Carboxyl-terminal Src kinase homologous kinase negatively regulates the chemokine receptor CXCR4 through YY1 and impairs CXCR4/CXCL12 (SDF-1α)- mediated breast cancer cell migration
Carboxyl-terminal Src kinase homologous kinase negatively regulates the chemokine receptor CXCR4 through YY1 and impairs CXCR4/CXCL12 (SDF-1α)- mediated breast cancer cell migration
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DOI：
10.1158/0008-5472.can-04-3309
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发表时间：
2005-04-01
期刊：
影响因子：
11.2
通讯作者：
Avraham, HK
中科院分区：
文献类型：
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作者：
Lee, BC;Lee, TH;Avraham, HK
通过基因芯片分析，我们发现羧基末端Src激酶同源激酶（CHK）调节趋化因子受体CXCR4的表达。Northern blot和荧光活化细胞分选分析显示，CHK分别下调了CXCR4 mRNA和蛋白水平。突变的CHK包含CHK的ATP结合位点突变，未能抑制CXCR4的表达，提示CHK激酶活性参与了CXCR4的调控。凝胶位移分析结果表明，CHK通过改变YY1与CXCR4启动子的结合来调节CXCR4的转录活性。虽然CHK对YY1、c-Myc、Max和其他YY1结合蛋白的表达没有显著影响，但CHK被发现可以调节YY1/c-Myc的关联。此外，CHK抑制cxcr4阳性乳腺癌细胞的迁移。综上所述，这些研究表明CHK通过YY1转录因子下调CXCR4，导致CXCR4介导的乳腺癌细胞运动和迁移减少的新机制。
Using microarray gene analysis, we found that carboxyl-terminal Src kinase homologous kinase (CHK) regulated the expression of the chemokine receptor, CXCR4. Northern blot and fluorescence-activated cell-sorting analyses showed that CHK down-regulated CXCR4 mRNA and protein levels, respectively. Mutated CHK, which contains a mutation within the ATP binding site of CHK, failed to inhibit CXCR4 expression, thus suggesting that CHK kinase activity is involved in the regulation of CXCR4. Results from gel shift analysis indicated that CHK regulates CXCR4 transcriptional activity by altering YY1 binding to the CXCR4 promoter. Whereas CHK had no significant effects on the expression of YY1, c-Myc, Max, and other YY1-binding proteins, CHK was found to modulate the YY1/c-Myc association. Furthermore, CHK inhibited CXCR4-positive breast cancer cell migration. Taken together, these studies show a novel mechanism by which CHK down-regalates CXCR4 through the YY1 transcription factor, leading to decreased CXCR4-mediated breast cancer cell motility and migration.