Journal
ONCOGENE
Volume 28, Issue 2, Pages 257-269Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2008.381
Keywords
bladder cancer; breast cancer; mitochondria; chromosome 12q; tumor suppressor
Funding
- Sidney Kimmel Foundation for Cancer Research
- Benjamin Perkins Bladder Cancer Fund
- Martin Greitzer Fund
- Telethon Italy
- AIRC Italy
- National Institutes of Health [RO1 CA39481, RO1 CA47282, RO1 CA120975, RO1 DK068419]
- NATIONAL CANCER INSTITUTE [R01CA120975, R01CA039481, R01CA047282] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK068419] Funding Source: NIH RePORTER
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Allelic deletions on human chromosome 12q24 are frequently reported in a variety of malignant neoplasms, indicating the presence of a tumor suppressor gene(s) in this chromosomal region. However, no reasonable candidate has been identified so far. In this study, we report the cloning and functional characterization of a novel mitochondrial protein with tumor suppressor activity, henceforth designated MITOSTATIN. Human MITOSTATIN was found within a 3.2-kb transcript, which encoded a similar to 62 kDa, ubiquitously expressed protein with little homology to any known protein. We found homozygous deletions and mutations of MITOSTATIN gene in similar to 5 and similar to 11% of various cancer-derived cells and solid tumors, respectively. When transiently overexpressed, MITOSTATIN inhibited colony formation, tumor cell growth and was proapoptotic, all features shared by established tumor suppressor genes. We discovered a specific link between MITOSTATIN overexpression and downregulation of Hsp27. Conversely, MITOSTATIN knockdown cells showed an increase in cell growth and cell survival rates. Finally, MITOSTATIN expression was significantly reduced in primary bladder and breast tumors, and its reduction was associated with advanced tumor stages. Our findings support the hypothesis that MITOSTATIN has many hallmarks of a classical tumor suppressor in solid tumors and may play an important role in cancer development and progression.
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