Apoptosis

Cells die with distinct morphological changes, involving cellular condensation, DNA fragmentation and cell corpse engulfment. They used to be called “pyknotic cells,” but since the 1970s, they’ve been referred to as “apoptosis”, a Greek word that means “to fall.” The name is a metaphor for leaves falling from a tree, to convey the message that the death of cells can help the survival of the body as a whole. Over the years, apoptosis has drawn significant research interest due to its pathological significance: For example, healthy tissues use apoptosis to eliminate potentially cancerous cells, and the surviving cancer cells tend to have defects in triggering apoptosis. Also, many degenerative diseases are caused by apoptosis of essential cells that cannot be replaced.

As in other animals, apoptosis in Drosophila is executed by caspases, which are proteases that orchestrate the cell death process. Caspases can be subdivided into two classes: Executioner caspases become active after being cleaved by Initiator caspases. Initiator caspases gain activity after being incorporated into oligomeric complexes with adaptor proteins. One well-established caspase-activating complex is the apoptosome, which consists of the caspases and its adaptor, Apaf-1. Recently, we showed that the apoptosome is heavily regulated through feedback inhibition. In living cells, Apaf-1 and its partner caspase, Dronc, do not accumulate together. This is in part because active Dronc is unstable, and because Apaf-1 is cleaved and destroyed by Dronc. We believe that this allows living cells to maintain low levels of caspase activity without initiating apoptosis (Shapiro et al., 2008).

We are also interested in Inhibitor of Apoptosis Proteins (IAPs), which primarily inhibit caspases. Many IAP family members are induced by oncogenes (e.g., Betz et al., 2008) and expressed at high levels in cancer cells, giving them a survival advantage. In order for caspases to become active for apoptosis, these IAPs themselves much be inhibited. In Drosophila, there are four IAP antagonists that form oligomeric complexes to inhibit IAPs for apoptosis (Sandu et al., 2010). Synthetic IAP-antagonists are actively being developed to target human cancer cells with high IAP levels. We had helped establish that Drosophila IAP1 acts as a ubiquitin-ligase, ubiquitinating itself and other apoptosis regulators to exert its anti-apoptotic function (Ryoo et. al., 2002; Ryoo et al., 2004; Herman-Bachinsky et al., 2007). We are currently studying another IAP family protein, called BRUCE (BIR domain containing Ubiquitin Conjugating Enzyme), which strongly affects cell death in the fly. While its role in cell death has been well documented, the underlying mechanism has remained elusive. Our ongoing work suggests that this protein uses its BIR domain to bind IAP-antagonists, and target certain IAP-antagonists for ubiquitination at unconventional acceptor residues (Domingues and Ryoo, 2011). We are currently investigating how these genes are regulated in cancer models, and whether they help prevent the loss of vital cells during development and differentiation. 

 

Reference:

  1. Ryoo, H.D., Bergmann, A., Gonen, H., Ciechanover, A., Steller, H. (2002) Regulation of Drosophila IAP1 degradation and apoptosis by reaper and ubcD1.Nat. Cell Biol. 4(6):432-438. PMID 12021769.
  2. Ryoo, H.D., Gorenc, T., Steller, H. (2004) Apoptotic cells can induce compensatory cell proliferation through the JNK and the Wingless signaling pathways. Dev. Cell 7(4): 491-501. PMID 15469838.
  3. Herman-Bachinsky, Y., Ryoo, H.D., Ciechanover, A., Gonen, H. (2007) Regulation fo the Drosophila ubiquitin ligase DIAP1 is mediated via several distinct ubiquitin system pathways. Cell Death Differ. 14(4): 861-871.
  4. Betz, A., Ryoo, H.D., Steller, H., Darnell, J.E.Jr. (2008) STAT92E is a postive regulator of Drosophila inhibitor of apoptosis 1 (DIAP1) and protects against radiation-induced apoptosis. Proc. Natl. Acad. Sci. U.S.A. 105(37):13805-13810. PMID 18779571.
  5. Shapiro, P.J., Hsu, H.H., Jung, H., Robbins, E.S., Ryoo, H.D. (2008) Regulation fo the Drosophila apoptosome through feedback inhibition. Nat. Cell Biol. 10(12): 1440-1446. PMID 19011620.
  6. Sandu, C., Ryoo, H.D., Steller, H. (2010) Drosophila IAP antagonists form multimeric complexes to promote cell death. J. Cell Biol. 190(6): 1039-1052. PMID 20837774.
  7. Domingues, C., Ryoo, H.D. (2011) Drosophila BRUCE inhibits apoptosis through non-lysine ubiquitination of the IAP-antagonist REAPER. Cell Death Differ. [Epub ahead of print] doi: 10.1038/cdd.2011.116.