FOXO transcription factors are required for DNA damage‐induced growth arrest checkpoints in hematopoietic cells

Abstract

Proliferation of hematopoietic cells is governed by cytokine‐regulated signaling pathways. We have previously shown that a cytokine‐induced PI3K/AKT signaling pathway promotes CDK2 activation and overrides DNA damage‐induced growth arrest in hematopoietic cells. In the present work, we have assessed the role of FOXO transcription factors as a potential intermediate in this signaling pathway. In this regard, overexpression of FOXO3a activity was found to reduce proliferation and CDK2 activity in cytokine‐dependent hematopoietic cell lines. Moreover, enhanced FOXO activity potentiated the growth arrests that were induced by DNA damage and PI3K/AKT inhibition. By contrast, shRNA‐knockdown of endogenous FOXO proteins attenuated the DNA damage‐induced growth arrest in cells lacking PI3K/AKT activity. We also show that the ability of FOXO3a to inhibit cytokine‐induced proliferation was dependent on expression of the CDK‐inhibitor, p27. Together, these observations suggest that FOXO‐mediated expression of p27 contributes to DNA damage‐induced growth arrest, and that inhibition of this activity by cytokine‐induced AKT can promote proliferation and override DNA damage checkpoints in hematopoietic cells. NIH Grant R01 CA79889