Abstract
Apoptosis is a regulated form of cell death that proceeds by defined biochemical pathways. Most apoptosis is controlled by interactions between pro-survival and pro-apoptotic Bcl-2 family proteins in which death is often the consequence of permeabilization of the mitochondrial outer membrane. Many drugs affect this equilibrium to favor apoptosis but this process is not completely understood. We show that the chemotherapeutic drug cisplatin initiates an apoptotic pathway by phosphorylation of a pro-survival Bcl-2 family member, Bcl-xL, by cyclin-dependent kinase 2. The phosphorylation occurred at a previously unreported site and its biologic significance was demonstrated by a phosphomimetic modification of Bcl-xL that was able to induce apoptosis without addition of cisplatin. The mechanism of cell death induction was similar to that initiated by pro-apoptotic Bcl-2 family proteins, that is, phosphorylated Bcl-xL translocated to the mitochondrial membrane, and formed pores in the membrane. This initiated cytochrome c release and caspase activation that resulted in cell death.
Highlights
Proteins of the Bcl-2 family are important regulators of apoptotic cell death in which pro-apoptotic members, such as Bax and Bak, can initiate cell death pathways and pro-survival members, such as Bcl-xL, interact with pro-apoptotic proteins to inhibit these activities.[1]
But not in cancer cells, we found that cisplatin cytotoxicity could be prevented by inhibition of cyclin-dependent kinase 2 (Cdk2), a serine–threonine protein kinase associated with cell cycle progression.[16]
Mitochondrial pore formation by Bcl-xL J Megyesi et al 2 death pathways, analog-sensitive Cdk[2] was isolated N6-benzyl-[γ-32P]ATP and separated by two-dimensional electrofrom untreated cells and cells exposed to cisplatin
Summary
Proteins of the Bcl-2 family are important regulators of apoptotic cell death in which pro-apoptotic members, such as Bax and Bak, can initiate cell death pathways and pro-survival members, such as Bcl-xL, interact with pro-apoptotic proteins to inhibit these activities.[1]. Activation of Bax is initiated by shifting the unstructured loop and allosterically displacing the transmembrane region from the other side of the protein.[3,4,5] Bax exists primarily as a monomer in the cytosol of healthy cells,[6] active Bax is translocated to the mitochondria[7] and after its insertion into the outer membrane it oligomerizes[8] causing the release of mitochondrial cytochrome c.9. The first indication that oligomerization of pro-apoptotic proteins was a mechanism for mitochondrial membrane permeabilization was the observation that Bax and Bak coalesced into mitochondrial-associated foci during apoptosis,[10] which led to the proposal of the pore hypothesis.[11] Activation of Bax is initiated by shifting the unstructured loop and allosterically displacing the transmembrane region from the other side of the protein.[3,4,5] Bax exists primarily as a monomer in the cytosol of healthy cells,[6] active Bax is translocated to the mitochondria[7] and after its insertion into the outer membrane it oligomerizes[8] causing the release of mitochondrial cytochrome c.9 The first indication that oligomerization of pro-apoptotic proteins was a mechanism for mitochondrial membrane permeabilization was the observation that Bax and Bak coalesced into mitochondrial-associated foci during apoptosis,[10] which led to the proposal of the pore hypothesis.[11]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
