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1.
Oncogene ; 28(2): 257-69, 2009 Jan 15.
Article in English | MEDLINE | ID: mdl-18931701

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.


Subject(s)
Breast Neoplasms/genetics , Chromosomes, Human, Pair 12/genetics , Genes, Tumor Suppressor , Neoplasm Proteins/biosynthesis , Tumor Suppressor Proteins/physiology , Urinary Bladder Neoplasms/genetics , Animals , Apoptosis/genetics , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Carrier Proteins , Cell Division/genetics , Cell Line, Tumor/metabolism , Cell Line, Tumor/ultrastructure , Cell Transformation, Neoplastic/genetics , Cloning, Molecular , Disease Progression , Down-Regulation , Female , Gene Expression Regulation, Neoplastic , HSP27 Heat-Shock Proteins/biosynthesis , HSP27 Heat-Shock Proteins/genetics , Heat-Shock Proteins , Humans , Male , Mitochondria/metabolism , Mitochondria/ultrastructure , Molecular Chaperones , Molecular Sequence Data , Neoplasm Proteins/genetics , RNA, Messenger/genetics , RNA, Neoplasm/genetics , Recombinant Fusion Proteins/physiology , Species Specificity , Tumor Stem Cell Assay , Tumor Suppressor Proteins/genetics , Tumor Suppressor Proteins/isolation & purification , Urinary Bladder Neoplasms/metabolism , Urinary Bladder Neoplasms/pathology
3.
Ann N Y Acad Sci ; 1010: 514-9, 2003 Dec.
Article in English | MEDLINE | ID: mdl-15033782

ABSTRACT

Clusterin gene expression is potently induced in experimental models in which apoptosis is activated, such as rat prostate involution following castration. Nevertheless, its precise physiological role has not yet been established, and both anti-apoptotic and pro-apoptotic functions have been suggested for this gene. Clusterin expression level depends on cell proliferation state, and we recently showed that its over-expression inhibited cell cycle progression of SV40-immortalized human prostate epithelial cells PNT2 and PNT1a. Here we studied clusterin expression in PNT1a cells subjected to serum-starvation with the aim of defining clusterin early molecular changes following apoptosis induction. Under serum-starvation conditions, decreased growth rate, slow rounding-up of cells, cell detachment, and formation of apoptotic bodies indicative of anoikis (detachment-induced apoptosis) were preceded by significant downregulation of 70 kDa clusterin precursor and upregulation of 45-40 kDa isoforms. On the 8th day of serum-free culturing, only the higher molecular weight protein-band of about 45 kDa was clearly induced and accumulated in detached cells and apoptotic bodies in which PARP was activated. Anoikis was preceded by induction and transloction of a 45-kDa clusterin isoform to the nucleus. Thus, nuclear targeting of a specific 45-kDa isoform of clusterin appeared to be an early and specific molecular signal triggering anoikis-death. Considering also that clusterin is downregulated during prostate cancer onset and progression, and that its upregulation has inhibited DNA synthesis and cell cycle progression of immortalized human prostate epithelial cells, we suggest that clusterin might be a new anti-oncogene in the prostate.


Subject(s)
Active Transport, Cell Nucleus/physiology , Apoptosis/physiology , Glycoproteins/genetics , Molecular Chaperones/genetics , Simian virus 40/genetics , Cell Division , Cell Line, Tumor , Cell Nucleus/metabolism , Cell Transformation, Viral , Clusterin , Culture Media, Serum-Free , Epithelial Cells/metabolism , Epithelial Cells/pathology , Gene Expression Regulation, Neoplastic , Glycoproteins/metabolism , Humans , Keratins/metabolism , Kinetics , Male , Molecular Chaperones/metabolism , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , Protein Isoforms/genetics , Protein Isoforms/metabolism
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