User:Taekyubabo/sandbox

add reference Takahashi, R, Deveraux, Q, Tamm, I, Welsh, K, Assa -Munt, N, Salvesen, GS and Reed, JC (1998). "A single BIR domain of XIAP sufficient for inhibiting caspases." J Biol Chem 273 (14): 7787-90.

start by adding some references that the previous user did not add

Apoptosis occurs through two pathways

• Intrinsic(Mitochondrial)
• Extrinsic
  • [1]

Inhibitors of apoptosis mostly act on intrinsic, mitochondrial apoptotic mechanisms.

Other Inhibitors of Apoptosis

Although the page is titled Inhibitors of Apoptosis, it only ever mentions IAPs, which are not the only inhibitors. There are other important inhibitors that also have been well studied and are worth a mention in this section.

Bcl-2

Bcl-2 is an oncogene that also acts as an inhibitor of apoptosis.

• explaining Bcl-2 (families, structure)
  • [2]
  • [3]
  • [4]
• what Bcl-2 acts on
  • [5]
• inhibitors of Bcl-2
• [6]

CrmA

Cytokine response modifier A is a viral protein that also inhibits cell apoptosis .

• [7]
  • not this particular website exactly but the sources that he sites.
• [8]
• [9]
• [10]

Role of Inhibitors of Apoptosis in Cancer

Inhibition of apoptosis has been an area of study regarding its role in cancer. The IAP survivin has been found in many cancerous cells, and some evidence points that it might play a role in the cell cycle regulation as well. I wish to add a section about the inhibitors' role in cancer and how possible inhibition of IAP's may lead to promising areas of cancer research.

• [11]
• [12]
• [13]
• [14]

save image files as .svg

Inhibitors of Apoptosis

Apoptosis, or programmed cell death, is a highly regulated process used by many multi cellular organisms. Like any regulated process, apoptosis is subject to either activation or inhibition by a variety of chemical factors. Apoptosis can be triggered through two main pathways; extrinsic and intrinsic. The extrinsic pathway mostly involves extracellular signals triggering intracellular apoptosis mechanisms by binding to and sending signals from the outside of the cell. Intrinsic pathways involved internal cell signaling primarily through the mitochondria [15]. Inhibitors of apoptosis are a group of proteins that mainly act on the intrinsic pathway that block programmed cell death, which can oftentimes lead to cancer or other effects for the cell. Many of these inhibitors act to block caspases, a family of cysteine proteases that play an integral role in apoptosis. Some of these inhibitors include the oncogene Bcl-2, viral inhibitor crmA, and IAP's.

Bcl-2

Bcl-2 is an oncogene that is part of the Bcl-2 family of proteins that can either inhibit or promote apoptosis. The Bcl-2 family is characterized by the Bcl-2 homologous domains BH1, BH2, BH3, and BH4, the combinations of which determine its role in the apoptosis process. Members of the family that inhibit apoptosis include Bcl-2 itself, Bcl-XL, and Bcl-w, which possess all four of the domains (physiology and look up more)[16]. Studies have shown that the Bcl-2 oncogene may inhibit apoptosis in two ways; either by directly controlling the activation of caspases, or by disrupting the channels that allow proapoptotic factors from leaving the mitochondria. Regarding the activation a caspases, there exists a gene called ced-9 in C. elegans that protects against cell death that is a part of the Bcl-2 family. ced-9 encodes for a protein that is structurally similar to Bcl-2, that has been shown to function quite similarly in inhibiting apoptosis. In C. elegans, the ced-9 protein binds to another protein ced-4, a homolog of APAF-1 in humans, and prevents it from activating caspase ced-3, which is necessary for killing of the cell. [17]. In humans APAF-1 actually doesn't interact with Bcl-2; rather is activated by cytochrome c, the release of which from the mitochondria is regulated by Bcl-2. BAX and BAK are multidomain proapoptoic members of the Bcl-2 family that lie in the cytosol and the mitochondria, respectively. After several stimuli leading to cell death are activated, BAX also moves to the mitochondria where it carries out its functions there. Bcl-2 and Bcl-xl have been found to sequester BH3 domain molecules in the mitochondria, which prevents the activation of BAX and BAK. [18] (look up more)

crmA

crmA, or cytokine response modifier A, is a cowpox serpin that inhibits caspases 1, 6 and 8, forming complexes with these caspases that renders them unable to perform their apoptotic functions. [19] Cowpox is a orthopox virus that increases their chances of survival and infection by inhibition of specific caspases and preventing inflammatory responses and apoptosis. [20]. By inhibiting caspase 1, also known as interleukin 1Beta converting enzyme (ICE)crmA prevents cytokines interleukin 1B from being formed, preventing an inflammatory response. Caspase 8 initiates apoptosis by activating "executioner" caspases, numbered 3, 6, and 7, and inhibiting that crmA prevents the other caspases from ever being activated. Although free floating crmA is relatively unstable, it becomes incredibly stable after binding to caspase 1, forming an irreversible stable complex. [21] Serpins generally inhibit serine proteases by a suicide substrate inhibition mechanism, in which upon binding to the protein it is to inhibit, serine undergoes a drastic change in structure that is no longer reversible. A reactive center loop is bound to the central beta loop of the serine, trapping the enzyme in a state where it is no longer able to perform its catalytic functions. Studies have shown that an analogous method is used by crmA to inhibit the cysteine protease caspases. [22]

'amino acids

Isoleucine (abbreviated as Ile or I; encoded by the codons AUU, AUC, and AUA is an ɑ-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated -+NH3 form under biological conditions), an α-carboxylic acid group (which is in the deprotonated –COO- form under biological conditions), and a hydrocarbon side chain, classifying it as a non-polar, uncharged(at physiological pH), aliphatic amino acid. It is essential in humans, meaning the body cannot synthesize it, and must be ingested in our diet. Isoleucine is synthesized from pyruvate employing leucine biosynthesis enzymes in other organisms such as bacteria.

Inability to break down isoleucine, along with other amino acids, is associated with the disease called Maple Syrup Urine Disease, which results in discoloration and a sweet smell in the patient's urine, which is where the name comes from. However in severe cases, MSUD can lead to damage to the brain cells and ultimately death.

Threonine (abbreviated as Thr or T) encoded by the codons ACU, ACC, ACA, and ACG is an ɑ-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated -+NH3 form under biological conditions), an α-carboxylic acid group (which is in the deprotonated –COO- form under biological conditions), and an alcohol containing side chain, classifying it as a polar, uncharged(at physiological pH) amino acid. It is essential in humans, meaning the body cannot synthesize it, and must be ingested in our diet. Isoleucine is synthesized from aspartate in bacterial cells such as E. coli.

Inability to break down isoleucine, along with other amino acids, is associated with the disease called Maple Syrup Urine Disease, which results in discoloration and a sweet smell in the patient's urine, which is where the name comes from. However in severe cases, MSUD can lead to damage to the brain cells and ultimately death.