Oncogenic Wip1 Phosphatase Is Inhibited by miR-16 in the DNA Damage Signaling Pathway

Abstract

Wild-type p53-induced phosphatase 1 (Wip1) was identified as an oncogene amplified and overexpressed in several human cancers. Recent evidence suggested that Wip1 is a critical inhibitor in the ATM/ATR-p53 DNA damage signaling pathway. Wip1 dephosphorylates several key DNA damage-responsive proteins and reverses DNA damage-induced cell cycle checkpoints. Previous reports showed that Wip1 was transcriptionally induced by p53 at the early stage of the DNA damage response. To investigate the temporal and functional regulation of Wip1, we identified a microRNA, miR-16, that specifically targets the mRNA of Wip1 and thus negatively regulates the expression level of Wip1. miR-16 itself is induced immediately after DNA damage. Therefore, the increase in Wip1 protein level is significantly postponed compared with that of its mRNA level, preventing a premature inactivation of ATM/ATR signaling and allowing a functional completion of the early DNA damage response. To better understand miR-16 biological functions in the context of cancer cells, we examined its expression in mammary tumor stem cells and found it to be markedly downregulated in mammary tumor stem cells. Overexpression of miR-16 or inhibition of Wip1 suppresses the self-renewal and growth of mouse mammary tumor stem cells and sensitizes MCF-7 human breast cancer cells to the chemotherapeutic drug doxorubicin. Together, our results suggest an important role of miR-16 in the regulation of Wip1 phosphatase in the DNA damage response and mammary tumorigenesis.

Downregulation of Wip1 phosphatase modulates the cellular threshold of DNA damage signaling in mitosis

“…23 Early after DNA damage, translation of Wip1 mRNA is blocked by miR-16 preventing premature termination of the DDR. 24 Later during the DDR, when the bulk of the lesions had been repaired, increased abundance of Wip1 allows termination of the DDR and by a negative feedback loop inactivates p53. However, a basal Wip1 activity needs to be present throughout the G 2 checkpoint to limit the p53-dependent transcriptional repression of cyclin B and to maintain the recovery competence.…”

Wip1 gene silencing enhances the chemosensitivity of human colon cancer cells

“…High expression of Wip1 could inhibit Daxx phosphorylation induced by DNA damage and prevent cell apoptosis from occurring, thus increasing the resistance of cells to stimulation (26). Wip1 gene silencing may inhibit the self-proliferation of cancer stem cells and therefore participate in the regulation of the chemosensitivity of cancer cells (27).…”

MicroRNAs, a subpopulation of regulators, are involved in breast cancer progression through regulating breast cancer stem cells (Review)

“…In addition, TGF-β expression synergizes with RAC-α serine/threonine-protein kinase-knockdown in promoting mammosphere formation through a decrease in the abundance of miR-200 (28). miR-16 inhibits the mammosphere-forming ability of mammary tumor cells by regulating wild-type p53-induced phosphatase 1 (WIP1) induction in the DNA damage response through targeting the 3'UTR of WIP1 (29). Pleckstrin homology-like domain, family A, member1 (PHLDA1) in mammospheres, inhibited by miR-181a/b, leads to attenuated mammosphere formation in estrogen receptor (ER) + BC.…”