School of Life Sciences and Biotechnology, Korea University, Seoul 136-701, South Korea.
Cancer Lett. 2012 Jan 28;314(2):185-97. doi: 10.1016/j.canlet.2011.09.028. Epub 2011 Sep 29.
ADP-ribosylation factor 4 (ARF4) is a member of the Ras superfamily of small guanine nucleotide-binding proteins. ARF4 is known to interact with the epidermal growth factor receptor (EGFR) and mediates the EGF-dependent signal pathway, and has an anti-apoptotic function in human glioblastoma-derived U373MG cells. Although ARF4 plays a role in cancer cells, the molecular mechanism underlying regulation of its expression and its exact functions in breast cancer are unknown. In this study, we investigated the regulatory mechanism of ARF4 expression and its involvement in breast cancer cell migration. Our results show that phorbol 12-myristate 13-acetate (PMA) treatment increases ARF4 expression at both the transcriptional and translational levels. We found that the novel transcription factor small leucine zipper protein (sLZIP) binds directly to the CRE motif of the -43 to -35 region in the ARF4 promoter and regulates PMA-induced ARF4 expression. We also found that PMA-stimulated ARF4 expression increases AP-1 promoter activity, leading to induction of breast cancer cell migration. These results indicate that sLZIP-regulated ARF4 expression in response to PMA is involved in breast cancer cell migration, and sLZIP and ARF4 are potential therapeutic target molecules for treating breast cancer invasion and metastasis.
ADP-核糖基化因子 4（ARF4）是 Ras 家族中 Ras 小 G 蛋白家族的成员。ARF4 已知与表皮生长因子受体（EGFR）相互作用，并介导 EGF 依赖性信号通路，在人胶质母细胞瘤衍生的 U373MG 细胞中具有抗凋亡功能。虽然 ARF4 在癌细胞中起作用，但调节其表达的分子机制及其在乳腺癌中的确切功能尚不清楚。在这项研究中，我们研究了 ARF4 表达的调节机制及其在乳腺癌细胞迁移中的作用。我们的结果表明，佛波醇 12-肉豆蔻酸 13-乙酸酯（PMA）处理在转录和翻译水平上均增加 ARF4 的表达。我们发现，新型转录因子小亮氨酸拉链蛋白（sLZIP）直接结合到 ARF4 启动子的-43 至-35 区域的 CRE 基序，并调节 PMA 诱导的 ARF4 表达。我们还发现，PMA 刺激的 ARF4 表达增加了 AP-1 启动子活性，导致乳腺癌细胞迁移的诱导。这些结果表明，sLZIP 调节 PMA 刺激的 ARF4 表达参与乳腺癌细胞迁移，sLZIP 和 ARF4 是治疗乳腺癌侵袭和转移的潜在治疗靶标分子。
