Tctp regulates the level and localization of Foxo for cell growth in Drosophila

Abstract

Regulation of cell size is crucial for organ development. Insulin signaling regulates organ size by antagonizing the subgroup O of forkhead box transcription factor (Foxo) through 14-3-3 in Drosophila. However, mechanisms for controlling the level and the nuclear localization of Foxo in developing organs are not well understood. Here, we investigate the role of Drosophila Translationally controlled tumor protein (Tctp) and its interacting partner 14-3-3 in Foxo regulation during organ development. Foxo overexpression in the developing eye disc results in growth inhibition. We show that Tctp overexpression antagonizes the Foxo effect by downregulating the Foxo level in the eye disc. Foxo overexpression or knockdown of Tctp in the larval salivary gland results in reduced gland size, mainly due to reduced cell size by defects in endoreplication. Whereas 14-3-3ζ knockdown has a negligible effect, knockdown of 14-3-3ε mimics the effect of Foxo overexpression or Tctp knockdown, suggesting an isoform-specific role of 14-3-3. Unlike nuclear enrichment of the endogenous Foxo in the salivary gland, overexpressed Foxo protein is largely distributed in the cytoplasm, and this mislocalization is restored by Tctp overexpression. Opposite to the effect of Tctp overexpression, Tctp knockdown increases cytoplasmic Foxo levels while decreasing nuclear Foxo levels. Together, our data suggest that Tctp and 14-3-3ε play critical roles in cell growth by reducing cytoplasmic Foxo levels. Knockdown of human TCTP also elevates the level of cytoplasmic FOXO1 in HeLa cells, suggesting that human TCTP may have a conserved role in downregulating FOXO in human cells.