Pathway Highlight: Three key factors that contribute to cellular heterogeneity in apoptosis

Mon, 05/01/2017 - 08:54

Have you ever wondered why cells in the same population respond differently to an apoptotic stimulus? Apoptosis, a form of programmed cell death, is vital for the removal of unwanted or damaged cells. As with most cellular processes, too much or too little activation can be detrimental and lead to various diseases including autoimmune disorders and cancer. While this process is tightly regulated, cells undergo apoptosis in a non-synchronized manner, which complicates the analysis of apoptotic events.  Here are 3 keys factors that determine how an individual cell will respond to an apoptotic stimulus.

caspase-3 antibody

Processed caspase 3 was detected in immersion fixed anti-FAS treated Jurkat human acute T cell leukemia cell line using Human/Mouse Active Caspase 3 Polyclonal Antibody (Catalog # AF835) and counterstained (green). Apoptotic cells are stained in red.

1. Bcl-2 family

One factor that contributes to cellular heterogeneity during apoptosis involves the Bcl-2 family of proteins. Members are divided based on their ability to either promote or inhibit cell death and their ratio is crucial to the way a cell progresses through the apoptosis signaling pathway. Elevated amounts of Bcl-2 family proteins, such as Mcl-1, Bcl-XL and Bcl-W, offer protection against apoptosis inducing stimuli. In contrast, Bax, Bak, PUMA, Bad, BID, and Bim include some of the pro-apoptotic members known to induce cell death via the mitochondrial (intrinsic) pathway. 

2. Cell cycle position

Another key factor that contributes to cellular heterogeneity involves an asynchronous cell cycle. Not all cells in a population are at the same stage of growth, and this can affect their response to an apoptotic stimulus.  Chen et al studied apoptosis related growth arrest in the cell cycle as a response to H202 in human diploid fibroblasts. They found that after H202 treatment, detached cells were apoptotic and stuck in the S phase, whereas attached cells were predominantly in the G1 or G2/M phase, destined for senescence.  What’s more, many of the main players involved in the cell cycle are also associated with apoptosis and interact with Bcl-2 family members. For instance, p53 recruits and directly interacts with Bcl-2 family members in order to permeabilize the outer mitochondrial membrane and subsequently release pro-apoptotic proteins.  Furthermore, the abundance of Bcl-2 proteins will affect the function of cell cycle proteins such as p53, cMyc, p21, and Rb

3. Transcriptional Activation

Lastly, differences in transcriptional activation between cells will also impact their apoptotic fate.  Individual cells in a population already start out with general differences in protein concentration because gene expression is a dynamic process with transcription occurring in stochastic bursts. This also results in differences in protein expression within the same cell over time and adds to the cell-to-cell variability observed in apoptosis.  

In summary, Bcl-2 family proteins, asynchronous cell cycle positions, and differences in transcriptional activity all contribute to cell heterogeneity and influence a cell’s response to an apoptotic stimulus. Novus Biologicals offers a variety of apoptosis research tools including Bcl-2 antibodies, caspase antibodies, and tissue microarrays, and we highly recommend using techniques such as flow cytometry and microscopy for single-cell measurements of apoptosis.

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  1. Pucci B, Kasten M, Giordano A. Cell cycle and apoptosis. [PMID: 11005563]
  2. Schuler M, Green DR. Transcription, apoptosis and p53: catch-22. [PMID: 15734577]
  3. Cory S, Huang DC, Adams JM. The Bcl-2 family: roles in cell survival and oncogenesis. [PMID: 14634621]
  4. Chen QM, Liu J, Merrett JB. Apoptosis or senescence-like growth arrest: influence of cell-cycle position, p53, p21 and bax in H2O2 response of normal human fibroblasts. [PMID: 10749685]
  5. Xia X, Owen MS, Lee RE, Gaudet S. Cell-to-cell variability in cell death: can systems biology help us make sense of it all? [PMID: 24874733]

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