Biomedical subjects

J E Chipuk

Publications and source records attributed to J E Chipuk.

3 recordsLinked to original sources

PubMed2006

Mitochondrial outer membrane permeabilization during apoptosis: the innocent bystander scenario.

Mitochondrial outer membrane permeabilization (MOMP) is considered the 'point of no return' as this event is responsible for engaging the apoptotic cascade in numerous cell death pathways. MOMP is directly governed by a subset of the BCL-2 family of proapoptotic proteins, which induce disruptions in the outer mitochondrial membrane (OMM) and subsequent release of death-promoting proteins like cytochrome c. The proposal here is centered on our hypothesis that MOMP is dictated by an interaction between the cytosol and the OMM, and although proteins of the OMM may be important in the process, the 'decision' to undergo apoptosis originates within the cytosol with no participation (in terms of yes, no and when) by mitochondria.

Animals↗

PubMed2006

Dissecting p53-dependent apoptosis.

The complexity of the p53 protein, coupled with the vast cellular responses to p53, is simply astonishing. As new isoforms, functional domains and protein-protein interactions are described; each morsel of information forces us to think (and re-think) about how it 'fits' into the current p53 paradigm. One aspect of p53 signaling that is under refinement is the mechanism(s) leading to apoptosis. Here we discuss what is known about p53-induced apoptosis, what proteins and protein-protein interactions are responsible for regulating apoptosis, how can this cascade be genetically dissected, and what pharmacological tools are available to modulate p53-dependent apoptosis. While everything may not comfortably fit into our understanding of p53, all of these data will certainly broaden our viewpoint on the complexity and significance of the p53-induced apoptotic pathway. Here, our discussion is primarily focused on the works presented at the 12th International p53 Workshop, except where appropriate background is required.

Animals↗

PubMed2001

Bcl-xL blocks transforming growth factor-beta 1-induced apoptosis by inhibiting cytochrome c release and not by directly antagonizing Apaf-1-dependent caspase activation in prostate epithelial cells.

The mechanism by which transforming growth factor-beta1 (TGF-beta1) induces apoptosis of prostate epithelial cells was studied in the NRP-154 rat prostate epithelial cell line. TGF-beta 1 down-regulates expression of Bcl-xL and poly(ADP-ribosyl)polymerase (PARP), promotes cytochrome c release, up-regulates expression of latent caspase-3, and activates caspases 3 and 9. We tested the role of Bcl-xL in this cascade by stably overexpressing Bcl-xL to prevent loss by TGF-beta 1. Clones overexpressing Bcl-xL are resistant to TGF-beta 1 with respect to induction of apoptosis, cytochrome c release, activation of caspases 9 and 3, and cleavage of PARP; yet they remain sensitive to TGF-beta 1 by cell cycle arrest, induction of both fibronectin and latent caspase-3 expression, and loss of PARP expression. We show that Bcl-xL associates with Apaf-1 in NRP-154 cells; but this association does not inhibit the activation of caspases 9 and 3 by cytochrome c. Together, our data suggest that TGF-beta1 induces apoptosis through loss of Bcl-xL, leading to cytochrome c release and the subsequent activation of caspases 9 and 3. Moreover, our data demonstrate that the antiapoptotic effect of Bcl-xL occurs by inhibition of mitochondrial cytochrome c release and not through antagonizing Apaf-1-dependent processing of caspases 9 and 3.

Apoptosis↗