Mtd, a Novel Bcl-2 Family Member Activates Apoptosis in the Absence of Heterodimerization with Bcl-2 and Bcl-XL*
- Naohiro Inohara,
- Daryoush Ekhterae,
- Irene Garcia‡,
- Roberto Carrio§,
- Jesus Merino§,
- Andrew Merry,
- Shu Chen and
- Gabriel Núñez¶
- From the Department of Pathology and Comprehensive Cancer Center, The University of Michigan Medical School, Ann Arbor, Michigan 48109, the ‡Department of Pathology, Centre Medical Universitaire, 1211 Geneva 4, Switzerland, and the §Unidad de Immunologia, Departamento de Biologia Molecular, Universidad de Cantabria, Santander 39011, Spain
Abstract
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.
Footnotes
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↵* This work was supported in part by Grant CA-64556 from the National Institutes of Health (to G. N.), Grant 96/104 from the Comisión Interministerial de Ciencia y Tecnologı́a, Spanish Ministry of Education and Science (to J. M.), a postdoctoral fellowship from the National Institutes of Health (to D. E.), Spanish Ministry of Education and Science Grant FP93–5058921 (to R. C), and Grants 31-42275.94 and 31.37516.93 from the Swiss National Foundation (to I. G.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
The nucleotide sequence(s) reported in this paper has been submitted to the GenBank™/EMBL Data Bank with accession number(s) AF027707.
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↵¶ Recipient of Research Career Development Award CA-64421 from the National Institutes of Health. To whom correspondence should be addressed: Dept. of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109. Tel.: 313-764-8514; Fax: 313-647-9654; E-mail:gabriel.nunez{at}umich.edu.
- Received December 10, 1997.
- Revision received January 10, 1998.
- The American Society for Biochemistry and Molecular Biology, Inc.
