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MITOSTATIN, a putative tumor suppressor on chromosome 12q24.1, is downregulated in human bladder and breast cancer.

Vecchione A, Fassan M, Anesti V, Morrione A, Goldoni S, Baldassarre G, Byrne D, D'Arca D, Palazzo JP, Lloyd J, Scorrano L, Gomella LG, Iozzo RV, Baffa R - Oncogene (2008)

Bottom Line: Human MITOSTATIN was found within a 3.2-kb transcript, which encoded a approximately 62 kDa, ubiquitously expressed protein with little homology to any known protein.We found homozygous deletions and mutations of MITOSTATIN gene in approximately 5 and approximately 11% of various cancer-derived cells and solid tumors, respectively.Finally, MITOSTATIN expression was significantly reduced in primary bladder and breast tumors, and its reduction was associated with advanced tumor stages.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.

ABSTRACT
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 approximately 62 kDa, ubiquitously expressed protein with little homology to any known protein. We found homozygous deletions and mutations of MITOSTATIN gene in approximately 5 and approximately 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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Ultrastructural analysis of MITOSTATIN-expressing PC3 prostate carcinoma cells show abnormal mitochondrial structure(a) Electron micrograph of a wild-type PC3 cell shows normal appearing mitochondria (empty arrows). Bar, 2 µm. (b) Ultrastructural analysis of a MITOSTATIN-expressing cells. Note the large number of small, swollen mitochondria (black arrows). Bar, 2 µm. (c) High magnification of the inset in B shows loss of mitochondrial matrix (asterisks) and abnormal christae (empty arrows). Bar, 0.2 µm.
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Figure 4: Ultrastructural analysis of MITOSTATIN-expressing PC3 prostate carcinoma cells show abnormal mitochondrial structure(a) Electron micrograph of a wild-type PC3 cell shows normal appearing mitochondria (empty arrows). Bar, 2 µm. (b) Ultrastructural analysis of a MITOSTATIN-expressing cells. Note the large number of small, swollen mitochondria (black arrows). Bar, 2 µm. (c) High magnification of the inset in B shows loss of mitochondrial matrix (asterisks) and abnormal christae (empty arrows). Bar, 0.2 µm.

Mentions: To further investigate MITOSTATIN’s relationship with mitochondria, we analyzed wild type PC3 prostate carcinoma derived cells and PC3 MITOSTATIN-over-expressing clones (PC3 B2) by transmission electron microscopy (TEM). Ultrastructural analysis of MITOSTATIN-over-expressing PC3 cells revealed that the mitochondria were often round and showed abnormal christae in contrast to the wild-type cells (Figure 4a). In addition, mitochondria were often swollen and lost some of their christae and matrix material (Figure 4b and 4c).


MITOSTATIN, a putative tumor suppressor on chromosome 12q24.1, is downregulated in human bladder and breast cancer.

Vecchione A, Fassan M, Anesti V, Morrione A, Goldoni S, Baldassarre G, Byrne D, D'Arca D, Palazzo JP, Lloyd J, Scorrano L, Gomella LG, Iozzo RV, Baffa R - Oncogene (2008)

Ultrastructural analysis of MITOSTATIN-expressing PC3 prostate carcinoma cells show abnormal mitochondrial structure(a) Electron micrograph of a wild-type PC3 cell shows normal appearing mitochondria (empty arrows). Bar, 2 µm. (b) Ultrastructural analysis of a MITOSTATIN-expressing cells. Note the large number of small, swollen mitochondria (black arrows). Bar, 2 µm. (c) High magnification of the inset in B shows loss of mitochondrial matrix (asterisks) and abnormal christae (empty arrows). Bar, 0.2 µm.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2628456&req=5

Figure 4: Ultrastructural analysis of MITOSTATIN-expressing PC3 prostate carcinoma cells show abnormal mitochondrial structure(a) Electron micrograph of a wild-type PC3 cell shows normal appearing mitochondria (empty arrows). Bar, 2 µm. (b) Ultrastructural analysis of a MITOSTATIN-expressing cells. Note the large number of small, swollen mitochondria (black arrows). Bar, 2 µm. (c) High magnification of the inset in B shows loss of mitochondrial matrix (asterisks) and abnormal christae (empty arrows). Bar, 0.2 µm.
Mentions: To further investigate MITOSTATIN’s relationship with mitochondria, we analyzed wild type PC3 prostate carcinoma derived cells and PC3 MITOSTATIN-over-expressing clones (PC3 B2) by transmission electron microscopy (TEM). Ultrastructural analysis of MITOSTATIN-over-expressing PC3 cells revealed that the mitochondria were often round and showed abnormal christae in contrast to the wild-type cells (Figure 4a). In addition, mitochondria were often swollen and lost some of their christae and matrix material (Figure 4b and 4c).

Bottom Line: Human MITOSTATIN was found within a 3.2-kb transcript, which encoded a approximately 62 kDa, ubiquitously expressed protein with little homology to any known protein.We found homozygous deletions and mutations of MITOSTATIN gene in approximately 5 and approximately 11% of various cancer-derived cells and solid tumors, respectively.Finally, MITOSTATIN expression was significantly reduced in primary bladder and breast tumors, and its reduction was associated with advanced tumor stages.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.

ABSTRACT
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 approximately 62 kDa, ubiquitously expressed protein with little homology to any known protein. We found homozygous deletions and mutations of MITOSTATIN gene in approximately 5 and approximately 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.

Show MeSH
Related in: MedlinePlus