Oncogenic Wip1 phosphatase is inhibited by miR-16 in the DNA damage signaling pathway.
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.
Zhang
Xinna
X
Department of Biological Sciences and Center for Colon Cancer Research, University of South Carolina, Columbia, SC 29208, USA.
Wan
Guohui
G
Mlotshwa
Sizolwenkosi
S
Vance
Vicki
V
Berger
Franklin G
FG
Chen
Hexin
H
Lu
Xiongbin
X
D020413:3' Untranslated Regions; D000818:Animals; D001859:Bone Neoplasms / Q000201:enzymology / Q000235:genetics*; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D048708:Cell Growth Processes / Q000235:genetics; D045744:Cell Line, Tumor; D004249:DNA Damage; D015536:Down-Regulation; D004790:Enzyme Induction; D005784:Gene Amplification; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000008:administration & dosage / Q000235:genetics*; D014411:Neoplastic Stem Cells / Q000502:physiology; D012516:Osteosarcoma / Q000201:enzymology / Q000235:genetics*; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D000071636:Protein Phosphatase 2C; D015398:Signal Transduction / Q000235:genetics; D014162:Transfection
D020413:3' Untranslated Regions; C505362:MIRN16 microRNA, human; D035683:MicroRNAs; C000607458:PPM1D protein, human; D010749:Phosphoprotein Phosphatases; C000607468:Ppm1d protein, mouse; D000071636:Protein Phosphatase 2C