Impaired intranuclear trafficking of Runx2 (AML3/CBFA1) transcription factors in breast cancer cells inhibits osteolysis in vivo
Impaired intranuclear trafficking of Runx2 (AML3/CBFA1) transcription factors in breast cancer cells inhibits osteolysis in vivo
复制标题
DOI：
10.1073/pnas.0409121102
复制
发表时间：
2005-02-01
影响因子：
11.1
通讯作者：
Stein, GS
中科院分区：
文献类型：
--
作者：
Javed, A;Barnes, GL;Stein, GS
Runx转录因子包括对器官发生必需的蛋白质家族。一个独特的核基质靶向信号的C端指导这些因素，其适当的亚核域。在这些位点，它们与辅调节蛋白和靶基因相互作用。我们先前已经表明，Runx 2 DNA结合域在转移性乳腺癌细胞中的异常表达可以防止骨中溶骨性病变的产生。在这里，我们表明，适当的Runx 2亚核靶向所需的骨质溶解。我们已经确定了Runx 2核基质靶向信号序列的点突变，这些点突变损害了Runx 2靶向核基质位点的能力。这些突变在体内阻断了MDA-MB-231乳腺癌细胞的侵袭性和溶骨性。表达Runx 2突变蛋白的细胞系在共培养试验中抑制骨髓基质细胞的成骨特性。突变乳腺癌细胞在体外也表现出降低的侵袭性，并且不表达参与侵袭和血管生成的基因（VEGF和MMP 13）。我们的研究结果表明，Runx 2核内组织的保真度是必要的靶基因介导的转移性乳腺癌细胞的溶骨活性的表达。
Runx transcription factors comprise a family of proteins that are essential for organogenesis. A unique nuclear matrix-targeting signal in the C terminus directs these factors to their appropriate subnuclear domains. At these sites, they interact with coregulatory proteins and target genes. We have previously shown that aberrant expression of the Runx2 DNA binding domain in metastatic breast cancer cells can prevent production of osteolytic lesions in bone. Here, we show that proper Runx2 subnuclear targeting is required for osteolysis. We have identified point mutations of the Runx2 nuclear matrix-targeting signal sequence that impair its targeting to nuclear matrix sites. These mutations block the invasive and osteolytic properties of MDA-MB-231 breast cancer cells in vivo. Cell lines expressing this Runx2 mutant protein inhibit the osteogenic properties of bone marrow stromal cells in coculture assays. The mutant breast cancer cells also exhibit reduced invasiveness in vitro and do not express genes involved in invasion and angiogenesis (VEGF and MMP13). Our findings suggest that fidelity of Runx2 intranuclear organization is necessary for expression of target genes that mediate the osteolytic activity of metastatic breast cancer cells.