKFYVE. CK2 inhibition results in increased IKAROS binding to the promoters of PIK3CD and PIKFYVE and the transcriptional repression of both these genes. Overall, the presented data demonstrate for the first time that in T-ALL, CK2 hyperactivity contributes to PI3K signaling pathway upregulation, at least in part, through impaired IKAROS transcriptional regulation of PIK3CD and PIKFYVE. Targeting CK2 restores IKAROS’s regulatory effects on the PI3K oncogenic signaling pathway.
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影响因子：
11.4
作者：
Buontempo, F.;Orsini, E.;Martelli, A. M.
通讯作者：
Martelli, A. M.
影响因子：
4.3
作者：
Dovat, Sinisa;Song, Chunhua;Payne, Kimberly J.;Li, Zhanjun
通讯作者：
Li, Zhanjun
影响因子：
11.4
作者：
Ding, Yali;Zhang, Bo;Dovat, Sinisa
通讯作者：
Dovat, Sinisa
影响因子：
2.9
作者：
Battistutta, Roberto;Cozza, Giorgio;Pinna, Lorenzo A.
通讯作者：
Pinna, Lorenzo A.
DOI：
10.4331/wjbc.v2.i6.108
发表时间：
2011-06-26
期刊：
World journal of biological chemistry
影响因子：
--
作者：
Kastner, Philippe;Chan, Susan
通讯作者：
Chan, Susan