Stress Kills: Activation of BH3-only Bcl-2 Proteins
 

Death and survival are two opposite fates of cells that ironically are often played out by the same molecular machinery. The Bcl-2 family plays central roles in the regulation of apoptotic pathways, and is a classical example of the intertwining of death and survival mechanisms.  The Bcl-2 machinery consists of both pro-apoptotic and anti-apoptotic (pro-survival) family members:

    1.  Pro-apoptotic:
         a. BH3-only: BAD, Bid, Bik, Bim, Bmf, Hrk, Noxa,
             Puma
         b. Multidomain: BAK, BAX, BOK, Bcl-XS
    2.  Pro-survival: A1, Bcl-2, Bcl-XL, Mcl-1

The BH3-only proteins are thought to be integrators of diverse stress signals.  They are normally present at low levels or in an inactive state, and undergo activating transcriptional induction or post-translational modifi-cations in response to various stress stimuli (Figure 1). For example Noxa and Puma are transcribed following DNA damage-p53 induction, whereas Bid is cleaved following death receptor engagement.  Active BH3-only pro-apoptotic proteins translocate from the cytoplasm to the mitochondria where they interfere with the function of pro-survival family members, thereby activating down-stream apoptotic signaling events.


Stress Activation of BH3-only Proteins


FIGURE 1. BH3-only proteins transmit apoptotic signals originating from various stress stimuli.  They are activated through transcriptional induction (Noxa, Puma and Hrk) or post-translational modification (BAD, Bid, Bim, Bmf).  Active BH-3-only proteins localize to the mitochondrial outer membrane where they bind to pro-survival or multidomain pro-apoptotic proteins, leading to cytochrome release, caspase activation and ultimate cell death. Click for detailed view of image. 
 

 

Noxa (IMG-349A)

Bid (IMG-5693)

  


FIGURE 2. Western blot analysis of Noxa in RL-7 human follicular lymphoma cells using IMG-349A at
1 ug/ml.

FIGURE 3. Immunohisto-chemical analysis of two cores (A and B) from a human ovarian carcinoma formalin-fixed, paraffin-embedded tissue microarray stained for Bid expression using IMG-5693 at 1:2000.  Hematoxylin-eosin counterstain.
 

Related Products

Specificity

Cat. No.

 React App

BAD

 Multiple H, M, R WB, IHC, IP

BAK

 Multiple H, M WB, IHC, IP

BAX

 Multiple Multi WB, IHC, Flow

Bcl-2

 Multiple Multi WB, IHC, IP

Bcl-XL+S

 Multiple Multi WB, IHC, IP

Bid

 Multiple Multi WB, IHC, IP

Bik

 Multiple Multi WB, IHC, IP

Bmf

 Multiple H, M WB

Cytochrome C

 Multiple Multi WB, IHC, IF/ICC,
IP, FA

Mcl-1

 Multiple H, M, R WB, IHC, IP

Noxa

 Multiple H, M, R WB

p53

 Multiple H, M, R WB, IHC, IP, ChIP

Puma

 Multiple H, M WB, IHC

Key Publications
1. Puthalakath, H. et al. 2002. Cell Death
    Differentiation 9: 505-512. View Abstract

2. Shibue, T. et al. 2006. Inter. J of Cancer PMID:
    16572413.  View Abstract