Loss of MCL-1 or inhibition of BCL-2/BCL-X_L potentiates heat shock-induced apoptosis.

<p>(<b><i>A</i></b>) Cartoon illustrating the interactions of BH3-only proteins with multidomain proapoptotic (BAX and BAK) and antiapoptotic (MCL-1, BCL-2, and BCL-X_L) BCL-2 family members. BH3-only proteins can function as BAX/BAK activators (BIM, tBID, PUMA), or as sensitizers (NOXA, BAD, BMF, BIK, and HRK) that displace activators from antiapoptotic family members. (<b><i>B-D</i></b>) Wild-type and <i>Mcl-1^−/−</i> MEFs (<i>panel B, inset</i>) were exposed to heat shock (44°C for 1–1.5 h) in a humidified incubator (5% CO₂–95% air). The cells were then transferred to a 37°C incubator and later collected for MOMP (16 h), caspase-3 activation, PARP cleavage (24 h, <i>panel D</i>), Δψm (24 h, <i>panel C</i>) and cell death measurements (24 h, <i>panel B</i>). *p<0.05, significantly different from wild-type cells. (<b><i>E and F</i></b>) Wild-type MEFs were preincubated with DMSO (control) or ABT-737 (250 nM) for 1 h and subsequently exposed to heat shock (44°C for 1.5 h) in a humidified incubator (5% CO₂–95% air). The cells were then transferred to a 37°C incubator and later collected for MOMP (16 h), caspase-3 activation, PARP cleavage (24 h, <i>panel F</i>) and cell death measurements (24 h, <i>panel E</i>). *p<0.05, cells treated with ABT-737 were significantly different from those treated with DMSO. cPARP, cleaved PARP; cCasp3, cleaved/active caspase-3; S/N, supernatant; Pel, mitochondrial pellet.