Bfl-1/A1 functions, similar to Mcl-1, as a selective tBid and Bak antagonist

TY - JOUR

T1 - Bfl-1/A1 functions, similar to Mcl-1, as a selective tBid and Bak antagonist

AU - Simmons, M. J.

AU - Fan, G.

AU - Zong, W. X.

AU - Degenhardt, K.

AU - White, E.

AU - Gélinas, C.

N1 - Funding Information: We thank R Sundararajan, D Perez and N Gupta for discussions. This work was supported by NIH Grant CA083937, the Charlotte Geyer Foundation and the Foundation of UMDNJ. MJS was partially supported by NIH predoctoral training Grant GM08360.

PY - 2008/2/28

Y1 - 2008/2/28

N2 - The prosurvival Bcl-2-family member Bfl-1/A1 is a transcriptional target of nuclear factor-κB (NF-κB) that is overexpressed in many human tumors and is a means by which NF-κB inhibits apoptosis, but its mode of action is controversial. To better understand how Bfl-1 functions, we investigated its interaction with proapoptotic multidomain proteins Bax and Bak, and the BH3-only proteins Bid and tBid. We demonstrate that in living cells Bfl-1 selectively interacts with Bak and tBid, but not with Bax or Bid. Bfl-1/Bak interaction is functional as Bfl-1 suppressed staurosporine (STS)-induced apoptosis in wild-type and Bax-deficient cells, but not in Bak-/- cells. We also show that Bfl-1 blocks tumor necrosis factor-α (TNFα)-induced activation of Bax indirectly, via association with tBid. C-terminal deletion decreased Bfl-1's interaction with Bak and tBid and reduced its ability to suppress Bak- and tBid-mediated cell death. These data indicate that Bfl-1 utilizes different mechanisms to suppress apoptosis depending on the stimulus. Bfl-1 associates with tBid to prevent activation of proapoptotic Bax and Bak, and it also interacts directly with Bak to antagonize Bak-mediated cell death, similar to Mcl-1. Thus, part of the protective function of NF-κB is to induce Mcl-1-like activity by upregulating Bfl-1.

AB - The prosurvival Bcl-2-family member Bfl-1/A1 is a transcriptional target of nuclear factor-κB (NF-κB) that is overexpressed in many human tumors and is a means by which NF-κB inhibits apoptosis, but its mode of action is controversial. To better understand how Bfl-1 functions, we investigated its interaction with proapoptotic multidomain proteins Bax and Bak, and the BH3-only proteins Bid and tBid. We demonstrate that in living cells Bfl-1 selectively interacts with Bak and tBid, but not with Bax or Bid. Bfl-1/Bak interaction is functional as Bfl-1 suppressed staurosporine (STS)-induced apoptosis in wild-type and Bax-deficient cells, but not in Bak-/- cells. We also show that Bfl-1 blocks tumor necrosis factor-α (TNFα)-induced activation of Bax indirectly, via association with tBid. C-terminal deletion decreased Bfl-1's interaction with Bak and tBid and reduced its ability to suppress Bak- and tBid-mediated cell death. These data indicate that Bfl-1 utilizes different mechanisms to suppress apoptosis depending on the stimulus. Bfl-1 associates with tBid to prevent activation of proapoptotic Bax and Bak, and it also interacts directly with Bak to antagonize Bak-mediated cell death, similar to Mcl-1. Thus, part of the protective function of NF-κB is to induce Mcl-1-like activity by upregulating Bfl-1.

KW - A1

KW - Apoptosis

KW - Bak

KW - Bcl2a1

KW - Bfl-1

KW - tBid

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U2 - https://doi.org/10.1038/sj.onc.1210771

DO - https://doi.org/10.1038/sj.onc.1210771

M3 - Article

C2 - 17724464

VL - 27

SP - 1421

EP - 1428

JO - Oncogene

JF - Oncogene

SN - 0950-9232

IS - 10

ER -