BH3‐only proteins: The death‐puppeteer's wires

Abstract

Most cell death in vertebrates proceeds through the intrinsic pathway of apoptosis and results from unregulated increase of mitochondrial membrane permeability. Bcl2-associated X protein (Bax) and Bcl2-antagonist/killer protein (Bak), the effector proapoptotic members of the Bcl-2 family, are, in their active state, the principal accomplices for this permeabilization process. How exactly Bax and Bak are activated has been a matter of major investigation in the last decade, and suitable tools offered by quantitative cytometric methodologies have significantly contributed to the understanding of the function of Bcl-2 family members. Here, we review the most relevant findings in this field and highlight one common trait that has emerged from the diverse new theories: a crucial role in the control of Bax/Bak activation has to be attributed to the BH3-only subset of the Bcl-2 family. BH3-only proteins exert their proapoptotic activity by hierarchical and tightly tuned interactions with other Bcl-2 family members and operate as sensors of intracellular/extracellular death signals and vectors of information to the core apoptotic machinery. Given their essential role in apoptosis, BH3-only molecules are proposed as molecular targets for the cure of diseases associated with abnormal cell death, as in the case with neurodegenerative conditions. As well, they are explored as possible tools for cancer therapy, according to the concept that molecules mimicking the BH3 domain of these proteins could selectively and efficiently cooperate in the cell killing by chemotherapeutic drugs. A few BH3 mimetics are currently being tested in clinical trials of hematologic and solid tumors. Nevertheless, the knowledge about the cellular and molecular mechanisms that regulate responsiveness to BH3 therapy has to be further expanded and will benefit from recent advances in cytometric quantitative technologies. ' 2009 International Society for Advancement of Cytometry

Matrine inhibits proliferation and induces apoptosis of the androgen‑independent prostate cancer cell line PC-3

“…The complex, multistep, apoptotic pathway is orchestrated by interactions between a large number of pro-and anti-apoptotic proteins such as Bcl-2, Bcl-xl, Mcl-1, Bax and Bak, among others (34). It has been suggested that pro-apoptotic Bax is sequestered by the anti-apoptotic Bcl-2 and is activated/liberated by specific apoptotic signals to initiate the apoptotic cascade (34).…”

“…The complex, multistep, apoptotic pathway is orchestrated by interactions between a large number of pro-and anti-apoptotic proteins such as Bcl-2, Bcl-xl, Mcl-1, Bax and Bak, among others (34). It has been suggested that pro-apoptotic Bax is sequestered by the anti-apoptotic Bcl-2 and is activated/liberated by specific apoptotic signals to initiate the apoptotic cascade (34). Mechanistic studies have shown that matrine-mediated apoptosis was accompanied by reduced Bcl-2/Bax ratios and upregulation in caspase 3, 8 and 9 expression levels in a number of different cancer cell types (26,27,35,36).…”

Puma, a critical mediator of cell death — one decade on from its discovery

“…In the active conformation, both proteins form ion channels in the mitochondrial membranes. These events ultimately lead to permeabilization of the outer membranes in the mitochondria and the release of apoptogenic factors such as cytochrome c, Smac/DIABLO and caspases from the intermembrane space of these organelles [20,[79][80][81]. Although a decade has passed since the discovery of PUMA, there are still some questions with no clear answers.…”

“…These proteins bind exclusively with the anti-apoptotic proteins of Bcl-2 family. Their function is to neutralize antiapoptotic members of Bcl-2 family and to allow the subsequent release of the inhibited activators [15,17,20,75,[81][82][83][84][85].…”

Neonatal monocytes express antiapoptotic pattern of Bcl-2 proteins and show diminished apoptosis upon infection with Escherichia coli

“…Bax and Bak are inhibited by the antiapoptotic proteins of the family, such as Bcl-2 and Bcl-xL (15). Bim and Bid can inactivate Bcl-2 and Bcl-xL, which leads to reduced inhibition of Bax and Bak (16), while Bax and Bak become directly activated by Bim and Bid (17).…”