Interaction of E1B 19K with Bax is required to block Bax-induced loss of mitochondrial membrane potential and apoptosis

Jeonghoon Han, Digant Modha, Eileen White

Research output: Contribution to journalArticlepeer-review

48 Scopus citations

Abstract

The Bcl-2 homologous region 3 (BH3) is sufficient for interaction of pro-apoptotic with anti-apoptotic Bcl-2 family members, and functional antagonism may determine whether cell survival or death is the outcome of this protein-protein interaction. To address the biological role of BH3, two Bax-Bcl2 chimeras were generated in which 13 amino acids encompassing BH3 was swapped between anti-apoptotic Bcl-2 and pro-apoptotic Bax, thereby generating Bax with BH3 of Bcl-2 (Bax-BH3Bcl2), and Bcl-2 with BH3 of Bax (Bcl2-BH3Bax). Function and binding of the chimeras was then assessed utilizing the adenoviral Bcl-2 homologue, E1B 19K, which blocks apoptosis, and interacts with Bar, but not with Bcl-2. E1B 19K did not interact with Bax-BH3Bcl2 but did interact with Bcl2-BH3Bax. Bax-BH3Bax retained pro-apoptotic function, while Bcl2-BH3Bax did not exhibit either pro- or anti-apoptotic activity. Thus, BH3 of Bcl-2 encodes binding specificity but not the apoptotic propensity. E1B 19K could not block Bax-BH3Bcl2-induced apoptosis, suggesting that E1B 19K may act to antagonize pro-apoptotic proteins rather than as an effector of survival. Furthermore, Bax expression disrupted the mitochondrial membrane potential, which could be rescued by E1B 19K expression. Thus, BH3 controls the binding specificity among Bcl-2 family members, and direct interaction between pro-apoptotic and anti-apoptotic proteins is a mechanism to regulate mitochondrial membrane potential and apoptosis.

Original languageEnglish (US)
Pages (from-to)2993-3005
Number of pages13
JournalOncogene
Volume17
Issue number23
DOIs
StatePublished - Dec 10 1998

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cancer Research

Keywords

  • Apoptosis
  • Bax
  • E1B 19K
  • Mitochondrial membrane potential

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