Abstract:B-cell lymphoma 2 (Bcl-2) protein is the archetype apoptosis suppressor protein. The N-terminal Bcl-2-homology 4 (BH4) domain of Bcl-2 is required for the antiapoptotic function of this protein at the mitochondria and endoplasmic reticulum (ER). The involvement of the BH4 domain in Bcl-2 0 s antiapoptotic functions has been proposed based on Gly-based substitutions of the Ile14/Val15 amino acids, two hydrophobic residues located in the center of Bcl-2 0 s BH4 domain. Following this strategy, we recently showed… Show more
“…2b, d ). These results differ compared to what we showed previously in cultured or permeabilized cells where the BH4 domain of Bcl-2 inhibited IP 3 R-mediated Ca 2+ release via its BH4 domain 4 , 27 – 29 . Fig.…”
Section: Resultscontrasting
confidence: 99%
“…The α-helical properties of the BH4-domain peptide of Bcl-2 were previously shown to be crucial for inhibiting both IP 3 R activity and suppressing apoptosis induction, rendering this an important feature for the biological activity of the BH4 domain of Bcl-2 28 . In the full-length protein, the BH4 domain also contributes to the overall stability of the Bcl-2 proteins 36 . PACs are known to take up small peptides that retain their bio-activity 37 .…”
Biliary acute pancreatitis (AP) is a serious condition, which currently has no specific treatment. Taurolithocholic acid 3-sulfate (TLC-S) is one of the most potent bile acids causing cytosolic Ca2+ overload in pancreatic acinar cells (PACs), which results in premature activation of digestive enzymes and necrosis, hallmarks of AP. The inositol 1,4,5-trisphosphate receptor (IP3R) and the ryanodine receptor (RyR) play major roles in intracellular Ca2+ signaling. Inhibition of these endoplasmic reticulum-located channels suppresses TLC-S-induced Ca2+ release and necrosis, decreasing the severity of AP. Anti-apoptotic B-cell lymphoma (Bcl)-2-family members, such as Bcl-2 and Bcl-XL, have emerged as important modulators of IP3Rs and RyRs. These proteins contain four Bcl-2 homology (BH) domains of which the N-terminal BH4 domain exerts critical roles in regulating intracellular Ca2+ release channels. The BH4 domain of Bcl-2, but not of Bcl-XL, binds to and inhibits IP3Rs, whereas both BH4 domains inhibit RyRs. Although clear cytoprotective effects have been reported for these BH4 domains, it remains unclear whether they are capable of inhibiting pathological Ca2+-overload, associated with AP. Here we demonstrate in PACs that the BH4 domains of Bcl-2 and Bcl-XL inhibit RyR activity in response to the physiological agonist cholecystokinin. In addition, these BH4 domains inhibit pathophysiological TLC-S-induced Ca2+ overload in PACs via RyR inhibition, which in turn protects these cells from TLC-S-induced necrosis. This study shows for the first time the therapeutic potential of BH4 domain function by inhibiting pathological RyR-mediated Ca2+ release and necrosis, events that trigger AP.
“…2b, d ). These results differ compared to what we showed previously in cultured or permeabilized cells where the BH4 domain of Bcl-2 inhibited IP 3 R-mediated Ca 2+ release via its BH4 domain 4 , 27 – 29 . Fig.…”
Section: Resultscontrasting
confidence: 99%
“…The α-helical properties of the BH4-domain peptide of Bcl-2 were previously shown to be crucial for inhibiting both IP 3 R activity and suppressing apoptosis induction, rendering this an important feature for the biological activity of the BH4 domain of Bcl-2 28 . In the full-length protein, the BH4 domain also contributes to the overall stability of the Bcl-2 proteins 36 . PACs are known to take up small peptides that retain their bio-activity 37 .…”
Biliary acute pancreatitis (AP) is a serious condition, which currently has no specific treatment. Taurolithocholic acid 3-sulfate (TLC-S) is one of the most potent bile acids causing cytosolic Ca2+ overload in pancreatic acinar cells (PACs), which results in premature activation of digestive enzymes and necrosis, hallmarks of AP. The inositol 1,4,5-trisphosphate receptor (IP3R) and the ryanodine receptor (RyR) play major roles in intracellular Ca2+ signaling. Inhibition of these endoplasmic reticulum-located channels suppresses TLC-S-induced Ca2+ release and necrosis, decreasing the severity of AP. Anti-apoptotic B-cell lymphoma (Bcl)-2-family members, such as Bcl-2 and Bcl-XL, have emerged as important modulators of IP3Rs and RyRs. These proteins contain four Bcl-2 homology (BH) domains of which the N-terminal BH4 domain exerts critical roles in regulating intracellular Ca2+ release channels. The BH4 domain of Bcl-2, but not of Bcl-XL, binds to and inhibits IP3Rs, whereas both BH4 domains inhibit RyRs. Although clear cytoprotective effects have been reported for these BH4 domains, it remains unclear whether they are capable of inhibiting pathological Ca2+-overload, associated with AP. Here we demonstrate in PACs that the BH4 domains of Bcl-2 and Bcl-XL inhibit RyR activity in response to the physiological agonist cholecystokinin. In addition, these BH4 domains inhibit pathophysiological TLC-S-induced Ca2+ overload in PACs via RyR inhibition, which in turn protects these cells from TLC-S-induced necrosis. This study shows for the first time the therapeutic potential of BH4 domain function by inhibiting pathological RyR-mediated Ca2+ release and necrosis, events that trigger AP.
“…Moreover, in contrast to wild-type Bcl-2, a full-length Bcl-2 Ile14Gly/Val15Gly mutant displayed markedly reduced structural stability and a shortened pro-tein half-life. Also, the mutant protein failed to interact with Bax, and was unable to inhibit IP 3 R-mediated Ca 2+ release or to protect against Ca 2+ -mediated apoptosis (Monaco et al 2018).…”
Section: Targeting Bcl-2/ip 3 R Interaction With a Synthetic Peptidementioning
Bcl-2 is a member of a family of proteins that regulate cell survival. Expression of Bcl-2 is aberrantly elevated in many types of cancer. Within cells of the immune system, Bcl-2 has a physiological role in regulating immune responses. However, in cancers arising from cells of the immune system Bcl-2 promotes cell survival and proliferation. This review summarizes discoveries over the past 30 years that have elucidated Bcl-2's role in the normal immune system, including its actions in regulating calcium (Ca 2+ ) signals necessary for the immune response, and for Ca 2+ -mediated apoptosis at the end of an immune response. How Bcl-2 modulates the release of Ca 2+ from intracellular stores via inositol 1,4,5-trisphosphate receptors (IP 3 R) is discussed, and in particular, the role of Bcl-2/IP 3 R interactions in promoting the survival of cancer cells by preventing Ca 2+ -mediated cell death. The development and usage of a peptide, referred to as TAT-Pep8, or more recently, BIRD-2, that induces death of cancer cells by inhibiting Bcl-2's control over IP 3 R-mediated Ca 2+ elevation is discussed. Studies aimed at discovering a small molecule that mimics BIRD-2's anticancer mechanism of action are summarized, along with the prospect of such a compound becoming a novel therapeutic option for cancer.
“…This same region is responsible for Bcl-2’s interaction with ryanodine receptors (125). In addition, a region in the BH4 domain of Bcl-2 (Ile14, Val15) has been found critical to stability and function as an inhibitor of Ca 2+ -mediated apoptosis (127). Furthermore, the significance of this region is further evidenced by findings indicating that the alpha helical nature of Ile14, Val15 region is essential to the function of the BH4 domain in inhibiting IP 3 R-mediated Ca 2+ release (128).…”
Section: Bcl-2 Promotion Of Normal Cell Survival Through Its Regulatimentioning
Bcl-2 inhibits cell death by at least two different mechanisms. On the one hand, its BH3 domain binds to pro-apoptotic proteins such as Bim and prevents apoptosis induction. On the other hand, the BH4 domain of Bcl-2 binds to the inositol 1,4,5-trisphosphate receptor (IPR), preventing Ca signals that mediate cell death. In normal T-cells, Bcl-2 levels increase during the immune response, protecting against cell death, and then decline as apoptosis ensues and the immune response dissipates. But in many cancers Bcl-2 is aberrantly expressed and exploited to prevent cell death by inhibiting IPR-mediated Ca elevation. This review summarizes what is known about the mechanism of Bcl-2's control over IPR-mediated Ca release and cell death induction. Early insights into the role of Ca elevation in corticosteroid-mediated cell death serves as a model for how targeting IPR-mediated Ca elevation can be a highly effective therapeutic approach for different types of cancer. Moreover, the successful development of ABT-199 (Venetoclax), a small molecule targeting the BH3 domain of Bcl-2 but without effects on Ca, serves as proof of principle that targeting Bcl-2 can be an effective therapeutic approach. BIRD-2, a synthetic peptide that inhibits Bcl-2-IPR interaction, induces cell death induction in ABT-199 (Venetoclax)-resistant cancer models, attesting to the value of developing therapeutic agents that selectively target Bcl-2-IPR interaction, inducing Ca-mediated cell death.
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