FLJ25439, a novel cytokinesis-associated protein, induces tetraploidization and maintains chromosomal stability via enhancing expression of endoplasmic reticulum stress chaperones.

Abstract

Investigation of the mechanisms leading to aneuploidy and polyploidy is critical to cancer research. Previous studies have provided strong evidence of the importance of tetraploidization as an early step in tumorigenesis. In cancer cells, tetraploid cells may contribute to abnormal mitotic progression, which may be associated with cytokinesis failure. Tetraploidy leads to genomic instability due to centrosome and chromosome over-replication. Until now, the mechanism by which cells maintain tetraploid status has been unknown. Here, we identified a novel D box-containing protein, FLJ25439, which displays a dynamic expression profile during mitosis/cytokinesis with the midbody as the most prominent associated structure. To understand the function of FLJ25439, we established stable cell lines overexpressing FLJ25439. FLJ25439-overexpression cells grew slower and displayed a tetraploid DNA content in comparison with diploid parental cells. They also showed aberrant mitosis and dysregulated expression of p53, pRb and p21, suggesting a defect in cell cycle progression. To explore the molecular mechanisms responsible for FLJ25439-induced tetraploidization, we conducted a comparative analysis of the global protein expression patterns of wild type and overexpressors using proteomics and bioinformatics approaches. Protein category profiling indicated that FLJ25439 is involved in pathways related to anti-apoptosis, protein folding, the cell cycle, and cytoskeleton regulation. Specifically, genotoxic-stress- and ER stress-related chaperone proteins greatly contributed to the FLJ25439 overexpression phenotypes. The results of this study pave the way to our further understanding of the role of this novel cytokinesis-related protein in protecting cells from environmental stress and tetraploid formation.

• Authors: Tai-Long Pan, Shu-Yuan Hsu, Pei-Wen Wang, Ya-Ting Cheng, Yu-Chen Chang, Sudipta Saha, Jiwei Hu, Pin Ouyang
• Journal: Cell cycle (Georgetown, Tex.) (Cell Cycle) Vol. 14 Issue 8 Pg. 1174-87 ( 2015) ISSN: 1551-4005 [Electronic] United States
• PMID: 25751302 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cell Cycle Proteins
• Cyclin-Dependent Kinase Inhibitor p21
• Molecular Chaperones
• Retinoblastoma Protein
• TTC23L protein, human
• Tumor Suppressor Protein p53
• Hydrogen Peroxide

Topics

• Amino Acid Sequence
• Base Sequence
• Cell Cycle Proteins (chemistry, genetics, metabolism)
• Centrosome (metabolism)
• Chromosomal Instability
• Cyclin-Dependent Kinase Inhibitor p21 (metabolism)
• Cytokinesis (physiology)
• Endoplasmic Reticulum Stress
• HeLa Cells
• Humans
• Hydrogen Peroxide (toxicity)
• Molecular Chaperones (metabolism)
• Molecular Sequence Data
• Oxidative Stress (drug effects)
• Protein Folding
• Proteomics
• Retinoblastoma Protein (metabolism)
• Tetraploidy
• Tumor Suppressor Protein p53 (metabolism)