BID Preferentially Activates BAK while BIM Preferentially Activates BAX, Affecting Chemotherapy Response

Abstract

SUMMARY Apoptosis is a highly regulated form of cell death that controls normal homeostasis as well as the anti-tumor activity of many chemotherapeutic agents. Commitment to death via the mitochondrial apoptotic pathway requires activation of the mitochondrial pore-forming proteins BAK or BAX. Activation can be effected by the activator BH3-only proteins BID or BIM, which have been considered to be functionally redundant in this role. Herein, we show that significant activation preferences exist between these proteins: BID preferentially activates BAK while BIM preferentially activates BAX. Furthermore, we find that cells lacking BAK are relatively resistant to agents that require BID activation for maximal induction of apoptosis including topoisomerase inhibitors and TRAIL. Consequently, patients with tumors that harbor a loss of BAK1 exhibit an inferior response to topoisomerase inhibitor treatment in the clinic. Therefore, BID and BIM have non-overlapping roles in the induction of apoptosis via BAK and BAX, affecting chemotherapy response.

Gli1 Protein Regulates the S-phase Checkpoint in Tumor Cells via Bid Protein, and Its Inhibition Sensitizes to DNA Topoisomerase 1 Inhibitors

“…Moreover, recent mechanistic studies have demonstrated a critical role for Bid in the association of RPA with the ATRIP-ATR complex in response to hydroxyurea (HU)-and UV-induced replication stress (50) and sensitivities of BID Ϫ/Ϫ MEFs (mouse embryonic fibroblasts) to several chemotherapeutic agents (75). Consistent with these studies, our data further support a Bid role in ATR-mediated Chk1 phosphorylation in response to the Top1 poison CPT.…”

“…Several studies have implicated Bid in mediating DDR signaling (50,58,75). Moreover, recent mechanistic studies have demonstrated a critical role for Bid in the association of RPA with the ATRIP-ATR complex in response to hydroxyurea (HU)-and UV-induced replication stress (50) and sensitivities of BID Ϫ/Ϫ MEFs (mouse embryonic fibroblasts) to several chemotherapeutic agents (75).…”

Analysis of transcription profile to reveal altered signaling pathways following the overexpression of human desumoylating isopeptidase 2 in pancreatic cancer cells

“…In the current study, microarray analysis identified that upstream BID expression levels were increased, which was corroborated at the protein level. As an essential apoptosis-associated protein, BID may be cleaved into tBID, which then activates Bax and Bcl-2 antagonist/killer, triggering the mitochondrial apoptosis pathway (14)(15)(16). The results suggest a mechanism that may underlie the DESI-2-induced apoptosis observed in our previous study (11).…”

Mouse Cytotoxic T Cell-derived Granzyme B Activates the Mitochondrial Cell Death Pathway in a Bim-dependent Fashion

“…Bim down-regulation by siRNA completely blocks human gzmB-induced apoptosis. Bim is a BH3-only member of the Bcl-2 family, which has been shown to activate Bak and/or Bax directly, independent of other BH3-only proteins like Bid (23)(24)(25). The combined studies suggest that caspase-3 and Bid are not the only intracellular targets of gzmB (26).…”