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p53 regulates mitochondrial membrane potential through reactive oxygen species and induces cytochrome c-independent apoptosis blocked by Bcl-2.
EMBO J. 1999 Nov 01; 18(21):6027-36.EJ

Abstract

Downstream mediators of p53 in apoptosis induction remain to be elucidated. We report that p53-induced apoptosis occurred in the absence of cytochrome c release into the cytosol. Although Bax was upregulated, it remained largely in the cytosol and there was no detectable translocation to the mitochondria. Bid was not activated as no cleavage could be detected. Thus, the absence of cytochrome c release may be due to the lack of Bax translocation to mitochondria and/or Bid inactivation. Nevertheless, p53-induced apoptosis is still caspase dependent because it could be abolished by z-VAD-fmk. To search for alternative downstream targets of p53, we detected production of reactive oxygen species (ROS) as well as mitochondrial membrane potential (Deltapsi). p53 induced ROS generation, which then caused a transient increase of Deltapsi followed by a decrease. Antioxidants could inhibit the alterations of Deltapsi, thereby preventing apoptosis. z-VAD-fmk was unable to abrogate Deltapsi elevation but inhibited Deltapsi decrease, indicating that Deltapsi elevation and its decrease are two independent events. Bcl-2 may abolish elevation as well as decrease of Deltapsi without interfering with ROS levels. Thus, the ROS-mediated disruption of Deltapsi constitutes a pivotal step in the apoptotic pathway of p53, and this pathway does not involve cytochrome c release.

Authors+Show Affiliations

Department of Cardiology, Franz Volhard Klinik, Universitätskliuikum Charité, Humboldt University, Wiltbergstrasse 50, 13125 Berlin, Germany.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

10545114

Citation

Li, P F., et al. "P53 Regulates Mitochondrial Membrane Potential Through Reactive Oxygen Species and Induces Cytochrome C-independent Apoptosis Blocked By Bcl-2." The EMBO Journal, vol. 18, no. 21, 1999, pp. 6027-36.
Li PF, Dietz R, von Harsdorf R. P53 regulates mitochondrial membrane potential through reactive oxygen species and induces cytochrome c-independent apoptosis blocked by Bcl-2. EMBO J. 1999;18(21):6027-36.
Li, P. F., Dietz, R., & von Harsdorf, R. (1999). P53 regulates mitochondrial membrane potential through reactive oxygen species and induces cytochrome c-independent apoptosis blocked by Bcl-2. The EMBO Journal, 18(21), 6027-36.
Li PF, Dietz R, von Harsdorf R. P53 Regulates Mitochondrial Membrane Potential Through Reactive Oxygen Species and Induces Cytochrome C-independent Apoptosis Blocked By Bcl-2. EMBO J. 1999 Nov 1;18(21):6027-36. PubMed PMID: 10545114.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - p53 regulates mitochondrial membrane potential through reactive oxygen species and induces cytochrome c-independent apoptosis blocked by Bcl-2. AU - Li,P F, AU - Dietz,R, AU - von Harsdorf,R, PY - 1999/11/2/pubmed PY - 1999/11/2/medline PY - 1999/11/2/entrez SP - 6027 EP - 36 JF - The EMBO journal JO - EMBO J VL - 18 IS - 21 N2 - Downstream mediators of p53 in apoptosis induction remain to be elucidated. We report that p53-induced apoptosis occurred in the absence of cytochrome c release into the cytosol. Although Bax was upregulated, it remained largely in the cytosol and there was no detectable translocation to the mitochondria. Bid was not activated as no cleavage could be detected. Thus, the absence of cytochrome c release may be due to the lack of Bax translocation to mitochondria and/or Bid inactivation. Nevertheless, p53-induced apoptosis is still caspase dependent because it could be abolished by z-VAD-fmk. To search for alternative downstream targets of p53, we detected production of reactive oxygen species (ROS) as well as mitochondrial membrane potential (Deltapsi). p53 induced ROS generation, which then caused a transient increase of Deltapsi followed by a decrease. Antioxidants could inhibit the alterations of Deltapsi, thereby preventing apoptosis. z-VAD-fmk was unable to abrogate Deltapsi elevation but inhibited Deltapsi decrease, indicating that Deltapsi elevation and its decrease are two independent events. Bcl-2 may abolish elevation as well as decrease of Deltapsi without interfering with ROS levels. Thus, the ROS-mediated disruption of Deltapsi constitutes a pivotal step in the apoptotic pathway of p53, and this pathway does not involve cytochrome c release. SN - 0261-4189 UR - https://www.unboundmedicine.com/medline/citation/10545114/p53_regulates_mitochondrial_membrane_potential_through_reactive_oxygen_species_and_induces_cytochrome_c_independent_apoptosis_blocked_by_Bcl_2_ L2 - https://doi.org/10.1093/emboj/18.21.6027 DB - PRIME DP - Unbound Medicine ER -