BOK (gene)

Last updated
BOK
Identifiers
Aliases BOK , BCL2L9, BOKL, BCL2-related ovarian killer, BCL2 family apoptosis regulator, BCL2 family apoptosis regulator BOK
External IDs OMIM: 605404 MGI: 1858494 HomoloGene: 9632 GeneCards: BOK
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_032515

NM_016778

RefSeq (protein)

NP_115904

NP_058058

Location (UCSC) Chr 2: 241.55 – 241.57 Mb Chr 1: 93.61 – 93.62 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Bok (Bcl-2 related ovarian killer) is a protein-coding gene of the Bcl-2 family that is found in many invertebrates and vertebrates. It induces apoptosis, a special type of cell death. Currently, the precise function of Bok in this process is unknown.

Contents

Discovery and homology

In 1997, the protein Bcl-2-related ovarian killer (Bok) was identified in a yeast two-hybrid experiment with a rat ovarian cDNA library in a screen for proteins interacting with Mcl-1, an abundant anti-apoptotic protein. [5] The overexpression of Bok induces apoptosis. Because of its high sequence similarity to Bak and Bax, [6] Bok is classified as a member of the Bcl-2 protein family. [7] The mouse homologue of Bok is called Matador (Mtd). This name is derived from the Latin term mactator which means butcher or killer. [8] Additionally, homologous proteins were found in Drosophila melanogaster (fruit fly) and Gallus gallus (chicken). [9]

Promoter and gene structure

The human BOK promoter is activated by the overexpression of members of the E2F hand transcription factor family. Typically, these transcription factors are involved in the promotion of S-phase, so there might be a connection between Bok expression and cell cycle progression. [10] Due to this regulation of Bok expression by the cell cycle, it was proposed that Bok sensitizes growing cells to stress-induced apoptosis. [10]

Bok mRNA comprises five exons which code for a 213 amino acid protein, [7] called Bok-L. This protein consists of four Bcl-2 homology domains (abbreviated BH1, BH2, BH3, BH4, respectively) and a C-terminal transmembrane region [7] (Figure 1). Its BH3 domain contains a stretch with many leucine residues. This is unique among the Bcl-2 family members. The leucine-rich stretch functions as a nuclear export signal. [11] It is recognized by the nuclear exportin Crm1. Mutations in the leucine-rich stretch impair the binding of Crm1 to Bok. [11] Consequently, Bok accumulates in the nucleus and triggers apoptosis. [11]

Splice variants

Due to alternative splicing, Bok mRNA gives rise to different Bok proteins: Figure 1 illustrates the different splice variants schematically. Full length Bok is named Bok-L.

Figure 1: Splice variants of Bok mRNA and the resulting proteins. Bok mRNA comprises five exons and two alternative start codons for translation (AUG). Exons are visualized as arrows and boxes in different colors; ovals indicate sequences that code for Bcl-2 homology domains (BH1, BH2, BH3, BH4) or the transmembrane domain (TM). In the Bok-S variant, the BH3 domain is truncated and fused to the shortened BH1 domain. Another known variant, Bok-P, lacks the BH4 domain and contains a truncated BH3 domain. Splice variants of Bok.png
Figure 1: Splice variants of Bok mRNA and the resulting proteins. Bok mRNA comprises five exons and two alternative start codons for translation (AUG). Exons are visualized as arrows and boxes in different colors; ovals indicate sequences that code for Bcl-2 homology domains (BH1, BH2, BH3, BH4) or the transmembrane domain (TM). In the Bok-S variant, the BH3 domain is truncated and fused to the shortened BH1 domain. Another known variant, Bok-P, lacks the BH4 domain and contains a truncated BH3 domain.

The shorter version, Bok-S, lacks exon 3. This results in a fusion of the BH3 domain with the BH1 domain. [6] [12] The BH3 domain is involved in the interaction of Bok with Mcl-1 and other molecules. It is dispensable for the induction of apoptosis. [12] Expression of Bok-S may be an immediate response to stress signals. It has been shown to induce apoptosis regardless of the presence of anti-apoptotic molecules. [6]

Another splice variant termed Bok-P was found in placental tissue from patients with pre-eclampsia. While Bok-S misses exon 3, Bok-P lacks exon 2. This deletion includes the BH4 domain and parts of the BH3 domain. Bok-P may be the cause for trophoblast cell death in pre-eclampsia, [7] a dangerous pregnancy complication. In pre-eclampsia, typical alterations occur in the maternal kidney and lead to hypertension and proteins in the urine. To date, the cause of this medical condition as well as an appropriate treatment have not been discovered.

Expression pattern

The Bok gene is activated and produces protein in different tissues. In mice, elevated Bok levels were detected in the ovary, the testis, and the uterus. [5] Nevertheless, it also exists in the brain and at low levels in most other tissues. [13] However, the expression pattern of the Bok gene varies among species.

In humans, Bok is found in a wide range of tissues. The gene is expressed in the colon, the stomach, the testes, the placenta, the pancreas, the ovaries, and the uterus. [14] Furthermore, more Bok is expressed in fetal tissue compared to adult tissue. Thus, Bok may influence development.

Subcellular localization

The subcellular localization of Bok protein is controversial. In proliferating cells, Bok is found in the nucleus. [15] Upon induction of apoptosis, it was found to tightly associate with mitochondrial membranes. [14] [15] On the other hand, another group found Bok shuttling between the cytoplasm and the nucleus. In their experiments, increased nuclear (not mitochondrial) localization correlated with a stronger apoptotic activity. [11]

Regulation

It was found that the cellular ratio of pro-apoptotic to anti-apoptotic Bcl-2 family members effects late apoptotic events such as release of cytochrome c from the mitochondria and the activation of caspases. Higher levels of pro-apoptotic proteins compared to anti-apoptotic proteins seem to cause apoptosis. In a current model, the formation of heterodimers between pro-apoptotic and anti-apoptotic proteins prevents induction of apoptosis. [12]

Interactions

The binding of Bok to its interacting partners seems to be mediated by its BH3 domain. [7] The splice variant Bok-S lacks this domain and is unable to form heterodimers with other proteins of the Bcl-2 family.

In yeast two-hybrid experiments, Bok was found to interact with the anti-apoptotic proteins Mcl-1, BHRF-1, and Bfl-1. However, interactions with other anti-apoptotic proteins such as Bcl-2, Bcl-xL, and Bcl-w were not detectable (1). Later studies aimed at confirming an interaction between Bok and pro-apoptotic Bak or Bax but were not successful. [8]

Accordingly, coexpression of anti-apoptotic proteins such as Mcl-1 suppresses apoptosis induced by Bok overexpression. [5] Consistent with the results mentioned above, coexpression of anti-apoptotic Bcl-2 does not prevent Bok-induced apoptosis. [5]

Knock-out mouse

Since its discovery in 1997, several attempts have been made to characterize Bok. Due to the increased expression levels in fetal tissue, scientists anticipated a developmental role for Bok. Recently, the Bok knock-out mouse was created. This mouse shows, however, no developmental defects and normal fertility. [13] This finding indicates that the function of Bok seems to overlap with the function of the related pro-apoptotic proteins Bak and Bax.

Several other roles were proposed for Bok, especially in developing cells. [12] [16] [17] [18] Since the action of Bok in triggering apoptosis seems to be redundant, it is difficult to assign a specific role to Bok in the presence of Bak and Bax. The study of cells deficient in Bak and Bok or deficient in Bax and Bok, respectively, could help to better characterize the role of Bok in apoptosis. If Bok exerts a critical function, it is likely that this function is limited to certain circumstances, e.g. specific cell types, stress conditions. Thus, these aspects should be assessed in more detail to analyze the physiological and pathological role of Bok.

Related Research Articles

Bcl-2 Mammalian protein found in Homo sapiens

Bcl-2, encoded in humans by the BCL2 gene, is the founding member of the Bcl-2 family of regulator proteins that regulate cell death (apoptosis), by either inhibiting (anti-apoptotic) or inducing (pro-apoptotic) apoptosis. It was the first apoptosis regulator identified in any organism.

Bcl-2-associated X protein 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.

Fas receptor Mammalian protein found in Homo sapiens

The Fas receptor, also known as Fas, FasR, apoptosis antigen 1, cluster of differentiation 95 (CD95) or tumor necrosis factor receptor superfamily member 6 (TNFRSF6), is a protein that in humans is encoded by the FAS gene. Fas was first identified using a monoclonal antibody generated by immunizing mice with the FS-7 cell line. Thus, the name Fas is derived from FS-7-associated surface antigen.

BH3 interacting-domain death agonist

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.

Phorbol-12-myristate-13-acetate-induced protein 1 Protein-coding gene in the species Homo sapiens

Phorbol-12-myristate-13-acetate-induced protein 1 is a protein that in humans is encoded by the PMAIP1 gene, and is also known as Noxa.

Bcl-2 homologous antagonist killer Protein-coding gene in the species Homo sapiens

Bcl-2 homologous antagonist/killer is a protein that in humans is encoded by the BAK1 gene on chromosome 6. The protein encoded by this gene belongs to the BCL2 protein family. BCL2 family members form oligomers or heterodimers and act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities. This protein localizes to mitochondria, and functions to induce apoptosis. It interacts with and accelerates the opening of the mitochondrial voltage-dependent anion channel, which leads to a loss in membrane potential and the release of cytochrome c. This protein also interacts with the tumor suppressor P53 after exposure to cell stress.

Bcl-2-associated death promoter

The BCL2 associated agonist of cell death (BAD) protein is a pro-apoptotic member of the Bcl-2 gene family which is involved in initiating apoptosis. BAD is a member of the BH3-only family, a subfamily of the Bcl-2 family. It does not contain a C-terminal transmembrane domain for outer mitochondrial membrane and nuclear envelope targeting, unlike most other members of the Bcl-2 family. After activation, it is able to form a heterodimer with anti-apoptotic proteins and prevent them from stopping apoptosis.

Bcl-xL 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.

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. Some of these inhibitors include the Bcl-2 family, viral inhibitor crmA, and IAP's.

Bcl-2-like protein 1 Protein-coding gene in the species Homo sapiens

Bcl-2-like protein 1 is a protein encoded in humans by the BCL2L1 gene. Through alternative splicing, the gene encodes both of the human proteins Bcl-xL and Bcl-xS.

MCL1

Induced myeloid leukemia cell differentiation protein Mcl-1 is a protein that in humans is encoded by the MCL1 gene.

BCL2L11 Protein-coding gene in the species Homo sapiens

Bcl-2-like protein 11, commonly called BIM, is a protein that in humans is encoded by the BCL2L11 gene.

BCL2-related protein A1

Bcl-2-related protein A1 is a protein that in humans is encoded by the BCL2A1 gene.

BCL2L2 Protein-coding gene in the species Homo sapiens

Bcl-2-like protein 2 is a 193-amino acid protein that in humans is encoded by the BCL2L2 gene on chromosome 14. It was originally discovered by Leonie Gibson, Suzanne Cory and colleagues at the Walter and Eliza Hall Institute of Medical Research, who called it Bcl-w.

HRK (gene)

Activator of apoptosis harakiri is a protein that in humans is encoded by the HRK gene.

BMF (gene)

Bcl-2-modifying factor is a protein that in humans is encoded by the BMF gene.

BCL2L10

Bcl-2-like protein 10 is a protein that in humans is encoded by the BCL2L10 gene.

Bcl-2 family

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.

Catherine Louise Day is a New Zealand biochemist. She is currently a professor and was the head of the biochemistry department at the University of Otago.

References

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