Work

WT1 interacts with MAD2 and regulates mitotic checkpoint function

Year: 2014

Type: article

Abstract: Tumour suppressors safeguard the fidelity of the mitotic checkpoint by transcriptional regulation of genes that encode components of the mitotic checkpoint complex (MCC). Here we report a new role for the tumour suppressor and transcription factor, WT1, in the mitotic checkpoint. We show that WT1 regulates the MCC by directly interacting with the spindle assembly checkpoint protein, MAD2. WT1 colocalizes with MAD2 during mitosis and preferentially binds to the functionally active, closed-conformer, C-MAD2. Furthermore, WT1 associates with the MCC containing MAD2, BUBR1 and CDC20, resulting in prolonged inhibition of the anaphase-promoting complex/cyclosome (APC/C) and delayed degradation of its substrates SECURIN and CYCLIN B1. Strikingly, RNA interference-mediated depletion of WT1 leads to enhanced turnover of SECURIN, decreased lag time to anaphase and defects in chromosome segregation. Our findings identify WT1 as a regulator of the mitotic checkpoint and chromosomal stability. The transcription factor WT1 can act as either a tumour suppressor or an oncogene by regulating gene expression. Shandilya et al. show that WT1 also directly activates the spindle assembly checkpoint by binding the checkpoint protein MAD2 to delay anaphase and promote chromosomal stability.

Source: Nature Communications

DOI: 10.1038/ncomms5903

Authors: Jayasha Shandilya, Eneda Toska, Derek J. Richard, Kathryn F. Medler, Stefan G. E. Roberts

Institutions: University at Buffalo, State University of New York, Translational Research Institute, Queensland University of Technology, University of Bristol

Language: English

Topic: Microtubule and mitosis dynamics

Subfield: Cell Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

Open Access status: hybrid

Estimated APC paid: $6,990

Funders: National Science Foundation, National Institute of General Medical Sciences