p27 transcriptionally coregulates cJun to drive programs of tumor progression
Abstract
p27 shifts from CDK inhibitor to oncogene when phosphorylated by PI3K effector kinases. Here, we show that p27 is a cJun coregulator, whose assembly and chromatin association is governed by p27 phosphorylation. In breast and bladder cancer cells with high p27pT157pT198 or expressing a CDK-binding defective p27pT157pT198 phosphomimetic (p27CK−DD), cJun is activated and interacts with p27, and p27/cJun complexes localize to the nucleus. p27/cJun up-regulates TGFB2 to drive metastasis in vivo. Global analysis of p27 and cJun chromatin binding and gene expression shows that cJun recruitment to many target genes is p27 dependent, increased by p27 phosphorylation, and activates programs of epithelial–mesenchymal transformation and metastasis. Finally, human breast cancers with high p27pT157 differentially express p27/cJun-regulated genes of prognostic relevance, supporting the biological significance of the work.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Mar 15, 2019
- Source ID
- 10.1073/pnas.1817415116
Entities
People
- Alexandra Besser
- Andy Minn
- Dekuang Zhao
- Hyunho Yoon
- Joyce M Slingerland
- Karoline Briegel
- Kibeom Jang
- Lluis Morey
- Minsoon Kim
- Miyoung Shin
- Seth A. Wander
- Xiao Xue
Organizations
- Doris Duke Charitable Foundation
- National Institutes of Health
- United States Department of Defense
- University of Miami
- University of Pennsylvania