The MYC-Associated Protein CDCA7 Is Phosphorylated by AKT To Regulate MYC-Dependent Apoptosis and Transformation

Abstract

Cell division control protein A7 (CDCA7) is a recently identified target of MYC-dependent transcriptional regulation. We have discovered that CDCA7 associates with MYC and that this association is modulated in a phosphorylation-dependent manner. The prosurvival kinase AKT phosphorylates CDCA7 at threonine 163, promoting binding to 14-3-3, dissociation from MYC, and sequestration to the cytoplasm. Upon serum withdrawal, induction of CDCA7 expression in the presence of MYC sensitized cells to apoptosis, whereas CDCA7 knockdown reduced MYC-dependent apoptosis. The transformation of fibroblasts by MYC was reduced by coexpression of CDCA7, while the non-MYC-interacting protein Δ(156–187)-CDCA7 largely inhibited MYC-induced transformation. These studies provide insight into a new mechanism by which AKT signaling to CDCA7 could alter MYC-dependent growth and transformation, contributing to tumorigenesis.

ACKNOWLEDGMENTS

This work was supported by funds from the Canadian Institute of Health Research, an Early Investigator award (to M.P.S.), and a Canadian Foundation of Innovation award (to M.P.S.).

We thank Veronique Nogueira of the University of Illinois at Chicago for the kind gift of Akt1/2-null MEFs.