Abstract
Wnt signaling is essential for early embryonic development, the maintenance of stem cell pluripotency, determination of cell polarity, and cellular differentiation. Alterations in Wnt signaling activity have dramatic effects, resulting in developmental defects and contributing to the development of cancer. We recently found that perturbations in Wnt signaling lead to chromosomal instability (CIN), which results in aneuploidy, a hallmark of many cancer cells. However, we currently do not understand the mechanism by which Wnt promotes this CIN. We hypothesize that the protein p53 (gene name = TP53), often described as “the guardian of the genome”, acts downstream of Wnt to influence the fidelity of chromosome segregation. The goals of my research are to further study the effect of Wnt signaling on CIN and to explore the potential involvement of p53 in this process. To this end, I am utilizing DNA fluorescence in situ hybridization (FISH) as a means to detect and quantify the frequency of chromosome mis‐segregation across a population of cells. This method will allow me to detect changes in chromosome numbers in response to Wnt stimulation over time. In addition, I am creating a human embryonic stem cell line (H1/WA01) that will express fusion proteins composed of a fluorescent protein and either a histone (H2B) or tubulin. These transgene expressing H1 cells will be used to visualize mitosis and chromosome mis‐segregation. To address the involvement of p53, I will monitor both changes in gene expression of TP53 and changes in p53 protein abundance and modification, including phosphorylation and acetylation. Any observed changes in TP53 gene expression or p53 protein in response to Wnt signaling may contribute to CIN and hence to the occurrence of aneuploidy. These studies into the mechanism of Wnt‐induced CIN and the role of p53 will provide valuable insights into the development of cancer and may help identify a novel target of cancer therapeutics.Support or Funding InformationThis work is supported by a grant from the CIRM (RB1‐01406, to K.W.) and was made possible in part by the California Institute for Regenerative Medicine (CIRM) Major Facilities Grant (FA1‐00607) to the Sanford Consortium for Regenerative Medicine.
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