Medical Biology - Research Publications

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Author: Herold, Marco × Author: Huang, David × Author: Kelly, Gemma × Start date: 2000 × Type: Journal Article ×

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    VDAC2 enables BAX to mediate apoptosis and limit tumor development
    Chin, HS ; Li, MX ; Tan, IKL ; Ninnis, RL ; Reljic, B ; Scicluna, K ; Dagley, LF ; Sandow, JJ ; Kelly, GL ; Samson, AL ; Chappaz, S ; Khaw, SL ; Chang, C ; Morokoff, A ; Brinkmann, K ; Webb, A ; Hockings, C ; Hall, CM ; Kueh, AJ ; Ryan, MT ; Kluck, RM ; Bouillet, P ; Herold, MJ ; Gray, DHD ; Huang, DCS ; van Delft, MF ; Dewson, G (NATURE PUBLISHING GROUP, 2018-11-26)
    Intrinsic apoptosis is critical to prevent tumor formation and is engaged by many anti-cancer agents to eliminate tumor cells. BAX and BAK, the two essential mediators of apoptosis, are thought to be regulated through similar mechanisms and act redundantly to drive apoptotic cell death. From an unbiased genome-wide CRISPR/Cas9 screen, we identified VDAC2 (voltage-dependent anion channel 2) as important for BAX, but not BAK, to function. Genetic deletion of VDAC2 abrogated the association of BAX and BAK with mitochondrial complexes containing VDAC1, VDAC2, and VDAC3, but only inhibited BAX apoptotic function. Deleting VDAC2 phenocopied the loss of BAX in impairing both the killing of tumor cells by anti-cancer agents and the ability to suppress tumor formation. Together, our studies show that efficient BAX-mediated apoptosis depends on VDAC2, and reveal a striking difference in how BAX and BAK are functionally impacted by their interactions with VDAC2.
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    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.