Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School Boston, MA 02115, USA.
Sci Adv. 2021 Jan 1;7(1). doi: 10.1126/sciadv.abe5357. Print 2021 Jan.
Cytokines are extracellular proteins that convey messages between cells by interacting with cognate receptors at the cell surface and triggering signaling pathways that alter gene expression and other phenotypes in an autocrine or paracrine manner. Here, we show that the calcium-dependent cytokines S100A8 and S100A9 are recruited to numerous promoters and enhancers in a model of breast cellular transformation. This recruitment is associated with multiple DNA sequence motifs recognized by DNA binding transcription factors that are linked to transcriptional activation and are important for transformation. The cytokines interact with these transcription factors in nuclear extracts, and they activate transcription when artificially recruited to a target promoter. Nuclear-specific expression of S100A8/A9 promotes oncogenic transcription and leads to enhanced breast transformation phenotype. These results suggest that, in addition to its classical cytokine function, S100A8/A9 can act as a transcriptional coactivator.
细胞因子是细胞外蛋白，通过与细胞表面的同源受体相互作用传递信息，以自分泌或旁分泌的方式改变基因表达和其他表型。在这里，我们表明钙依赖性细胞因子 S100A8 和 S100A9 被招募到乳腺细胞转化模型中的许多启动子和增强子。这种招募与多个 DNA 结合转录因子识别的多种 DNA 序列基序相关联，这些基序与转录激活有关，对转化很重要。细胞因子在核提取物中与这些转录因子相互作用，并且当被人为招募到靶启动子时，它们会激活转录。S100A8/A9 的核特异性表达促进致癌转录，并导致增强的乳腺转化表型。这些结果表明，除了其经典的细胞因子功能外，S100A8/A9 还可以作为转录共激活因子。
