Medical Biology - Research Publications

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Author: Bouillet, Philippe × Author: Herold, Marco × End date: 2019 × Start date: 2010 ×

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    Impact of conditional deletion of the pro-apoptotic BCL-2 family member BIM in mice
    Herold, MJ ; Stuchbery, R ; Merino, D ; Willson, T ; Strasser, A ; Hildeman, D ; Bouillet, P (NATURE PUBLISHING GROUP, 2014-10)
    The pro-apoptotic BH3-only BCL-2 family member BIM is a critical determinant of hematopoietic cell development and homeostasis. It has been argued that the striking hematopoietic abnormalities of BIM-deficient mice (accumulation of lymphocytes and granulocytes) may be the result of the loss of the protein throughout the whole animal rather than a consequence intrinsic to the loss of BIM in hematopoietic cells. To address this issue and allow the deletion of BIM in specific cell types in future studies, we have developed a mouse strain with a conditional Bim allele as well as a new Cre transgenic strain, Vav-CreER, in which the tamoxifen-inducible CreER recombinase (fusion protein) is predominantly expressed in the hematopoietic system. We show that acute loss of BIM in the adult mouse rapidly results in the hematopoietic phenotypes previously observed in mice lacking BIM in all tissues. This includes changes in thymocyte subpopulations, increased white blood cell counts and resistance of lymphocytes to BIM-dependent apoptotic stimuli, such as cytokine deprivation. We have validated this novel conditional Bim knockout mouse model using established and newly developed CreER strains (Rosa26-CreER and Vav-CreER) and will make these exciting new tools for studies on cell death and cancer available.
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    Evidence against upstream regulation of the unfolded protein response (UPR) by pro-apoptotic BIM and PUMA
    Herold, MJ ; O'Reilly, LA ; Lin, A ; Srivastava, R ; Doerflinger, M ; Bouillet, P ; Strasser, A ; Puthalakath, H (NATURE PUBLISHING GROUP, 2014-07)
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    Male sterility in Mcl-1-flox mice is not due to enhanced Mcl1 protein stability
    Ah-Cann, C ; Tailler, M ; Kueh, AJ ; Herold, MJ ; Opferman, JT ; Asselin-Labat, M-L ; Bouillet, P (NATURE PUBLISHING GROUP, 2016-12)
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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.