Abstract 2468: A p53 and microRNA-mediated pathway regulates mesenchymal stem cell differentiation

The tumor suppressor p53 plays important roles in bone density regulation and osteosarcoma suppression. However, the relationship between p53-mediated bone density regulation and osteosarcoma suppression is unclear mainly because the underlying molecular and cellular mechanisms are elusive. Here, we reported that p53 controls differentiation of mouse mesenchymal stem cells (mMSCs) in a cell cycle and apoptosis independent manner. The loss of p53 predisposes mMSCs towards osteogenic lineage but not adipogenic and chondrogenic lineages. This pro-osteogenic effect caused by p53 loss is associated with the up-regulation of Runt related transcription factor 2, a factor required for the osteogenic differentiation of mMSCs. Without extrinstic stress, studies show that p53 does not directly repress the transcription of Runt related transcription factor 2. Instead, it indirectly represses Runt related transcription factor 2 through activating microRNAs (miRs), which suppress Runt related transcription factor 2 at a post-transcriptional level. In osteosarcoma cells, the loss of p53 correlates with high levels of Runt related transcription factor 2 and the oncogene addiction of these cells to Runt related transcription factor 2. Together, our results discover a p53 and miR-mediated pathway regulating the differentiation of MSCs and this pathway is dysregulated in osteosarcoma cells. This lineage controlling role links the role of p53 in the osteogenic differentiation of MSC to its suppressive functions in osteosarcoma. Citation Format: Yunlong He, Shunlin Jiang, Wendy Dubois, Ling Ren, Chand Khanna, Jing Huang. A p53 and microRNA-mediated pathway regulates mesenchymal stem cell differentiation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2468. doi:10.1158/1538-7445.AM2014-2468