Interrelated roles for Mcl-1 and BIM in regulation of TRAIL-mediated mitochondrial apoptosis
Authors: Hannah Rabinowich
Jie Han
Leslie A Goldstein
Brian R Gastman
Journal: Journal of Biological Chemistry (2006)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: TRAIL receptor; mitochondria; Bcl-2; Mcl-1; Bim
Affiliations: Department of Pathology, The University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.

Abstract:  The current study demonstrates a novel cross-talk mechanism between the TRAIL receptor death signaling pathway and the mitochondria. This newly identified pathway is regulated at the mitochondrial outer membrane by a complex between the prosurvival Bcl-2 member, Mcl-1 and the BH3-only protein, Bim. Under non-apoptotic conditions, Bim is sequestered by Mcl-1. Direct degradation of Mcl-1 by TRAIL-activated caspase-8 or caspase-3 produces Mcl-1-free Bim that mediates a Bax-dependent apoptotic cascade. Using Mcl-1 or Bim RNAi, we demonstrate that a loss in Mcl-1 expression significantly enhances the mitochondrial apoptotic response to TRAIL that is now mediated by freed Bim. Whereas overexpression of Mcl-1 contributes to the preservation of the mitochondrial membrane potential, Mcl-1 knockdown facilitates the Bim-mediated dissipation of this potential. Loss of Mcl-1 contributes to an increased level of caspase activity downstream of the mitochondrial response to TRAIL. Furthermore, the Mcl-1 expression level at the mitochondrial outer membrane determines the release efficiency for the apoptogenic proteins cytochrome c, Smac, and HtrA2 in response to Bim. These are the first findings to demonstrate the involvement of Bim in the TRAIL-mediated mitochondrial cascade. They also suggest that Mcl-1 may serve as a direct substrate for TRAIL-activated caspases implying the existence of a novel TRAIL/caspase-8/Mcl-1/Bim communication mechanism between the extrinsic and the intrinsic apoptotic pathways. 

Retracted: No

PubPeer comments:
 Figure 6A, 4h and 8h ODC appear to be very similar. 6A contrast enhanced (top) 6A original (bottom) *** ![file] *** ![file] , 
 But the third, rotated version of the tissue slice shows manipulations. Features have been moved and duplicated. ![file] , 
  Figure 8. Histopathological examination (100u00d7) of mice skin at (a) 4th h, (b) 8th h, (c) 16th h, and (d) 24th h after exposure of DMBA and IP6, in various forms. Most affected epidermis thickness is shown by the double head arrow. SH, squamous hyperplasia; D, dermis; EP, epidermis; C, capillary; HF, hair follicle; SG, sebaceous gland; SGL, sebaceous gland loss; E, erosion. I, Placebo formulation; II, DMBA+ placebo formulation; III, DMBA + IP6 in acetone; IV, DMBA + F1 (dose 1); V, DMBA + F1 (dose 2); VI, DMBA + F2. Double headed arrow showing skin thickness Triplicated panel (one copy rotated. ![] , 
 Erratum published. https: pubs.acs.org doi 10.1021 acs.molpharmaceut.2c00030# , 
 #4  In the Figure 6A 4h ODC Western blot image (protein level), there was an error and a correction is supplied. The article also contains an inadvertent error in Figure 8IV(b) and Figure 8VI(b); hence, these images have been replaced with the following correct images. ![] ![] Just to remind readers, the  inadvertent error in Figs 8IV(b) and 8VI(b) involved image rotation and manipulation. ![] ,