The Full Wiki

Caspase: Wikis


Note: Many of our articles have direct quotes from sources you can cite, within the Wikipedia article! This article doesn't yet, but we're working on it! See more info or our list of citable articles.


From Wikipedia, the free encyclopedia

Caspases, or cysteine-aspartic proteases, are a family of cysteine proteases, which play essential roles in apoptosis (programmed cell death), necrosis and inflammation.

Caspases are essential in cells for apoptosis, or programmed cell death, in development and most other stages of adult life, and have been termed "executioner" proteins for their roles in the cell. Some caspases are also required in the immune system for the maturation of cytokines. Failure of apoptosis is one of the main contributions to tumour development and autoimmune diseases; this coupled with the unwanted apoptosis that occurs with ischemia or Alzheimer's disease, has stimulated interest in caspases as potential therapeutic targets since they were discovered in the mid 1990s.


Types of caspase proteins

As of November 2009, twelve caspases have been identified in humans.[1] There are two types of apoptotic caspases: initiator (apical) caspases and effector (executioner) caspases. Initiator caspases (e.g. CASP2, CASP8, CASP9 and CASP10) cleave inactive pro-forms of effector caspases, thereby activating them. Effector caspases (e.g. CASP3, CASP6, CASP7) in turn cleave other protein substrates within the cell, to trigger the apoptotic process. The initiation of this cascade reaction is regulated by caspase inhibitors.

CASP4 and CASP5, which are overexpressed in some cases of vitiligo and associated autoimmune diseases caused by NALP1 variants,[2] are not currently classified as initiator or effector in MeSH[3], because they are inflammatory enzymes which, in concert with CASP1, are involved in cytokine maturation. CASP14 is not involved in apoptosis or inflammation, but instead is involved in skin cell development.

Caspase cascade

Caspases are regulated at a post-translational level, ensuring that they can be rapidly activated. They are first synthesized as inactive pro-caspases, that consist of a prodomain, a small subunit and a large subunit. Initiator caspases possess a longer prodomain than the effector caspases, whose prodomain is very small. The prodomain of the initiator caspases contain domains such as a CARD domain (e.g. caspases-2 and -9) or a death effector domain (DED) (caspases-8 and -10) that enables the caspases to interact with other molecules that regulate their activation. These molecules respond to stimuli which cause the clustering of the initiator caspases. Such clustering allows them to activate automatically, so that they can proceed to activate the effector caspases.

The caspase cascade can be activated by:

Overview of signal transduction pathways involved in apoptosis.

Some of the final targets of caspases include:

  • nuclear lamins
  • ICAD/DFF45 (inhibitor of caspase activated DNase or DNA fragmentation factor 45)
  • PARP (poly-ADP ribose polymerase)
  • PAK2 (P 21-activated kinase 2).

The role of caspase substrate cleavage in the morphology of apoptosis is not clear. However, ICAD/DFF45 acts to restrain CAD (caspase activated DNase). The cleavage and inactivation of ICAD/DFF45 by a caspase allows CAD to enter the nucleus and fragment the DNA, causing the characteristic 'DNA ladder' in apoptotic cells.

In 2009 Queensland researchers announced caspase 1 and 3 in macrophages are regulated by p202 (a double-stranded DNA binding protein) reducing caspase response, and AIM2 (another double-stranded DNA binding protein) increasing caspase activation.[1]

Discovery of caspases, functions

Robert Horvitz initially established the importance of caspases in apoptosis and found that the ced-3 gene was required for the cell death that took place during the development of the nematode C. elegans. Horvitz and his colleague Junying Yuan found in 1993 that the protein encoded by the ced-3 gene was cysteine protease with similar properties to the mammalian interleukin-1-beta converting enzyme (ICE) (now known as caspase 1) which at the time was the only known caspase[4]. Other mammalian caspases were subsequently identified, in addition to caspases in organisms such as fruit fly Drosophila melanogaster.

Researchers decided upon the nomenclature of the caspase in 1996. In many instances, a particular caspase had been identified simultaneously by more than one laboratory, who would each give the protein a different name. For example, caspase 3 was variously known as CPP32, apopain and Yama. Caspases therefore were numbered in the order in which they were identified. ICE was therefore renamed as caspase 1. ICE was the first mammalian caspase to be characterised because of its similarity to the nematode death gene ced-3, but it appears that the principal role of this enzyme is to mediate inflammation rather than cell death.

For the discovery of caspases and other aspects of apoptosis, see articles by Danial and Korsmeyer,[5] Yuan and Horvitz,[6] and by Li et al.[7] in the January 23, 2004 edition of the journal Cell.

Recent studies have demonstrated that caspase proteases are also regulators of non-death functions, most notably those involving the maturation of a wide variety of cells such as red blood cells and skeletal muscle myoblasts.

See also


  1. ^ HUGO Gene Nomenclature Committee
  2. ^ Gregersen, P.K. (March 22 2007). "Modern genetics, ancient defenses, and potential therapies". N Engl J Med. 356: 1263–6. doi:10.1056/NEJMe078017. PMID 17377166.  [PMID 17377166]
  3. ^ NIH Medical Subject Headings
  4. ^ Yuan, J et al. (1993). "The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1 beta-converting enzyme". Cell 75: 641–652. doi:10.1016/0092-8674(93)90485-9.  
  5. ^ . Danial, N. N.; Korsmeyer, S. J. (January 2004). "Cell Death: Critical Control Points". Cell 116: 205–219. doi:10.1016/S0092-8674(04)00046-7. Retrieved 2006-11-06.  
  6. ^ Yuan, J.; Horvitz, H. R. (January 2004). "A First Insight into the Molecular Mechanisms of Apoptosis". Cell 116: 53–56. doi:10.1016/S0092-8674(04)00028-5. Retrieved 2006-11-06.  
  7. ^ Li, P.; et al. (January 2004). "Mitochondrial Activation of Apoptosis". Cell 116: 57–59. doi:10.1016/S0092-8674(04)00031-5. Retrieved 2006-11-06.  

External links



Got something to say? Make a comment.
Your name
Your email address