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Regulation of the mitochondrial checkpoint in p53-mediated apoptosis confers resistance to cell death.
Oncogene. 2002 Jan 24; 21(5):748-60.O

Abstract

The p53 tumor suppressor protein inhibits tumor formation, in part by inducing apoptosis, which is inhibited by anti-apoptotic Bcl-2 family members Bcl-2 and adenovirus E1B 19K. We have identified p53-apoptotic signaling events which are targeted for inhibition by E1B 19K. Apoptotic signaling by p53 induced a Bid-independent conformational change in Bax, a Bax-Bak interaction, release of cytochrome c and Smac/DIABLO from mitochondria, caspase-9 and -3 activation, cleavage of known caspase substrates, and apoptosis. When p53-dependent apoptosis was blocked by E1B 19K expression, E1B 19K bound Bak, and the Bax-Bak interaction was inhibited. Cytochrome c and Smac/DIABLO release from mitochondria was also inhibited in E1B 19K expressing cells and cells remained viable. After a prolonged p53 death stimulus, the inhibition of the mitochondrial death checkpoint by E1B 19K failed, and cytochrome c and Smac/DIABLO were released from mitochondria, and became degraded. Despite this eventual failure to inhibit the mitochondrial checkpoint, caspase-9 and -3 were not activated, and cells remained viable even upon treatment with an exogenous death stimulus. Thus, p53 induces apoptosis in part through Bax and Bak, and even an incomplete inhibition of this mitochondrial checkpoint may be sufficient to confer resistance to cell death.

Authors+Show Affiliations

Howard Hughes Medical Institute, 679 Hoes Lane, Piscataway, New Jersey, NJ 08854, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

11850803

Citation

Henry, Holly, et al. "Regulation of the Mitochondrial Checkpoint in P53-mediated Apoptosis Confers Resistance to Cell Death." Oncogene, vol. 21, no. 5, 2002, pp. 748-60.
Henry H, Thomas A, Shen Y, et al. Regulation of the mitochondrial checkpoint in p53-mediated apoptosis confers resistance to cell death. Oncogene. 2002;21(5):748-60.
Henry, H., Thomas, A., Shen, Y., & White, E. (2002). Regulation of the mitochondrial checkpoint in p53-mediated apoptosis confers resistance to cell death. Oncogene, 21(5), 748-60.
Henry H, et al. Regulation of the Mitochondrial Checkpoint in P53-mediated Apoptosis Confers Resistance to Cell Death. Oncogene. 2002 Jan 24;21(5):748-60. PubMed PMID: 11850803.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Regulation of the mitochondrial checkpoint in p53-mediated apoptosis confers resistance to cell death. AU - Henry,Holly, AU - Thomas,Anju, AU - Shen,Yan, AU - White,Eileen, PY - 2001/08/14/received PY - 2001/10/02/revised PY - 2001/10/29/accepted PY - 2002/2/19/pubmed PY - 2002/3/19/medline PY - 2002/2/19/entrez SP - 748 EP - 60 JF - Oncogene JO - Oncogene VL - 21 IS - 5 N2 - The p53 tumor suppressor protein inhibits tumor formation, in part by inducing apoptosis, which is inhibited by anti-apoptotic Bcl-2 family members Bcl-2 and adenovirus E1B 19K. We have identified p53-apoptotic signaling events which are targeted for inhibition by E1B 19K. Apoptotic signaling by p53 induced a Bid-independent conformational change in Bax, a Bax-Bak interaction, release of cytochrome c and Smac/DIABLO from mitochondria, caspase-9 and -3 activation, cleavage of known caspase substrates, and apoptosis. When p53-dependent apoptosis was blocked by E1B 19K expression, E1B 19K bound Bak, and the Bax-Bak interaction was inhibited. Cytochrome c and Smac/DIABLO release from mitochondria was also inhibited in E1B 19K expressing cells and cells remained viable. After a prolonged p53 death stimulus, the inhibition of the mitochondrial death checkpoint by E1B 19K failed, and cytochrome c and Smac/DIABLO were released from mitochondria, and became degraded. Despite this eventual failure to inhibit the mitochondrial checkpoint, caspase-9 and -3 were not activated, and cells remained viable even upon treatment with an exogenous death stimulus. Thus, p53 induces apoptosis in part through Bax and Bak, and even an incomplete inhibition of this mitochondrial checkpoint may be sufficient to confer resistance to cell death. SN - 0950-9232 UR - https://www.unboundmedicine.com/medline/citation/11850803/Regulation_of_the_mitochondrial_checkpoint_in_p53_mediated_apoptosis_confers_resistance_to_cell_death_ L2 - https://doi.org/10.1038/sj.onc.1205125 DB - PRIME DP - Unbound Medicine ER -