Mcl-1 determines the Bax dependency of Nbk/Bik-induced apoptosis.
B cell lymphoma 2 (Bcl-2) homology domain 3 (BH3)-only proteins of the Bcl-2 family are important functional adaptors that link cell death signals to the activation of Bax and/or Bak. The BH3-only protein Nbk/Bik induces cell death via an entirely Bax-dependent/Bak-independent mechanism. In contrast, cell death induced by the short splice variant of Bcl-x depends on Bak but not Bax. This indicates that Bak is functional but fails to become activated by Nbk. Here, we show that binding of myeloid cell leukemia 1 (Mcl-1) to Bak persists after Nbk expression and inhibits Nbk-induced apoptosis in Bax-deficient cells. In contrast, the BH3-only protein Puma disrupts Mcl-1-Bak interaction and triggers cell death via both Bax and Bak. Targeted knockdown of Mcl-1 overcomes inhibition of Bak and allows for Bak activation by Nbk. Thus, Nbk is held in check by Mcl-1 that interferes with activation of Bak. The finding that different BH3-only proteins rely specifically on Bax, Bak, or both has important implications for the design of anticancer drugs targeting Bcl-2.
Gillissen
Bernhard
B
Department of Hematology, Oncology, and Tumor Immunology, University Medical Center Charité, 13125 Berlin, Germany.
Essmann
Frank
F
Hemmati
Philipp G
PG
Richter
Antje
A
Richter
Anja
A
Oztop
Ilker
I
Chinnadurai
Govindaswamy
G
Dörken
Bernd
B
Daniel
Peter T
PT
D000256:Adenoviridae / Q000235:genetics; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001562:Benzimidazoles; D002232:Carbocyanines; D002460:Cell Line; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability; D045304:Cytochromes c / Q000378:metabolism; D005456:Fluorescent Dyes; D045325:HCT116 Cells; D006801:Humans; D007668:Kidney / Q000166:cytology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D008928:Mitochondria / Q000502:physiology; D024101:Mitochondrial Proteins; D008954:Models, Biological; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D019076:Transgenes; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000235:genetics / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; C096820:BIK protein, human; D001562:Benzimidazoles; D002232:Carbocyanines; D005456:Fluorescent Dyes; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; C068624:5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolocarbocyanine; D045304:Cytochromes c