Mtd, a novel Bcl-2 family member activates apoptosis in the absence of heterodimerization with Bcl-2 and Bcl-XL.
We have identified and characterized Mtd, a novel regulator of apoptosis. Sequence analysis revealed that Mtd is a member of the Bcl-2 family of proteins containing conserved BH1, BH2, BH3, and BH4 regions and a carboxyl-terminal hydrophobic domain. In adult tissues, Mtd mRNA was predominantly detected in the brain, liver, and lymphoid tissues, while in the embryo Mtd mRNA was detected in the liver, thymus, lung, and intestinal epithelium. Expression of Mtd promoted the death of primary sensory neurons, 293T cells and HeLa cells, indicating that Mtd is a proapoptotic protein. Unlike all other known death agonists of the Bcl-2 family, Mtd did not bind significantly to the survival-promoting proteins Bcl-2 or Bcl-XL. Furthermore, apoptosis induced by Mtd was not inhibited by Bcl-2 or Bcl-XL. A Mtd mutant with glutamine substitutions of highly conserved amino acids in the BH3 domain retained its ability to promote apoptosis, further indicating that Mtd does not promote apoptosis by heterodimerizing with Bcl-2 or Bcl-XL. Mtd-induced apoptosis was not blocked by broad range synthetic caspase inhibitors z-VAD-fmk or a viral protein CrmA. Mtd is the first example of a naturally occurring Bcl-2 family member that can activate apoptosis independently of heterodimerization with survival-promoting Bcl-2 and Bcl-XL.
Inohara
N
N
Department of Pathology and Comprehensive Cancer Center, The University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
Ekhterae
D
D
Garcia
I
I
Carrio
R
R
Merino
J
J
Merry
A
A
Chen
S
S
Núñez
G
G
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D002460:Cell Line; D002470:Cell Survival; D017124:Conserved Sequence; D019281:Dimerization; D004622:Embryo, Mammalian; D018507:Gene Expression Regulation, Developmental; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D009475:Neurons, Afferent / Q000166:cytology / Q000502:physiology*; D009928:Organ Specificity; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D017783:Superior Cervical Ganglion / Q000166:cytology / Q000502:physiology; D014158:Transcription, Genetic; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; C494813:Bcl2l1 protein, rat; C111858:Bok protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D011994:Recombinant Proteins; D051020:bcl-X Protein