RAS/ERK pathway transcriptional regulation through ETS/AP-1 binding sites.
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.
Medical Sciences, Indiana University School of Medicine, Bloomington, IN, USA. pchollen@indiana.edu
Peter C
PC
Hollenhorst
D000818:Animals; D001665:Binding Sites; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D050783:Proto-Oncogene Proteins c-ets / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D018631:ras Proteins / Q000235:genetics*
D050783:Proto-Oncogene Proteins c-ets; D018808:Transcription Factor AP-1; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins