Cytokinetic failure-induced tetraploidy develops into aneuploidy, triggering skin aging in phospho-vimentin deficient mice [Molecular Bases of Disease]

April 6th, 2015 by Tanaka, H., Goto, H., Inoko, A., Makihara, H., Enomoto, A., Horimoto, K., Matsuyama, M., Kurita, K., Izawa, I., Inagaki, M.

Tetraploidy, a state in which cells have doubled chromosomal sets, is observed in ~20% of solid tumors and considered to frequently precede aneuploidy in carcinogenesis. Tetraploidy is also detected during terminal differentiation and represents a hallmark of aging. Most tetraploid cultured cells are arrested by p53 stabilization. However, the fate of tetraploid cells in vivo remains largely unknown. Here, we analyze the ability to repair wounds in the skin of phospho-vimentin deficient (VIMSA/SA) mice. Early into wound healing, subcutaneous fibroblasts failed to undergo cytokinesis, resulting in binucleate tetraploidy. In accordance, the mRNA level of p21 (a p53-responsive gene) was elevated in a VIMSA/SA-specific manner. Disappearance of tetraploidy coincided with an increase in aneuploidy. Thereafter, senescence-related markers were significantly elevated in VIMSA/SA mice. Since our tetraploidy-prone mouse model also exhibited subcutaneous fat loss at the age 14 months, another premature aging phenotype, our data suggest that following cytokinetic failure, a subset of tetraploid cells enter a new cell cycle and develop into aneuploid cells in vivo, which promotes premature aging.
  • Posted in Journal of Biological Chemistry, Publications
  • Comments Off on Cytokinetic failure-induced tetraploidy develops into aneuploidy, triggering skin aging in phospho-vimentin deficient mice [Molecular Bases of Disease]