Medical Biology - Research Publications

Permanent URI for this collection

http://hdl.handle.net/11343/238

Filters

2016 1
1
Reset filters

Settings
Statistics
Citations
Author: Strasser, Andreas × Author: Kelly, Gemma × Author: Aubrey, Brandon × Start date: 2016 × End date: 2016 ×

Search Results

Now showing 1 - 1 of 1
  • Item
    Thumbnail Image
    Therapeutic Response to Non-genotoxic Activation of p53 by Nutlin3a Is Driven by PUMA-Mediated Apoptosis in Lymphoma Cells
    Valente, LJ ; Aubrey, BJ ; Herold, MJ ; Kelly, GL ; Happo, L ; Scott, CL ; Newbold, A ; Johnstone, RW ; Huang, DCS ; Vassilev, LT ; Strasser, A (CELL PRESS, 2016-03-01)
    Nutlin3a is a small-molecule antagonist of MDM2 that promotes non-genotoxic activation of p53 through p53 protein stabilization and transactivation of p53 target genes. Nutlin3a is the forerunner of a class of cancer therapeutics that have reached clinical trials. Using transgenic and gene-targeted mouse models lacking the critical p53 target genes, p21, Puma, and Noxa, we found that only loss of PUMA conferred profound protection against Nutlin3a-induced killing in both non-transformed lymphoid cells and Eμ-Myc lymphomas in vitro and in vivo. CRISPR/Cas9-mediated targeting of the PUMA gene rendered human hematopoietic cancer cell lines markedly resistant to Nutlin3a-induced cell death. These results demonstrate that PUMA-mediated apoptosis, but not p21-mediated cell-cycle arrest or senescence, is a critical determinant of the therapeutic response to non-genotoxic p53 activation by Nutlin3a. Importantly, in human cancer, PUMA expression may predict patient responses to treatment with MDM2 antagonists.