Inhibitor of apoptosis

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Inhibitors of apoptosis are a group of proteins that mainly act on the intrinsic pathway that block programmed cell death, which can frequently lead to cancer or other effects for the cell if mutated or improperly regulated. Many of these inhibitors act to block caspases, a family of cysteine proteases that play an integral role in apoptosis. [1] Some of these inhibitors include the Bcl-2 family, viral inhibitor crmA, and IAP's.

Contents

Apoptosis, or programmed cell death, is a highly regulated process used by many multicellular 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 pathways. The extrinsic pathway mostly involves extracellular signals triggering intracellular apoptosis mechanisms by binding to receptors in the cell membrane and sending signals from the outside of the cell. Intrinsic pathways involved internal cell signaling primarily through the mitochondria. [2]

Bcl-2 family

Bcl-2 Crystal Structure with visible domains BCL2 Crystal Structure.rsh.png
Bcl-2 Crystal Structure with visible domains

The Bcl-2 family of proteins can either inhibit or promote apoptosis and members are characterized by the Bcl-2 homologous domains BH1, BH2, BH3, and BH4. The combinations of the domains in the proteins 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. [3] Bcl-2 is the most well known of the anti-apoptotic members, and is classified as an oncogene. 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.

Activity in the cell

Regarding the activation of 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 a protein that is structurally similar to Bcl-2 that 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. [4] In humans APAF-1 actually doesn't interact with Bcl-2; rather it 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. [5]

crmA

Cytokine response modifier A
Crmaedit.png
crmA structure with visible domain
Identifiers
Organism Cowpox virus
SymbolCrmA
Alt. symbolsSerine proteinase inhibitor 2
Entrez 1486086
RefSeq (Prot) NP_619988.1
UniProt P07385
Other data
Chromosome genomic: 0.19 - 0.19 Mb
Search for
Structures Swiss-model
Domains InterPro

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. Cowpox is an orthopox virus that increases their chances of survival and infection by inhibition of specific caspases and preventing inflammatory responses and apoptosis. [6]

Serpins generally inhibit serine proteases by a suicide substrate inhibition mechanism, in which the serpin undergoes a drastic change in structure to form an acyl enzyme intermediate. A reactive center loop of the protease is bound to the central beta loop of the serpin, trapping the protease in a state where it is no longer able to perform its catalytic functions. Studies have shown crmA uses a method analogous to serpin inhibition of serine proteases to inhibit cysteine protease caspases. [6]

IAPs

The Inhibitors of apoptosis proteins (IAP) are a family of functionally and structurally related proteins that serve as endogenous inhibitors of programmed cell death (apoptosis). A common feature of all IAPs is the presence of a BIR (Baculovirus IAP Repeat, a ~70 amino acid domain) in one to three copies. The human IAP family consists of 8 members, and IAP homologs have been identified in numerous organisms.

The first members of the IAPs identified were from the baculovirus IAPs, Cp-IAP and Op-IAP, which bind to and inhibit caspases as a mechanism that contributes to its efficient infection and replication cycle in the host. Later, five more human IAPs were discovered which included XIAP, cIAP1 , C-IAP2, NAIP, Livin and Survivin.

The best characterized IAP is XIAP, which binds caspase-9, caspase-3 and caspase-7, thereby inhibiting their activation and preventing apoptosis. Also cIAP1 and cIAP2 have been shown to bind caspases, although how the IAPs inhibit apoptosis mechanistically at the molecular level is not completely understood.

Activity of XIAP is blocked by binding to DIABLO (Smac) and HTRA2 (Omi) proteins released from mitochondria after proapoptotic stimuli. [8]

Since the mid-2000s, significant progress has been made into the development of small molecule mimics of the endogenous IAP ligand Smac. One recent example published in 2013 describes the synthesis and testing of peptidomimetics whose structure is based on the AVPI tetrapeptide IAP binding motif present in the N-terminus of mature Smac. These peptidomimetic compounds were specifically noted for their exceptionally high level of binding to Livin, one of the important IAP family members yet to receive much attention from a drug discovery perspective. [9]

LCL161 is a drug that promotes cancer cell death by antagonizing IAPs. Clinical trials are ongoing, but have received mixed response. A Phase I clinical trial determined that LCL161 is well tolerated in the treatment of patients with advanced solid tumors, though they experienced vomiting, nausea, fatigue, and loss of appetite. [10] Another study found that LCL161 reduced survival and promoted endotoxic shock when used in MYC-driven lymphoma. [11] Other clinical trials are still enrolling to determine the drugs efficacy. [12]

See also

Related Research Articles

<span class="mw-page-title-main">Apoptosis</span> Programmed cell death in multicellular organisms

Apoptosis is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemical events lead to characteristic cell changes (morphology) and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, DNA fragmentation, and mRNA decay. The average adult human loses between 50 and 70 billion cells each day due to apoptosis. For an average human child between eight and fourteen years old, each day the approximate lost is 20 to 30 billion cells.

<span class="mw-page-title-main">Apoptosome</span>

The apoptosome is a large quaternary protein structure formed in the process of apoptosis. Its formation is triggered by the release of cytochrome c from the mitochondria in response to an internal (intrinsic) or external (extrinsic) cell death stimulus. Stimuli can vary from DNA damage and viral infection to developmental cues such as those leading to the degradation of a tadpole's tail.

<span class="mw-page-title-main">CARD (domain)</span> Interaction motifs found in a wide array of proteins

Caspase recruitment domains, or caspase activation and recruitment domains (CARDs), are interaction motifs found in a wide array of proteins, typically those involved in processes relating to inflammation and apoptosis. These domains mediate the formation of larger protein complexes via direct interactions between individual CARDs. CARDs are found on a strikingly wide range of proteins, including helicases, kinases, mitochondrial proteins, caspases, and other cytoplasmic factors.

<span class="mw-page-title-main">Apoptosis regulator BAX</span> Mammalian protein found in Homo sapiens

Apoptosis regulator BAX, also known as bcl-2-like protein 4, is a protein that in humans is encoded by the BAX gene. BAX is a member of the Bcl-2 gene family. BCL2 family members form hetero- or homodimers and act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities. This protein forms a heterodimer with BCL2, and functions as an apoptotic activator. This protein is reported to interact with, and increase the opening of, the mitochondrial voltage-dependent anion channel (VDAC), which leads to the loss in membrane potential and the release of cytochrome c. The expression of this gene is regulated by the tumor suppressor P53 and has been shown to be involved in P53-mediated apoptosis.

<span class="mw-page-title-main">BH3 interacting-domain death agonist</span> Protein-coding gene in the species Homo sapiens

The BH3 interacting-domain death agonist, or BID, gene is a pro-apoptotic member of the Bcl-2 protein family. Bcl-2 family members share one or more of the four characteristic domains of homology entitled the Bcl-2 homology (BH) domains, and can form hetero- or homodimers. Bcl-2 proteins act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities.

p53 upregulated modulator of apoptosis Protein-coding gene in the species Homo sapiens

The p53 upregulated modulator of apoptosis (PUMA) also known as Bcl-2-binding component 3 (BBC3), is a pro-apoptotic protein, member of the Bcl-2 protein family. In humans, the Bcl-2-binding component 3 protein is encoded by the BBC3 gene. The expression of PUMA is regulated by the tumor suppressor p53. PUMA is involved in p53-dependent and -independent apoptosis induced by a variety of signals, and is regulated by transcription factors, not by post-translational modifications. After activation, PUMA interacts with antiapoptotic Bcl-2 family members, thus freeing Bax and/or Bak which are then able to signal apoptosis to the mitochondria. Following mitochondrial dysfunction, the caspase cascade is activated ultimately leading to cell death.

<span class="mw-page-title-main">Caspase-9</span> Protein-coding gene in the species Homo sapiens

Caspase-9 is an enzyme that in humans is encoded by the CASP9 gene. It is an initiator caspase, critical to the apoptotic pathway found in many tissues. Caspase-9 homologs have been identified in all mammals for which they are known to exist, such as Mus musculus and Pan troglodytes.

<span class="mw-page-title-main">Bcl-xL</span> Transmembrane molecule in the mitochondria

B-cell lymphoma-extra large (Bcl-xL), encoded by the BCL2-like 1 gene, is a transmembrane molecule in the mitochondria. It is a member of the Bcl-2 family of proteins, and acts as an anti-apoptotic protein by preventing the release of mitochondrial contents such as cytochrome c, which leads to caspase activation and ultimately, programmed cell death.

<span class="mw-page-title-main">Caspase 8</span> Protein-coding gene in the species Homo sapiens

Caspase-8 is a caspase protein, encoded by the CASP8 gene. It most likely acts upon caspase-3. CASP8 orthologs have been identified in numerous mammals for which complete genome data are available. These unique orthologs are also present in birds.

<span class="mw-page-title-main">Caspase 2</span> Protein-coding gene in the species Homo sapiens

Caspase 2 also known as CASP2 is an enzyme that, in humans, is encoded by the CASP2 gene. CASP2 orthologs have been identified in nearly all mammals for which complete genome data are available. Unique orthologs are also present in birds, lizards, lissamphibians, and teleosts.

<span class="mw-page-title-main">XIAP</span> Protein-coding gene in the species Homo sapiens

X-linked inhibitor of apoptosis protein (XIAP), also known as inhibitor of apoptosis protein 3 (IAP3) and baculoviral IAP repeat-containing protein 4 (BIRC4), is a protein that stops apoptotic cell death. In humans, this protein (XIAP) is produced by a gene named XIAP gene located on the X chromosome.

<span class="mw-page-title-main">Caspase 3</span> Protein-coding gene in the species Homo sapiens

Caspase-3 is a caspase protein that interacts with caspase-8 and caspase-9. It is encoded by the CASP3 gene. CASP3 orthologs have been identified in numerous mammals for which complete genome data are available. Unique orthologs are also present in birds, lizards, lissamphibians, and teleosts.

<span class="mw-page-title-main">Caspase 7</span> Protein-coding gene in the species Homo sapiens

Caspase-7, apoptosis-related cysteine peptidase, also known as CASP7, is a human protein encoded by the CASP7 gene. CASP7 orthologs have been identified in nearly all mammals for which complete genome data are available. Unique orthologs are also present in birds, lizards, lissamphibians, and teleosts.

<span class="mw-page-title-main">Baculoviral IAP repeat-containing protein 3</span> Protein-coding gene in the species Homo sapiens

Baculoviral IAP repeat-containing protein3 is a protein that in humans is encoded by the BIRC3 gene.

<span class="mw-page-title-main">Baculoviral IAP repeat-containing protein 2</span> Protein-coding gene in the species Homo sapiens

Baculoviral IAP repeat-containing protein 2 is a protein that in humans is encoded by the BIRC2 gene.

<span class="mw-page-title-main">Diablo homolog</span> Protein-coding gene in the species Homo sapiens

Diablo homolog (DIABLO) is a mitochondrial protein that in humans is encoded by the DIABLO gene on chromosome 12. DIABLO is also referred to as second mitochondria-derived activator of caspases or SMAC. This protein binds inhibitor of apoptosis proteins (IAPs), thus freeing caspases to activate apoptosis. Due to its proapoptotic function, SMAC is implicated in a broad spectrum of tumors, and small molecule SMAC mimetics have been developed to enhance current cancer treatments.

<span class="mw-page-title-main">HtrA serine peptidase 2</span> Enzyme found in humans

Serine protease HTRA2, mitochondrial is an enzyme that in humans is encoded by the HTRA2 gene. This protein is involved in caspase-dependent apoptosis and in Parkinson's disease.

<span class="mw-page-title-main">Bcl-2 family</span>

The Bcl-2 family consists of a number of evolutionarily-conserved proteins that share Bcl-2 homology (BH) domains. The Bcl-2 family is most notable for their regulation of apoptosis, a form of programmed cell death, at the mitochondrion. The Bcl-2 family proteins consists of members that either promote or inhibit apoptosis, and control apoptosis by governing mitochondrial outer membrane permeabilization (MOMP), which is a key step in the intrinsic pathway of apoptosis. A total of 25 genes in the Bcl-2 family were identified by 2008.

<span class="mw-page-title-main">Necroptosis</span> Programmed form of necrosis, or inflammatory cell death

Necroptosis is a programmed form of necrosis, or inflammatory cell death. Conventionally, necrosis is associated with unprogrammed cell death resulting from cellular damage or infiltration by pathogens, in contrast to orderly, programmed cell death via apoptosis. The discovery of necroptosis showed that cells can execute necrosis in a programmed fashion and that apoptosis is not always the preferred form of cell death. Furthermore, the immunogenic nature of necroptosis favors its participation in certain circumstances, such as aiding in defence against pathogens by the immune system. Necroptosis is well defined as a viral defense mechanism, allowing the cell to undergo "cellular suicide" in a caspase-independent fashion in the presence of viral caspase inhibitors to restrict virus replication. In addition to being a response to disease, necroptosis has also been characterized as a component of inflammatory diseases such as Crohn's disease, pancreatitis, and myocardial infarction.

cIAP1 is the abbreviation for a human protein, cellular inhibitor of apoptosis protein-1. It belongs to the IAP family of proteins and therefore contains at least one BIR domain. cIAP1 is a multi-functional protein which can be found in the cytoplasm of cells and in the nucleus of tumor cells. Its function in this particular case is yet to be understood. However, it is well known that this protein has a big influence in the growth of diverse cancers. cIAP1 is involved in the development process of osteosarcoma and gastric cancer among others.

References

  1. ↑ Jacobson, Michael; McCarthy, Nicola (2002). Apoptosis. Oxford, OX: Oxford University Press. pp. 93–101. ISBN   0199638497.
  2. ↑ Schwerk C, Schulze-Osthoff K (July 2005). "Regulation of apoptosis by alternative pre-mRNA splicing". Molecular Cell. 19 (1): 1–13. doi: 10.1016/j.molcel.2005.05.026 . PMID   15989960.
  3. ↑ Mayer B, Oberbauer R (2003). "Mitochondrial regulation of apoptosis". News in Physiological Sciences. 18 (3): 89–94. doi:10.1152/nips.01433.2002. PMID   12750442.
  4. ↑ Conradt B, Horvitz HR (1998). "The C. elegans protein EGL-1 is required for programmed cell death and interacts with the Bcl-2-like protein CED-9". Cell. 93 (4): 519–29. doi: 10.1016/S0092-8674(00)81182-4 . PMID   9604928.
  5. ↑ Cheng EH, Wei MC, Weiler S, Flavell RA, Mak TW, Lindsten T, Korsmeyer SJ (2001). "BCL-2, BCL-X(L) sequester BH3 domain-only molecules preventing BAX- and BAK-mediated mitochondrial apoptosis". Molecular Cell. 8 (3): 705–11. doi: 10.1016/S1097-2765(01)00320-3 . PMID   11583631.
  6. 1 2 Dobó J, Swanson R, Salvesen GS, Olson ST, Gettins PG (December 2006). "Cytokine response modifier a inhibition of initiator caspases results in covalent complex formation and dissociation of the caspase tetramer". The Journal of Biological Chemistry. 281 (50): 38781–90. doi: 10.1074/jbc.M605151200 . PMID   17052983.
  7. 1 2 Callus BA, Vaux DL (January 2007). "Caspase inhibitors: viral, cellular and chemical". Cell Death and Differentiation. 14 (1): 73–8. doi: 10.1038/sj.cdd.4402034 . PMID   16946729.
  8. ↑ Takahashi R, Deveraux Q, Tamm I, Welsh K, Assa-Munt N, Salvesen GS, Reed JC (1998). "A single BIR domain of XIAP sufficient for inhibiting caspases". The Journal of Biological Chemistry. 273 (14): 7787–90. doi: 10.1074/jbc.273.14.7787 . PMID   9525868.
  9. ↑ Vamos M, Welsh K, Finlay D, Lee PS, Mace PD, Snipas SJ, Gonzalez ML, Ganji SR, Ardecky RJ, Riedl SJ, Salvesen GS, Vuori K, Reed JC, Cosford ND (April 2013). "Expedient synthesis of highly potent antagonists of inhibitor of apoptosis proteins (IAPs) with unique selectivity for ML-IAP". ACS Chemical Biology. 8 (4): 725–32. doi:10.1021/cb3005512. PMC   3953502 . PMID   23323685.
  10. ↑ Infante JR, Dees EC, Olszanski AJ, Dhuria SV, Sen S, Cameron S, Cohen RB (October 2014). "Phase I dose-escalation study of LCL161, an oral inhibitor of apoptosis proteins inhibitor, in patients with advanced solid tumors". Journal of Clinical Oncology. 32 (28): 3103–10. doi: 10.1200/JCO.2013.52.3993 . PMID   25113756.
  11. ↑ West AC, Martin BP, Andrews DA, Hogg SJ, Benerjee A, Grigoriadis G, Johnstone RW, Shortt J (2016). "The SMAC mimetic, LCL-161, reduces survival in aggressive MYC-driven lymphoma while promoting susceptibility to endotoxic shock". Oncogenesis. 5 (4): e216. doi:10.1038/oncsis.2016.26. PMC   4848837 . PMID   27043662.
  12. ↑ "Clinical trials using Smac Mimetic LCL161". National Cancer Institute. Retrieved April 20, 2018.
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