Hollenhorst Peter C
Medical Sciences, Indiana University School of Medicine, Bloomington, IN, USA.
Small GTPases. 2012 Jul-Sep;3(3):154-8. doi: 10.4161/sgtp.19630. Epub 2012 Jun 1.
The RAS/RAF/MEK/ERK signaling pathway is activated by mutation in many cancers. Neighboring ETS and AP-1 DNA binding sequences can act as response elements for transcriptional activation by this pathway. ERK phosphorylation of an ETS transcription factor is one mechanism of activating the RAS/ERK gene expression program that can promote cancer cell phenotypes such as proliferation, invasion, and metastasis. Recent genome-wide mapping of ETS proteins over-expressed by chromosomal rearrangement in prostate cancer reveals a second mechanism for activation of this gene expression program. An oncogenic subset of ETS transcription factors can activate RAS/ERK target genes even in the absence of RAS/ERK pathway activation by binding ETS/AP-1 sequences. Thus, regulation of cancer cell invasion and metastasis via ETS/AP-1 sequence elements depends on which ETS protein is bound, and the status of the RAS/ERK pathway. This commentary will focus on what is known about the selectivity of ETS/AP-1 sequences for different ETS transcription factors and the transcriptional consequences of ETS protein selection.
RAS/RAF/MEK/ERK信号通路在许多癌症中因突变而被激活。相邻的ETS和AP-1 DNA结合序列可作为该通路转录激活的反应元件。ERK对ETS转录因子的磷酸化是激活RAS/ERK基因表达程序的一种机制，该程序可促进癌细胞的增殖、侵袭和转移等表型。最近对前列腺癌中因染色体重排而过度表达的ETS蛋白进行的全基因组图谱分析揭示了激活该基因表达程序的另一种机制。即使在没有RAS/ERK通路激活的情况下，ETS转录因子的一个致癌亚群也可以通过结合ETS/AP-1序列来激活RAS/ERK靶基因。因此，通过ETS/AP-1序列元件对癌细胞侵袭和转移的调控取决于所结合的ETS蛋白以及RAS/ERK通路的状态。本评论将聚焦于已知的ETS/AP-1序列对不同ETS转录因子的选择性以及ETS蛋白选择的转录后果。
