TY - JOUR
T1 - Measurement of BH3-only protein tolerance
AU - Dai, Haiming
AU - Ding, Husheng
AU - Peterson, Kevin L.
AU - Meng, X. Wei
AU - Schneider, Paula A.
AU - Knorr, Katherine L.B.
AU - Kaufmann, Scott H.
N1 - Funding Information:
Acknowledgements. This work was supported in part by R01 CA166741. HD was also supported by the Hundred-Talent Program of Chinese Academy of Sciences. We gratefully acknowledge assistance of the Mayo Clinic Microscopy and Cell Analysis Core for cell sorting, helpful discussions with members of the Kaufmann laboratory, editorial assistance of Deb Strauss and thoughtful comments of the anonymous referees.
Publisher Copyright:
© 2018 ADMC Associazione Differenziamentoe.
PY - 2018
Y1 - 2018
N2 - The BCL2 family of proteins regulates cellular life and death decisions. Among BCL2 family members, BH3-only proteins have critical roles by neutralizing antiapoptotic family members, as well as directly activating BAX and BAK. Despite widespread occurrence of BH3-only protein upregulation in response to various stresses, this process is rarely quantified. Moreover, it is unclear whether all BH3-only proteins are equipotent at inducing cell death. Here we show that BH3-only proteins increase as much as 15- to 20-fold after various treatments and define a parameter, termed BH3-only tolerance, which measures how many copies of a particular BH3-only protein can be expressed before the majority of cells in a population undergo apoptosis. We not only assess the relative contributions of anti- and proapoptotic BCL2 family members to BH3-only tolerance, but also illustrate how the study of this parameter can be used to understand cellular sensitivity to anticancer drugs and new combinations. These observations provide a new quantitative framework for assessing apoptotic susceptibility under various conditions.
AB - The BCL2 family of proteins regulates cellular life and death decisions. Among BCL2 family members, BH3-only proteins have critical roles by neutralizing antiapoptotic family members, as well as directly activating BAX and BAK. Despite widespread occurrence of BH3-only protein upregulation in response to various stresses, this process is rarely quantified. Moreover, it is unclear whether all BH3-only proteins are equipotent at inducing cell death. Here we show that BH3-only proteins increase as much as 15- to 20-fold after various treatments and define a parameter, termed BH3-only tolerance, which measures how many copies of a particular BH3-only protein can be expressed before the majority of cells in a population undergo apoptosis. We not only assess the relative contributions of anti- and proapoptotic BCL2 family members to BH3-only tolerance, but also illustrate how the study of this parameter can be used to understand cellular sensitivity to anticancer drugs and new combinations. These observations provide a new quantitative framework for assessing apoptotic susceptibility under various conditions.
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U2 - 10.1038/cdd.2017.156
DO - 10.1038/cdd.2017.156
M3 - Article
C2 - 29053140
AN - SCOPUS:85047993135
SN - 1350-9047
VL - 25
SP - 282
EP - 293
JO - Cell Death and Differentiation
JF - Cell Death and Differentiation
IS - 2
ER -