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Apoptosis and cell cycle: distinct checkpoints with overlapping upstream control
E Jacotot1, K F Ferri, G Kroemer
1Centre national de la recherche scientifique, ERS 1984, Villejuif, France.
Abstract:
The question as to whether apoptosis (programmed cell death) is controlled by one or few checkpoints is still unresolved. A growing body of evidence suggests that (one of) the decisive event(s) of cell death consists in the permeabilization of mitochondrial membranes. Indeed, multiple pro-apopotic signal transduction pathways converge on the proteins of the Bcl-2/Bax family which, in concert with the so-called permeability transition pore complex (PTPC), regulate mitochondrial membrane barrier function. Mitochondrial permeabilization causes the release of soluble intermembrane proteins, some of which are involved in the activation of apoptotic proteases and nucleases. Thus, the putative checkpoint determining the death/life decision is clearly different from the known checkpoints of cell cycle progression. Prominent oncogenes (e.g., c-Myc, Ras, Raf, Bcl-2) and tumor suppressor genes (e.g., p53, Bax) have been shown to modulate apoptosis via a direct or indirect effect on mitochondrial membranes. All these oncoproteins and tumor suppressor proteins may simultaneously influence the cell cycle and the propensity to undergo apoptosis. Several cell cycle regulatory proteins (e.g., cyclins, cdk, etc.) can induce or inhibit apoptosis via yet unknown pathways.
Insights
Apoptosis, or programmed cell death, may be regulated by mitochondrial membrane permeabilization. Key proteins like Bcl-2/Bax and the PTPC control this crucial cell death checkpoint.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- The regulation of apoptosis (programmed cell death) by specific checkpoints remains an open question.
- Mitochondrial membrane permeabilization is increasingly recognized as a critical event in initiating cell death.
- This process involves the convergence of multiple signaling pathways onto Bcl-2/Bax family proteins and the permeability transition pore complex (PTPC).
Purpose of the Study:
- To explore the role of mitochondrial membrane permeabilization as a potential checkpoint in apoptosis.
- To investigate the involvement of Bcl-2/Bax family proteins and the PTPC in regulating mitochondrial membrane integrity.
- To understand how oncogenes and tumor suppressor genes influence apoptosis through mitochondrial pathways.
Main Methods:
- Review of existing evidence on apoptosis regulation.
- Analysis of signaling pathways converging on Bcl-2/Bax proteins and the PTPC.
- Examination of the impact of oncogenes and tumor suppressor genes on mitochondrial function and apoptosis.
Main Results:
- Mitochondrial membrane permeabilization is a key event in apoptosis, leading to the release of proteins that activate cell death machinery.
- The Bcl-2/Bax protein family and the PTPC are central regulators of mitochondrial membrane barrier function.
- Oncogenes (e.g., c-Myc, Ras, Bcl-2) and tumor suppressor genes (e.g., p53, Bax) modulate apoptosis by affecting mitochondrial membranes.
- Cell cycle regulatory proteins may also influence apoptosis through interactions with mitochondrial pathways.
Conclusions:
- The primary checkpoint for the life/death decision in apoptosis appears to be linked to mitochondrial membrane permeabilization, distinct from cell cycle checkpoints.
- Mitochondrial regulation of apoptosis is a complex process involving interplay between Bcl-2 family proteins, the PTPC, and various oncoproteins and tumor suppressor proteins.
- Further research is needed to elucidate the precise mechanisms by which cell cycle regulators impact apoptosis via mitochondrial pathways.